Welcome to the Open Learning Initiative Introduction to Anatomy and Physiology course!

We are happy that you have decided to introduce yourself to this important field, and we hope that your learning experience will be an enriching and enjoyable one.

The purpose of this introductory section is to prepare you conceptually and technically for this course. We will start with a short orientation to the course, including some learning strategies that will explain a little about how the course works and give you some pointers on how to use the material most efficiently.

We will then discuss what Anatomy and Physiology is all about—the "Big Picture" of Anatomy and Physiology—and look at how the major themes discussed in the Big Picture tie in to the material presented in the course.

## Orientation to Anatomy and Physiology

The Introduction to Anatomy and Physiology is a preparatory course that will introduce you to basic terms and concepts and provide a foundation for your future study in this discipline.

This course is primarily intended for community college students who need Anatomy and Physiology knowledge for their selected discipline, and for students who are planning on entering an allied health program (such as nursing) that requires prerequisites in Anatomy and Physiology.

Prerequisite knowledge needed to succeed in this course:

• Understanding of the Scientific Method.
• Introductory, college-level Biology and Chemistry.
• Basic math and language skills.
• Study skills.

The course is designed to be offered in a hybrid format to allow you the full affordances of the online learning environment and the expertise and support of your instructor.

Your instructor is your first line of support. He or she will be available to you, in the same way as in your traditional courses. Ask questions in class, or submit questions and comments through the system. You can e-mail your professor directly, or provide feedback within the My Response activities provided throughout the course material.

If you have technical difficulty, you can press the Help button at the top of any page's browser window. This will open a web form where you can type your questions or comments and send it to the OLI help desk. Asking for help this way will send several pieces of contextual information with the message (such as the course page, your browser, your computer platform) that will help our technical team diagnose your issue quickly.

If you do submit a question or report an error, please provide as much detail as possible about the error.

## Overall Course Structure

OLI Anatomy and Physiology is not your typical course. Our goal is for you to work through the course materials online in the way that is most efficient given your prior knowledge.

While you may have more flexibility than you do in a traditional course, you will also have more responsibility for your own learning. You will need to:

• Plan how to work through each unit.
• Determine how to use the various features of the course to help you learn.
• Decide when you need to seek additional support.

Each unit in this course has features designed to support you as an independent learner and consists of the following:

Learning Objectives: Found at the top of each page, these will help prepare you for what you are about to learn and help check your understanding of the material on each page.

Explanatory Content: This is the informational introduction of the basic structures learned in each chapter. It consists of short passages of text with information, examples, images, and explanations.

Activities: Activities such as 'Learn By Doing', 'Walkthroughs' and 'Did I Get This?' These are the most important aspects of the course. Different types of activities are interspersed throughout the course that will help you build or test your mastery of the learning objectives.

End of Unit Quizzes: Taking these quizzes at the end of every unit will assess your mastery of the learning objectives identified for that unit.

Vocabulary/Terms: There are many important vocabulary terms throughout the course. Where appropropriate, audio pronunciation is provided for the terms, as well as definitions in context that will pop up if you hover over the word.

## What is a Big Picture?

One goal of all OLI courses is to promote coherence by teaching students how the discrete skills they are learning fit together in a meaningful big picture of the domain. The Big Picture gives students an organizational structure through which they learn the material.

The Big Picture explains why the material in a course is being covered, as well as how the material is related or organized. The Big Picture illustrates why one might want to invest time in learning this material, and what it can do, in a way that students entering the course will easily understand.

## Why Study Anatomy and Physiology?

You probably have a general understanding of how your body works, but to truly understand the intricate functions of the human body and dispel many misconceptions that you have learned about your body over the years, you must approach the study of the body in an organized way.

This course will help you understand those intricacies and attack misconceptions head-on. This course will expose you to the complex levels of organization taking place inside the body and provide you with the information you need to delve deeply into the specific aspects of the body systems. This will prepare you for the more complex topics you will encounter in your future courses.

There is some agreement among professionals about how to do this, and what information must be common across all Anatomy and Physiology courses. This is presented as the Big Picture in Anatomy and Physiology.

## Big Picture Ideas in Anatomy and Physiology

Big Picture, Big Ideas, core principles, are all ways to describe the necessary concepts that make up a discipline. For Anatomy and Physiology, many research studies have been conducted by various groups to determine what are the Big Ideas in this discipline. In 2007, Joel Michael and his colleagues compiled a list of Big Ideas in Anatomy and Physiology and then went on to test these ideas with several comprehensive surveys of professionals and educators in the field.

They determined that the “Big Ideas in Physiology” are:

1. Living organisms are causal mechanisms whose functions are to be understood by applications of the laws of physics and chemistry.
2. The cell is the basic unit of life.
3. Life requires information flow within and between cells and between the environment and the organism.
4. Living organisms must obtain matter and energy from the external world. This matter and energy must be transformed and transferred in varied ways to build the organism and to perform work.
5. Homeostasis (and “stability” in a more general sense) maintains the internal environment in a more or less constant state compatible with life.
6. Understanding the behavior of the organism requires understanding the relationship between structure and function (at each and every level of organization).
7. Living organisms carry out functions at many different levels of organization simultaneously.
8. All life exists within an ecosystem made up of the physiochemical and biological worlds.
9. Evolution provides a scientific explanation for the history of life on Earth and the mechanisms by which changes to life have occurred.

This course has taken these Big Ideas and used them to structure the material of the course. We will explain this further on the next page.

Our intention is for you to begin to think and speak in the language of the domain while integrating the knowledge you gain about anatomy to support explanations of physiological phenomenon. The course focuses on a few themes derived from the Big Ideas, that when taken together, provide a full view of what the human body is capable of and the exciting processes going on inside of it. The themes are:

• Structure and function of the body, and the connection between the two.
• Homeostasis, the body’s natural tendency to maintain a stable internal environment.
• Levels of Organization, the major levels of organization in the human organism from the chemical and cellular levels to the tissues, organs and organ systems.
• Integration of Systems, concerning which systems are subsets of larger systems, and how they function together in harmony and conflict.

You can see how these themes directly relate to the Big Ideas. As these themes are used to describe the inner workings of each of the body’s organ systems, those can be categorized into the specific vital functions for human life. The vital functions provide the context for the whole body, and how each organ system plays a role in keeping us alive. So, the information provided for each of the organ systems is organized according to those functions that are essential to the survival of the human body. The vital functions for human life are:

• Exchange of substances and information with the environment
• Transport within the body
• Structure, support, and movement
• Control and regulation
• Growth and reproduction

All multicellular organisms need these vital functions to operate properly in order to survive. In addition to understanding the Themes and Vital Functions, knowing body planes and directional terms will also help you in your quest for Anatomy and Physiology mastery.

## Body Planes and Directional Terms

Those in the health professions must speak the same language with regard to locating and identifying specific body parts and organs. Body planes and directional terms are part of this common language. The imaginary vertical and horizontal planes run through the body, essentially cutting it into parts. You will be introduced to this new “language” and given opportunities to practice using it in context so that you become comfortable locating and describing all organs and parts in the body and in relation to each other. Everything that you learn after body planes and directional terms will be referring to this terminology to help you visualize, identify, and locate anatomical structures.

## Body Systems

You will be first introduced to all of the body systems in this introductory unit. In the units that follow, with the exception of Levels of Organization, and Homeostasis, you will learn and explore each body system in-depth. The order in which you learn each system will be determined by your instructor, but the aspects of each system will be similarly described according to the Big Picture themes.

Everyone has a body and, by adulthood, a general understanding of how it works. But to truly understand the intricate functions of the human body—and the problems that occur when something goes wrong—you must approach the study of the body in an organized way. This course will help you understand the functions of the human body. The course will discuss the details of many complex functional systems, but will also look at how all of these systems work in harmony to keep you healthy. As you move through this course, you should keep four main themes in mind: structure and function, homeostasis, levels of organization, and integration of systems.

## Structure and Function

The first theme is the connection between structure and function. You will be studying both anatomy , which focuses on the body’s structures, and physiology , which focuses on the body’s functions. In fact, it is virtually impossible to study one without the other, because function relies so completely upon structure. For example, the structure of the bones in the skeletal system provides the support necessary for the function of walking upright. The vocal cords would not be able to fulfill their function—the production of sound—if their structure were disrupted. The large surface area of the small intestine allows it to efficiently perform its primary function: absorbing nutrients from food. And the list goes on.

## Homeostasis

The second theme will be homeostasis , or the body’s natural tendency to maintain a relatively stable internal environment. Most of the body’s functions are driven by homeostasis. Homeostasis occurs at all different levels. For example, body temperature is regulated around 98.6, a temperature that is optimal for cell function and organism function. To maintain this temperature, we sweat to cool down on a hot day and we shiver to increase temperature when we are cold. Other variables, like blood pressure, blood pH, blood calcium concentrations are similarly maintained within a narrow range that is optimal for human health. Many diseases occur because of disruptions in homeostasis.

learn by doing

## Levels of Organization

The third theme will be the hierarchical organization of the parts of the body. You can think of the body's parts as being organized into a hierarchy of levels. Your body, like all things in the physical world, is built from chemical building blocks. The smallest of these building blocks are atoms of elements, which combine to form bigger and more complicated structures called molecules. These molecules, such as water, proteins, carbohydrates (glucose), and lipids are used to build cells, the smallest unit of structure capable of carrying out all life processes. Groups of related cells that work together to perform specific functions make up tissuesA tissue is a group of cells with similar shape and function. , and tissues that work together form organs. Organs do not work independently; they are organized into organ systems that complete more complex tasks.

The digestive system, for example, includes the mouth, stomach, intestines, and many other organs—all of which are integral to proper functioning of the system as a whole. The organ systems work together to support life in the entire organism—in this case, a human being.

Understanding this hierarchy is important because disruptions might occur at any level. For example, a depletion of calcium atoms from the body can lead to weak bones. Or a single mutation in a DNA molecule can lead to organ dysfunction, such as the disturbed lung function found in individuals with cystic fibrosis.

## Integration of Systems

Finally, each section of the course will discuss the integration of all the body’s systems. In order to carry out its functions, every organ system relies on the healthy functioning of other systems. When these systems all work together, the organism thrives. A breakdown in one system can cause failures in other systems as well.

In this section, you will be introduced to the major organ systems of the body. To put these systems in context, we will first discuss vital functions of life.

Within any organism, there are a multitude of functions taking place at any given time. Humans, for example, can breathe, talk, digest food, process visual images, and move their bodies all at the same time. While all of these activities are important, some are essential to the survival of the human body itself. They are vital functionsOur body's anatomy and physiology works together to perform the vital functions that keep us alive - processes or actions of the body on which life is directly dependent. You will examine four main vital functions in this course: exchange with the environment; transport within the body; structure, support, and movement; and control and regulation.

For human life, there are several vital functions.

learn by doing

So you now know that all multicellular organisms need to do the following in order to survive:

• Exchange with the environment
• Transport fluids and material throughout the body
• Provide structure, support, protection and movement
• Regulate and control processes

So what does this mean? What does this involve? How does the human body do these things? Try answering the questions below to begin broadly thinking about bodily function within these categories and how they are linked to one of the primary organ systems.

learn by doing

## Exchange with the Environment

An organism constantly interacts with its environment. In order to survive, the human body must obtain food, water, and oxygen from the world around it. The human body must also rid itself of wastes before they build up to toxic levels. Three organ systems are primarily responsible for exchange with the environment. The digestive system brings food and water into the body and eliminates solid wastes. The respiratory system brings in oxygen and removes carbon dioxide.

## Fluids and Transport within the Body

Single-celled organisms can absorb nutrients and oxygen directly from the environment into the cells, where they are used to support basic cell functions. Waste products are excreted from these single cells in a similar fashion. In multi-celled organisms like humans, however, most cells are not exposed directly to the outside environment. Instead, body cells rely on organ systems to transport molecules throughout the body. Three main body systems, the cardiovascular system, the lymphatic system, and the urinary system, take care of this vital bodily function. The urinary system filters out and eliminates the waste products of metabolism. The cardiovascular and lymphatic systems also participate in the function of immunity, to help defend the body's cells from foreign organisms that may enter the body tissues or fluids.

## Structure, Support, Protection, and Movement

For the organs of the human body to function, they must be protected from potentially damaging substances in the environment. One level of defense is provided by the integumentary system, made up of the skin, hair, and nails. This system prevents many potentially harmful irritants from entering the body. Eyelashes, for example, help keep sand or other items out of the eyes, where they could potentially cause serious damage, and the skin prevents most pathogens (disease-causing microorganisms) from entering the body and destroying healthy body cells. Certain parts of the skeletal system, such as the skull and ribcage, also help to protect the internal organs, such as the brain, heart and lungs, from damage. The skeletal system and the muscular system also support the body and allow it to move away from danger, toward food sources, etc.

## Control and Regulation

To keep itself in a state of equilibrium, an organism must constantly gather information and react accordingly. In humans, the nervous system, made up of the brain, nerves, spinal cord and sensory organs, reacts to stimuli in the environment and signals other systems when actions are needed to bring the body back into balance. The endocrine system, which produces hormones and other regulatory substances, plays a key role in maintaining balance among chemical messengers within the body.

Several organ systems control these various vital functions throughout the body. Since the organ systems control large regions of the human body, it is necessary to define orientation within the body and communicate the proper terminology as you study these integrated structures and functions.

did I get this

To better identify the locations of the organs that contribute to vital functions, you need some points of reference for description. To serve that function, we will now define different planes of the body. These imaginary flat surfaces run through the body in different directions. They are used by medical professionals to examine various internal body parts. Directional orientation is another anatomical tool used to describe how parts of the body are related to one another.

Each organ system spans large regions of the human body. It is helpful, therefore, to establish reference planes and directions that can help us describe specific locations of structures as we discuss them. To make sure everyone is talking about the same thing, anatomists and physiologists often refer to anatomical position and the body planes that penetrate it. Anatomical position describes a person standing upright, with the arms at the sides and the palms facing forward (as demonstrated in the image below). Body planes (a plane is a flat, two-dimensional surface) are imaginary surfaces that run through the body and divide it into different sections. We can talk about a specific location using the planes as reference points within the anatomical position.

There are an infinite number of planes running through the human body in all directions. However, we will focus on the three planes that are traditionally used when discussing human anatomy. First is the transverse plane , (also called the horizontal plane), which divides the body into top and bottom. In anatomical position, transverse planes are parallel to the ground. The second is the coronal plane , which is a vertical plane that divides the body into the front and back sections. If you do a “belly flop” into the water, you sink into the water via the coronal planes. Finally, we will refer to the sagittal plane , which divides the body into left and right sections with a vertical plane that passes from the front to the rear.

Walkthrough

This example shows planes passing through midpoint of body, producing two equal sections. The plane, however, can be positioned at any point along the body's horizontal or vertical axis, while maintaining the same direction of the plane; this would produce unequal sections.

Example
##### Body Planes in Medicine

Many imaging modalities used in medicine (CT scans, MRI scans and ultrasounds) image the body in cross sections. The three main planes described above are used to orient and describe where the cross section is and how it passes through the body so that the viewer knows what they are viewing. For example, the image below from a CT (or CAT) scan shows a cross section of the body that runs along the sagittal plane .

These images can sometimes be reconstructed in a computer to show the same body in a different plane, making some features of the body easier to see. Below is a coronal reconstruction of a CT:

learn by doing
did I get this

You can use other terms to further pinpoint an anatomical location. These terms are used to describe a location in relation to other structures. Some of them may be terms you have heard in everyday conversation; a lateral pass in football, for example, is a pass toward the sideline.

## Superior, Inferior, Anterior and Posterior

The first set of directions that we will explore are superior , inferior , anterior , and posterior .

Walkthrough

In humans, which stand upright on two feet, there are other terms that are synonymous with these four terms. Cephalic means toward the head and is the same as superior for a human in anatomical position. Caudal means toward the tail, or same as inferior for a human in anatomical position. Dorsal means toward the back and ventral means toward the belly; so dorsal and posterior are the same direction and ventral and anterior are the same direction for a human in anatomical position. This would not be true for a four-legged animal, such as a rat or cat you might dissect in lab.

did I get this

## Medial, Lateral, Intermediate

Next, we will discuss terms that relate structures to the midline. These are medial , lateral and intermediate .

Walkthrough
did I get this

## Proximal, Distal, Superficial, Deep

These next terms are used when referring to either appendicular parts of the body (arms and legs) or position in body relative to the external surface. These are Proximal , Distal , Superficial , Deep

Walkthrough
did I get this

The following table lists all of the human anatomical directions that we discussed. You will practice using these planes and directional terms when describing the locations of organs and organ systems in the following sections.

Directional Term Meaning
superior (cephalic) above (or toward the head)
inferior (caudal) below (or toward the feet or tail)
intermediate between
distal farther from the trunk
proximal closer to the trunk
superficial toward or on the surface
deep (internal) away from the surface
anterior (ventral) toward the front (or toward the belly)
posterior (dorsal) toward the rear (or toward the back)
medial toward the midline
lateral toward the side
did I get this

## Directional Terms in Medicine

Now that you have reviewed ways to describe location and orientation, you will learn about the organ systems that are necessary for the vital functions of life. You will also get a chance to practice using body planes and directional orientations to explain the anatomical integration and relative location of structures within organ systems. The next section will systematically describe the organ systems of the body, as well as the major anatomical structures and functions.

Organ System
(Definition)
An organ system is an integrated collection of organs in the body that work together to perform a vital function. This course will organize the organ systems of the body based on the vital functions defined earlier.

The major organ systems of the body are shown in the table below.

Major Organ Systems of the Body Grouped by Primary Function
Function Organ System
Exchange with the Environment Digestive System
Respiratory System
Urinary System
Fluids and Transport within the Body Cardiovascular System
Lymphatic System and Immunity
Structure, Support, Protection and Movement Integumentary System
Skeletal System
Muscular System
Control and Regulation Nervous System
Endocrine System
Example
##### Skeletal System

As an example of how the components of an organ system work together, let’s look at the skeletal system. The most obvious components of this system are the bones, which form a rigid framework for the body. The bones contribute to our ability to stand upright and move around, but they can’t do it alone. Ligaments and cartilage are also parts of the skeletal system. Ligaments connect the bones to each other. Cartilage cushions the spaces between the bones, allowing for smooth movement. And the bones couldn’t move at all without the skeletal muscles, and tendons that connect muscles to bones (parts of the muscular system). The bones provide the muscles with something to pull against.

If one component of an organ system is damaged or malfunctions, the function of the organ system will be affected. Think about a broken bone. If the femur breaks, it will be much harder to maintain an upright posture, or to walk or run. These might also be more difficult if the cartilage of the femur is destroyed by arthritis or a ligament in the knee is injured while playing a sport. If any component of the skeletal system is damaged—bone, ligament or cartilage—the knee will not function properly.

The sections that follow will describe the details of the organ systems that perform the vital functions of life. You will learn how they contribute to homeostasis and how imbalances in homeostasis lead to various disease states.

## Digestive System - Function

Also called the gastrointestinal system, the digestive system breaks down eaten material into nutrient molecules, absorbs water and ions, and eliminates undigested residue.

The digestive system is a continuous tube (the digestive tract or alimentary canal). Areas along this tube are specialized to perform different functions related to getting the nutrients from your food to the cells that need them. Accessory organs add secretions into different areas along the tube.

Your cells can’t use the pizza you had for lunch in pizza form. It needs to be broken down into molecules that are small enough to be absorbed. As the pizza travels along the digestive tract, each organ along the way breaks it down further. Muscles in the walls of the digestive tract keep things moving along, and glands in the tissues secrete digestive juices—mostly enzymes and acids—that break up the larger substances in the pizza into smaller molecules. Food is physically broken into smaller pieces in a process termed mechanical digestion. These pieces are then chemically broken down into smaller units in a process termed chemical digestion. Proteins are broken down into amino acids. Carbohydrates are broken down into simple sugars. Fats are broken down into molecules like fatty acids and cholesterol. It is important that the large particles are broken into their smallest units so they can be absorbed from the digestive tract into the bloodstream. Therefore, the main functions of the digestive system are to ingest, break down, and absorb the nutrients from our food. It also eliminates the wastes (anything not absorbed) as feces.

learn by doing

## Digestive System - Organs

The specialized organs of the digestive tract extend in a roughly superior to inferior direction from the mouth (where food goes in) to the anus (where waste comes out) in the following order:

• Mouth
• Pharynx
• Esophagus
• Stomach
• Small intestine (including the duodenum, jejunum, and ileum)
• Large Intestine (including the cecum, colon, and rectum )
• Anus

Accessory organs in the digestive system are connected to the digestive tract and secrete additional digestive juices.

The salivary glands produce saliva containing (among others) amylase, an enzyme that breaks down carbohydrates.

The pancreas secretes a variety of enzymes that break down fats, carbohydrates, and proteins, as well as bicarbonate ions that neutralize stomach acids. It is important to note that this function corresponds to the exocrine portion of the pancreas.

The liver produces bile, which aids in fat digestion and absorption.

The gall bladder stores and concentrates bile and secretes it into the small intestine.

The stomach is a sort of muscular sac that can expand to hold a large meal. Glands in the walls of the stomach secrete enzymes and acids that break down food. Muscles in the walls of the stomach churn the food and digestive juices together. Although the stomach can receive a large amount of food at a time, it releases its contents gradually into the small intestine, so that the intestine can better perform its function.

Digestion continues in the small intestine, with additional digestive juices produced by the pancreas, liver, and the walls of the small intestine itself. The walls of the small intestine have numerous tiny folds, which increase its surface area, allowing for efficient absorption of nutrients into the circulatory system, which in turn takes the nutrients to all the cells of the body.

Excess water is reabsorbed in the large intestine, and the undigested portion of your pizza leaves the body. Resident microbes of the large intestine (gut microbiota) can digest substances that our cells cannot.

Walkthrough
learn by doing
did I get this

## Digestive System - Anatomy and Direction

The digestive system is located primarily in the abdomen.

learn by doing

## Respiratory System - Function

When humans breathe, air enters and exits via the respiratory system. This allows the body to obtain oxygen, which is needed for metabolic processes, and eliminate carbon dioxide, which is a metabolic waste product and can affect the body's pH homeostasis.

Like the digestive system, the respiratory system can be thought of as a tube, or rather, as a branching series of tubes that get smaller and smaller as they branch off. Unlike the digestive system, which moves solids and liquids in a single direction, the respiratory system moves gases in both directions, when we inhale and exhale.

When we inhale, air passes through the nose or mouth into the pharynx, larynx , trachea , lungs, and into smaller and smaller airways termed bronchi and then bronchioles, until it reaches the air sacs, or alveoli . Only a single cell thick, the walls of the alveoli allow the oxygen in air to diffuse into the blood, and the cardiovascular system carries it to each cell in the body.

Carbon dioxide, a waste product of cell metabolism, also diffuses through the alveolar walls, but in the opposite direction, from the blood to the airways. Carbon dioxide is then exhaled through the airways to the external environment.

learn by doing

## Respiratory System - Organs

The organs of the respiratory system are arranged in a roughly superior to inferior direction and include:

• Nose
• Mouth
• Pharynx
• Larynx
• Trachea
• Lungs

Within the lungs, the respiratory system can be further divided into:

Note that the pharynx (the part of the throat just behind the mouth) is listed as a part of both the digestive and respiratory systems.

• Food and beverages pass through the pharynx on the way through the digestive tract.
• Air passes through the pharynx on its way to and from the lungs.

Food and water are prevented from entering the airway when we swallow by a structure called the epiglottis. It is not uncommon for organs to be part of more than one organ system. The pancreas, for example, has both digestive and endocrine functions, and the kidneys play a role in both the urinary and endocrine systems.

Walkthrough
learn by doing
did I get this

## Respiratory System - Anatomy and Direction

The respiratory system is superior to the abdomen and internal to the ribs.

learn by doing

## Cardiovascular System - Function

The cardiovascular system transports, from one part of the body to another: nutrients, oxygen, ions, proteins, hormones and other signaling molecules, as well as waste products, including carbon dioxide. This system also helps to maintain homeostasis of fluid volume, pH, and temperature.

## Cardiovascular System - Organs

The primary components of the cardiovascular system are blood, the heart, and the vessels of the circulatory system, which work together to transport nutrients, wastes, and gases to every cell in the body.

The blood that is circulated throughout the body contains two main components:

• Plasma contains water, electrolytes, glucose, proteins (including enzymes, hormones, and blood clotting factors) and metabolic wastes
• Formed elements or blood cells

There are three types of formed elements:

• Red blood cells transport oxygen and carbon dioxide.
• White blood cells fight infection by attacking foreign cells, and clear old or diseased cells.
• Platelets are important for hemostasis (not to be confused with homeostasis); hemostasis is our ability to stop bleeding after vascular injury (injury to blood vessels).

The blood functions to transport molecules and blood cells and contributes to the maintenance of pH balance. Blood cells are formed in the red bone marrow.

The heart is divided into four chambers. The two lower chambers, called ventricles, force blood out into the arteries. The two upper chambers of the heart, called atria, receive blood returning from the veins. The heart contracts as a unit, both atria (named right and left) contract together to move blood into the ventricles and then both ventricles contract at the same time to move blood out of the heart into the pulmonary artery and the aorta.

The cardiovascular system is divided into two functional subsystems.

• The systemic circuit transports blood and its components to the body.
• The pulmonary circuit transports blood and its components between the heart and the lungs.

Arteries of the systemic circuit (also known as the systemic circulatory circuit) carry oxygenated blood from your heart to provide oxygen and nutrients dissolved in the blood to every cell in your body. When blood leaves the left ventricle it first enters the aorta, the largest artery in the human body. Arteries gradually branch into smaller and more numerous arterioles which then supply blood to the smallest vessels, termed capillaries. It is estimated that your body contains approximately 60,000 miles of capillaries, that is enough to encircle earth three times! Capillaries allow the exchange of oxygen, nutrients and waste between the blood and tissue cells. After waste has been picked up, blood is moved through vessels of increasing size venules into the larger veins. Veins return oxygen-poor blood back to the heart, where the blood is passed to the pulmonary circuit to the lungs to pick up oxygen.

The pulmonary artery (part of the pulmonary circuit) carries oxygen-poor blood from the right ventricle of the heart to the lungs for oxygenation and removal of carbon dioxide. The pulmonary veins carry oxygenated blood from the lungs to the left side of the heart.

Without this system in place that involves both the pumping of the heart to squeeze blood out, and the network of vessels to distribute the pumped blood, the cells of your body would not have an adequate supply of nutrients and oxygen.

learn by doing
did I get this

## Cardiovascular System - Anatomy and Direction

The heart lies medial to the lungs, anterior to the spinal cord, posterior to the sternum, and superior to the diaphragm. The heart is divided into four chambers. The two lower chambers, called ventricles, force blood out into the arteries. The two upper chambers of the heart, called atria, receive blood returning from the veins.

learn by doing

## Lymphatic System and Immunity - Function

Our body is in constant exchange with the environment, through breathing, eating and other activities. Therefore, it is important to screen the body and its components regularly to identify foreign invaders that might enter during these activities (or in any other manner). Further, it is important to rapidly and effectively remove these invaders before they can cause significant harm. Our body has specialized transport systems to carry out these functions. The cardiovascular and lymphatic systems work together to transport excess fluids (blood and lymph fluid, respectively) away from body tissues. Once fluid enters the lymphatic system it is termed lymph. Lymph travels through lymph vessels and passes through many lymph nodes which filter and clean the lymph. The immune system also produces and matures immune cells, which protect the body from invasion by agents that cause disease. One additional function of the lymphatic system is to transport absorbed fat from the digestive system to the body cells.

The immune system coordinates the activities required to respond to disease and infection. This response can provide two types of immunity:

• Specific immunity, in which specialized cells (such as T and B cells) recognize specific foreign molecules called antigens within the body and respond to them.
• Nonspecific immunity, in which the body uses several general methods such as physical barriers (that is, the skin and mucous membranes), fever, inflammation, specific action by immune cells, and enzyme activity to protect itself against general harmful agents.

## Lymphatic System and Immunity - Organs

The major organs of the lymphatic and immune systems (described below) can be classified based on their role in lymphocyte (a type of white blood cell) maturation. Maturation of lymphocytes takes place within the red bone marrow and the thymus gland, which are primary lymphoid organs. Antigens become trapped within secondary lymphoid organs such as the lymph nodes, spleen, and tonsils. These organs are sites that contain lymphocytes for destruction of invading pathogens.

Organ Description
Tonsils and Adenoids Adenoids are one of three sets of tonsils. They trap pathogens that enter through the mouth and nose. Also, the tonsils monitor the external environment that the mouth and nose are exposed to, and can react with an appropriate immune response for certain pathogens.
Thymus A lobular (of or pertaining to a lobe) structure, which contains many immature, inactive lymphocytes. As the lymphocytes mature, they leave the thymus to attack infected cells in lymphatic tissues throughout the body.
Spleen The largest of the lymphatic organs, it houses lymphocytes for potential immune response. Also, the resident phagocytes within the spleen perform the most basic function of removing cell debris from the blood.
Lymph Nodes These house lymphocytes and macrophages, which destroy foreign material contained in the lymph fluid.
Lymph Vessels These transport lymph fluid throughout the lymphatic system.
Red Bone Marrow All of our blood cells are generated from red bone marrow stem cells. These stem cells differentiate into red blood cells, platelets, and several cells that play roles in immunity. These “immune cells” include lymphocytes, which carry out specific immunity, and neutrophils and macrophages (macrophages start as monocytes and mature into macrophages in the tissues), which are nonspecific phagocytic cells.

While many people know that we are protected from foreign micro-organisms by an immune system, few people realize how the immune system is able to patrol the entire body. White blood cells of the immune system are produced in the red bone marrow and travel through the blood. They can leave blood capillaries to travel through tissues. White blood cells are then able to remove dead or damaged cells and "foreign" organisms they encounter and recognize specific foreign organisms again if necessary. Additionally, lymph collects from tissues and circulates through lymph vessels, making "rest stops" in discrete points throughout the body called lymph nodes or lymph organs. In these nodes and organs, including the spleen, tonsils and other tissue clusters, there are large collections of white blood immune cells. Lymph slowly travels through these organs ensuring that the lymphocytes have plenty of time to react to these foreign organisms in the lymph before returning it to the blood.

learn by doing
learn by doing

## Lymphatic System and Immunity - Anatomy and Direction

The lymph nodes are located in several regions along the path of lymphatic vessels in our body. The thymus is located within the upper chest, lies posterior to the upper portion of the sternum, and extends from the root of the neck onto the pericardium. The spleen is found in the upper left abdominal cavity; it lies superior, posterior, and lateral to the stomach. The tonsils are masses of lymphatic tissue within the nasopharyngeal (nose and mouth) region.

learn by doing

## Urinary System - Function

The urinary system filters blood and adjusts the composition of blood/interstitial fluid by removing excess water, salt, acid, and metabolic waste from the body as urine. This allows the urinary system to control body fluid volume, blood pressure, pH, and electrolyte balance. It is a critical system for maintaining homeostasis.

We have seen how the digestive and respiratory systems remove some wastes from the body—undigested food leaves the digestive tract through the anus and carbon dioxide leaves through the lungs and airways. The urinary system (or excretory system) filters blood to remove excess water, electrolytes and other metabolic wastes and reabsorbs water, electrolytes and other molecules as needed to maintain homeostasis in the body fluid. The resulting excess and wastes are excreted as urine. In this way, the urinary system also works with the respiratory system to maintain pH balance in the body.

## Urinary System - Organs

The organs of the urinary system include:

• Kidneys
• Ureters
• Urethra

The kidneys, the main organs of the urinary system, are located against the posterior wall of the abdomen. They serve as a filtration and reabsorption system, where soluble substances are filtered and then those that the body needs to keep are reabsorbed. Those that are not reabsorbed (or not reabsorbed fully), such as our metabolic waste products, end up in the urine. Because our bodies are constantly producing wastes, the kidneys continuously work to prevent the buildup of waste products and toxins, filtering about 180 liters of fluid a day. Because the average person has about three liters of plasma (the fluid fraction of blood), this means that our plasma is filtered about 60 times a day!

One of the most important of the waste products removed from the blood is urea, the main end product of protein metabolism. Other waste products and some toxins are also removed from the blood by the kidneys.

In addition, ions and water are also filtered by the kidneys, but a large fraction of these are reabsorbed to keep the fluid and electrolyte concentration of the blood and other body fluids within an optimal range for proper cell function. The kidneys also play an important role in the regulation of pH by managing the amount of acid in the urine.

As previously described the kidneys filter the blood to form urine. Urine leaves the kidneys and flows through the ureters to the urinary bladder, where it is stored until it passes out of the body through the urethra . On average, two liters of urine are produced per day, but this can vary greatly depending upon fluid intake, fluid loss through perspiration, and other factors.

learn by doing
did I get this

## Urinary System - Anatomy and Direction

The right and left kidneys are located against the posterior wall of the abdominal cavity. The kidneys’ location is also described as retroperitoneal because they are behind the peritoneal cavity that encloses the intestines.

learn by doing

## Integumentary System - Function

We often don't think of the skin as a complex organ, but it is. The skin is the primary organ in the integumentary system, which also includes hair, nails, and certain glands. The integumentary system helps to provide support and structure for the body, but it also plays several other important roles:

• It is the first line of defense against foreign organisms and the external environment.
• It helps to regulate body temperature.
• It senses changes in the environment (pain, pressure, touch).
• It supports the removal of wastes (as sweat).
• It aids in the production of vitamin D.

The integumentary system is one of the most active parts of our body, even though we are not as aware of its activity as we are with the heart, lungs or stomach. The integumentary system encapsulates and protects the body. The skin is actually the largest organ in the body because of its large surface area. In some ways, the skin can be thought of as an immune system organ, since it protects the body from foreign organisms. In other ways the skin can be thought of as a sensory organ because it contains many nerves that are related to the sense of touch. The skin also integrates with muscles and allows for movements such as facial expression.

## Integumentary System - Organs and Structures

If we take a closer look at the skin, you can see that there are many layers. Within the skin there are hair follicles from which hair grows. Also, there are sweat glands that produce sweat for thermal regulation of the body and sebaceous glands that secrete oil to waterproof and moisturize the skin. Nails are also included in the integumentary system, as are horns, feathers, claws and hooves...but hopefully you don't have any of those.

The major structures within the integumentary system are:

• skin
• hair, nails
• sebaceous glands
• sweat glands

Skin, the largest organ of the body, is the primary organ of the integumentary system. Skin is composed of three main layers, each of which has specific functions related to its structure. The three main layers of the skin are:

• epidermis, which acts as a seamless, waterproof barrier to the external environment and prevents excessive water loss from the body (the root "epi-" means "above").
• dermis, which provides the tensile strength and elasticity of the skin, contains nerves and sensory receptors and contains blood vessels that aid in regulating body temperature.
• hypodermis, which attaches skin to other structures below it and acts as an insulator and shock absorber (the root "hypo-" means "below"); the hypodermis is also known as the subcutaneous layer.

Hair, another component of the integumentary system, is found in nearly all regions of the skin, except on the palms, soles of the feet, and some parts of the genitals. Hair grows from hair follicles that are part of the epidermis, even though they extend down and the dermis extends up around them. Hair helps regulate body temperature and protect the surface of the body, including eyelashes that protect the eyes.

Nails are located on the end of each distal phalanx (each finger and each toe). They protect the phalanges from trauma, and provide mechanical support for manipulating objects. Nails grow from epidermal cells in the nail beds.

Glandular structures are also part of the epidermis, and are present in different regions of the skin. They secrete substances that are important for many physiological functions. There are three main types of glands:

• sebaceous glands, whose secretions maintain the softness and hydrophobicity (water repellency) of the hair and skin.
• apocrine glands, whose secretions moisten the skin during pain, fear, sexual arousal and emotional upset.
• merocrine (eccrine) glands, which secrete sweat to regulate body temperature.
learn by doing
learn by doing
did I get this

## Integumentary System - Anatomy and Direction

The skin covers the outside surface of the body. Special structures such as hair, nails and glands are part of the integumentary system.

learn by doing

## Skeletal System - Function

The skeletal system, which includes the skeleton and articulations (joints), provides support and protection for soft tissues and organs, aids in movement, serves as a reservoir of calcium, and produces all blood cells.

Although we often think of bones as the only organs of the skeletal system, cartilage, ligaments and tendons are equally important organs. These structures of the skeletal system work together to:

• provide leverage and resist forces from muscles and gravity.
• keep joints together.
• allow flexibility within joints.
• maintain a safe range of motion.

Bones are found throughout the body from the skull in the head to the 26 bones in the foot. Bones allow us to maintain our stature, they protect softer internal organs, and they let us move around. Bones are interconnected by articulations, another word for joints. In an articulation, where bone meets bone, there is a layer of softer cartilage. Articulations are then stabilized by ligaments, which help keep the bones aligned properly. Bones are connected to the muscular system by tendons, which allow the body to move.

did I get this

## Skeletal System - Organs

The major structures within the skeletal system are:

• bones
• cartilage
• ligaments
• tendons

The skeletal system consists of bones, ligaments, tendons, and cartilage. Bone is the primary organ of the skeletal system. Although there are different types of bones in our body, the basic components of all bone tissue are the same:

• Osteoblasts, osteoclasts, and osteocytes, which are specialized cells that are responsible for bone formation, regulation and repair.
• Collagens and other proteins, which give bone its flexibility.
• Inorganic calcium and phosphate minerals, which give bone its hardness.
• Red bone marrow, which produces all blood cells in a process termed hematopoiesis (or hemopoiesis).

These basic components give bone tissue its load-bearing, protective qualities. The living cells in bone allow it to sense and respond to stress. The inorganic matrix of bone gives the bone rigidity and also acts as a storage depot for calcium and phosphorus in the body.

Cartilage is a firm, flexible, and smooth connective tissue found at the ends of bones. Cartilage is present in joints to protect the bone and to evenly distribute forces to the underlying bone.

Ligaments are band-like elastic structures that surround joints to hold them together. Ligaments connect one bone to another bone, and allow movement in very specific directions.

Tendons are band-like structures similar to ligaments. However, tendons are more rigid and connect bones to muscles. Tendons play a role in integrating the force generation of the muscle with the rigid bone, which helps actuate large-scale motion.

The numerous organs and structures of the skeletal system allow it to serve an important role in the support and protection of our body. Bones are very strong, yet flexible which makes them perfect for supporting our weight and allowing movement. The connective tissues such as cartilage, ligaments, and tendons aid in protecting our joints and providing stability. The red bone marrow inside the bone is vital for hematopoiesis or the production of all blood cells. Bones are also a reservoir for calcium. If your diet is deficient in calcium, a hormone will mobilize calcium from the bones to the blood, and your bones will be weaker.

learn by doing
learn by doing
did I get this

## Skeletal System - Anatomy and Direction

Bones are found throughout the body. Regions capable of more intricate movements, such as the hands and feet, have more articulations and therefore more bones. Each articulation has cartilage and is stabilized by ligaments.

learn by doing

## Muscular System - Function

The muscular (musculoskeletal) system generates force for movement of bones around articulations, facial expression, breathing, posture, and assists with temperature regulation. The muscular system only contains skeletal muscle, although the body also has smooth and cardiac muscle tissue, which are important in other body systems. There are over 650 skeletal muscles in the human body!

The skeletal muscle converts signals from the nervous system into movement via muscle contractions. Muscles, like the biceps and triceps, are the organs of the skeletal muscular system. The main functions of skeletal muscles include:

• responding to neural information (conscious control)
• applying forces to the bones to cause movement
• producing heat to warm the body
• changing the size of the thoracic cavity for breathing
• applying forces for conscious control of openings to the outside of the body (sphincters)

The muscular system contains muscle tissues and interconnects with both the nervous system and skeletal system. Nerves control the muscles and allow us to consciously direct movements. Some muscles, such as the muscles that control the pupil of your eye, cannot be controlled consciously but react to nerve stimuli. The skeletal system provides a stiff support for muscles to pull on. Muscles generate force to lift as well as to balance us. The energy produced by contracting muscles (such as when shivering) in the muscle system helps keep us warm. There are many muscle fiber types throughout the body that vary based on function. Parallel muscles form along the long bones, pennate and convergent muscle fibers attach to tendons and circular muscles assist with closing our eyes or puckering our lips.

## Muscular System - Organs

The major structures within the muscular system are:

• skeletal muscles
• tendons

Skeletal muscles are voluntary muscles that attach to, and contract to move the bones. Skeletal muscles often work in pairs. When one muscle is contracting, the other is relaxing. For example, to bend your arm at the elbow, your biceps muscle contracts, and your triceps muscle relaxes. To straighten your arm, the biceps relaxes, and the triceps contracts. The diaphragm is skeletal muscle that contracts and relaxes for inhalation and exhalation. Hiccups are a spasm in your diaphragm muscle.

Skeletal muscles are made of long cylinder shaped cells called muscle fibers, which have many nuclei within each cell. Therefore we say that skeletal muscle is multi-nucleate. The functional unit within a skeletal muscle fiber, called a sarcomere (note that “sarc” means flesh), contains filaments of the proteins actin and myosin. Myosin is a thicker protein (appears darker) than actin and the two proteins create a pattern so the muscle appears striped or striated. Notice the appearance of skeletal muscle in this transmission electron microscope view.

Sarcomere - By Louisa Howard Human skeletal muscle tissue 1). Public Domain.

A muscle contraction occurs when the myosin filaments pull on the actin to shorten the sarcomere. This results in shortening of the muscle fiber and ultimately the entire muscle shortens or contracts to pull on the bone.

An electrical signal from the nervous system is necessary to cause a skeletal muscle contraction. The area where the nerve meets the muscle to stimulate it is termed neuromuscular junction. When a nerve signal reaches the neuromuscular junction, the muscle fiber is stimulated and the muscle contracts.

In the image below the #1 is termed the axon or the part of a neuron that carries the instructions from the brain and spinal cord. #2 is the end of the axon called the axon terminal or synaptic vesicle. #3 is the muscle and #4 is a group or bundle of muscle fibers.

Neuromuscular Junction - By Synapse_diag3.png: User: DakeMusculus_diagram.svg: *Skeletal_muscle.jpg: User:Deglr6328derivative work: Marek M (talk)derivative work: Marek M Neuromuscular.svg)CC-BY-SA-3.0

Tendons are grouped in both the skeletal system and the muscular system since they connect the two systems (connect muscle to bone). Tendons play a role in transmitting force from the muscles to the bones to permit movement.

learn by doing

## Other Muscle Types

Although only skeletal muscle is part of the muscular system, there are three types of muscle tissue. Smooth muscle and cardiac muscle are similar to skeletal muscle, but perform specialized functions in the body. Most of these functions are involuntary and do not include the skeletal system.

Smooth muscles control involuntary functions of the body, such as arterial contractions to move blood and peristaltic contractions in the digestive system to move food. Smooth muscles lack striations thus, are termed smooth due to their appearance. They are composed of muscle fibers with a single nucleus in each cell and are uninucleate. Smooth muscles do not have any attachment to the skeletal system. Smooth muscle has the ability to produce its own contractions involuntarily. However, as with skeletal muscle, electrical signals from the nervous system can modulate the activities of smooth muscle. The organization of smooth muscle on a cellular level is irregular and unorganized. Therefore, smooth muscle does not contain sarcomeres.

Cardiac muscle contains similarities to both skeletal and smooth muscle. Like skeletal muscle, cardiac muscle is composed of organized muscle fibers and sarcomeres, and is striated. However, cardiac muscle does not attach to the skeletal system and is under involuntary control, and is uninucleate. Cardiac muscle is not long and cylinder shaped like skeletal muscle but is more branched.

learn by doing
did I get this

## Muscular System - Anatomy and Direction

Like bones, skeletal muscles are found throughout the body. Skeletal muscles are found under the skin of the integumentary system and attached to and surrounding the bones of the skeletal system.

learn by doing

## Nervous System - Function

The basic functional units of the nervous system that transmit messages are cells called neurons. Signals travel through a neuron as electrical impulses. Neurons release chemical substances, known as neurotransmitters, to transmit information to other neurons, to muscles, or to glands. The chemical messages of the nervous system are transmitted over short distances, and their effects are short-lived. The nervous system allows for control and coordination of skeletal muscular movements that may be consciously predetermined, or may happen automatically, such as reflexes. Other parts of the nervous system control and coordinate subconscious body activities, including heart rate, gland secretions and smooth muscle movement in the digestive system. Some activities, such as breathing, can be controlled both subconsciously and consciously. The nervous system typically works quickly. It also allows us to integrate and store information, such as when you are learning.

The nervous system transmits signals to different parts of the body to coordinate function. Electrochemical signals are processed in the brain and sent down the spinal cord, which runs the length of the back. From the spinal cord, peripheral nerves send signals out to the extremities. Return signals come in through sensory nerves and either return to the spinal cord for processing or back to the brain. The spinal cord processes reflexes and repeated patterns.

learn by doing

## Nervous System - Organs and Structures

The nervous system is often divided into two functional parts:

• The central nervous system, which processes incoming information and initiates a response.
• The peripheral nervous system, which brings sensory information to, or carries motor output from, the central nervous system to initiate a reaction.

### Central Nervous System

The major structures within the central nervous system are:

• brain
• spinal cord

The brain has several lobes, each of which carries out specific functions and processes information associated with specific parts of the body. The spinal cord is located within the vertebral column and processes some reflexes but primarily transmits information to and from the brain along neurons. Specialized membranes called meninges cover the brain and the spinal cord to protect them. Additionally, a special fluid, called cerebrospinal fluid, chemically and mechanically protects the brain and spinal cord.

### Peripheral Nervous System

The major structures within the peripheral nervous system are:

• cranial nerves
• spinal nerves

The peripheral nervous system is composed of nerves outside the brain and spinal cord. Nerves are bundles of extensions from neurons that extend through the body in the peripheral nervous system. These nerves are categorized into the following functional groups:

• sensory nerves, which carry sensory input to the brain or spinal cord from the environment.
• motor nerves, which carry motor impulses from the brain or spinal cord to muscles or glands.
• mixed nerves, which have a combination of sensory and motor neurons in one nerve.

The peripheral nervous system can be subdivided into two subdivisions: the somatic and autonomic divisions. The somatic nervous system includes sensory neurons that send sensory information from sensory receptors of the skeletal muscle, skin and special senses (including smell, taste, sight, hearing and equilibrium) to the central nervous system and motor neurons that control skeletal muscle.

The autonomic nervous system monitors and regulates changes in the body's internal environment. These changes are not under voluntary control. Body processes controlled by the autonomic nervous system include the contractions of the stomach and other digestive organs, the heart rate, and contractions of blood vessels to control blood pressure and flow though the body.

The autonomic nervous system is further divided into the sympathetic and parasympathetic divisions. The sympathetic nervous system controls functions that speed up the heart and increase energy usage during emergencies or times of stress. On the other hand, the parasympathetic nervous system controls functions that have the opposite effect—they reduce heart rate and decrease overall energy usage when the body is returning to normal after an emergency or during normal functioning.

learn by doing
did I get this

## Nervous System - Anatomy and Direction

The brain is protected inside the skull. The spinal cord runs from the brain down through the bones of the spinal column. From the brain and spinal cord, nerves run throughout the body, including to the limbs.

learn by doing

## Endocrine System - Function

The endocrine system is an equally important method of sending messages within the body for control and coordination of multiple body systems. The functional unit of the endocrine system is a gland, or a group of cells that secrete chemicals called hormones. Hormones circulate throughout the body within the bloodstream and act as long-term messengers. In comparison with neurotransmitters, hormones act over long distances for a longer time.

## Endocrine System - Organs and Structures

The major organs of the endocrine system are:

1. hypothalamus
2. pituitary gland
3. pineal gland
4. thyroid and parathyroid glands
5. thymus (note that this gland is also part of the lymphatic system)
7. pancreas (note that this gland is also part of the digestive system)
8. gonads (that is, ovaries or testes—note that these glands are also part of the reproductive system)

As a specialized part of the brain, the hypothalamus is an endocrine gland that produces hormones that regulate many basic functions such as hunger, thirst and sleep through control of the pituitary gland. The hypothalamus receives sensory input from receptors and perceptual information from the brain, such as changes in emotional state, temperature, and lighting.

The pituitary gland is sometimes called the master gland, because it controls the release of hormones from many other endocrine glands.

The pineal gland secretes the hormone melatonin, which is important for transmitting information about environmental lighting and inducing sleep.

The thyroid glands and parathyroid gland are located together in the neck. The thyroid glands secrete hormones that regulate metabolism and calcium levels. The parathyroid gland also secretes hormones that regulate calcium levels.

The thymus gland secrets the hormones thymosin and thymopoietin that stimulate the production of special lymphocytes (white blood cells) called T-cells, which play an important role in the immune system by attacking foreign or abnormal cells.

The adrenal glands produce steroid hormones that regulate metabolic functions during stress, kidney function, and sexual function. The adrenal glands also secrete epinephrine (adrenaline) when stimulated by the autonomic nervous system.

The pancreas secretes insulin, to lower blood sugar levels, and glucagon to raise blood sugar levels. Therefore, the pancreas is an important endocrine organ for regulating the fuels available for energy production by cells.

The gonads, or sex organs (ovaries and testes) secrete sex hormones which control production of sperm and eggs as well as other secondary sex characteristics that are different for males and females. The secretion of sex hormones by the gonads is under the control of pituitary gland hormones.

learn by doing
learn by doing
did I get this
did I get this

## Endocrine System - Anatomy and Direction

The hypothalamus is found deep inside the brain and lies inferior to the thalamus. The pituitary gland is located at the base of the brain, inferior to the hypothalamus. The pineal gland is a small gland on the midline at the posterior of the brain. The thyroid and parathyroid glands lie inferior to the larynx, around the trachea. The parathyroid gland lies on the posterior surface of the thyroid gland. The adrenal glands are located superior to each kidney. The pancreas is located posterior to the stomach and is connected to the part of the small intestine called the duodenum. The ovaries are located in the pelvic cavity lateral to the uterus, while the testes are held external to the abdominopelvic cavity inside the scrotum.

learn by doing

Life is a complex continuum of flows of energy and matter. Discrete structures such as organs and cells allow us to divide life into levels of organization. This organization is to some extent artificial, and to some extent practical.

The human body is a complex, hierarchical system—that is, a system made up of smaller subsystems, which are themselves made up of even smaller systems. We commonly study these different hierarchical levels—levels of organization—separately. By breaking down the complex system into simpler parts, we can make the whole system easier to understand. This “reductionist” approach, reducing a complex system to simpler components, is central to how we practice modern science.

Regarding the body, therefore, we consider the body as a whole, then its subsystems, and then the components of these subsystems. We can model the hierarchy of organization within the body as comprised of organs, tissues, cells, cell organelles, macromolecules, molecules and finally atoms.

The levels of organization that we will consider in this course are, from smallest to largest:

• The chemical level, which consists of atoms, ions, and small molecules
• The macromolecule level, which consists of large molecules
• The cell level, which consists of individual cells; this is the smallest level that contains living entities
• The tissue level, which consists of groups of related cells working together to perform a specific function
• The organ level, which consists of groups of tissues working together to perform a higher-level function
• The organ system level, which consists of all of the organs involved in performing a vital function
• The organism or whole body level, which consists of a whole person
• The population or environment level, which involves the interactions of the person with his or her environment

Although we will consider each level individually, it is important for you to keep in mind the connections between the levels. Processes and events at one level can affect other levels. An alteration in the structure of a protein (macromolecule level) can prevent a cell from functioning properly; this improper function can affect the tissues, organs, organ systems, and the whole body. And the reverse is true: changes to the body (organism level) can affect organs, tissues, cells and molecules.

For example, suppose a single nitrogenous base in DNA (chemical level) is incorrect. This mutation causes an alteration in the structure of the beta globin (β-globin) protein (macromolecule level), which is part of hemoglobin. The altered structure of β-globin causes the proteins to stick together and form fiber-like structures. Under certain physiological conditions, the fibers in turn distort the shape of red blood cells (cell level), so that the cells become curved and twisted. The abnormal cells get stuck in capillaries, reducing blood flow to tissues and organs (tissue and organ levels). Organ damage may result, permanently affecting body function (whole body level).

This example describes sickle cell anemia, a genetic blood disorder. We can clearly see the connections between levels of organization. A seemingly tiny error at the genetic (chemical) level causes significant changes in the body’s systems at higher levels. Many genetic diseases arise in this way—through small alterations in the genetic code.

But scientists are homing in on the genetic basis for some diseases, such as cancer. In some instances, our understanding may hint at genetic therapies for a disease. Such technology is still largely experimental, but it shows the practical value of looking at the levels of organization of complex systems.

At every level of organization, structure is related to function. For example water is able to peform many of its unique and life-sustaining properties because of its structure. It is a bent polar molecule that can form attractions with neighboring water molecules through hydrogen bonds. At the macromolecular level, the unique structures of enzymes allow these proteins to help speed up reactions. On the cell and tissue level, the rigid matrix structure of your bones allows them to be able to support the weight of your body. At the organ level, the "J" shape of the stomach allows for partial segregation of its contents at the early stages of digestion.

Look around you. Everything is made of chemicals of one sort or another. Life is chemistry organized into astonishing complexity and intricacy. To make sense of this organization we can look at life’s chemistry as a hierarchy—levels of organization. From simple elemental ions, to simple organic molecules, complexity rises with increasingly larger macromolecules.

A person is between 1-2 meters (m) tall, but there are many length scales and biological levels of detail which are important for understanding anatomy and physiology. For perspective on size difference, considered an atomAtoms are basic units of matter. Atoms contain a positive center (nucleus) surrounded by a cloud of electrons that allow interatomic interactions. at 10-10 m. We can’t really grasp how small that is, but think big instead of small. A length of 1010 m is more than the distance from the Earth to the moon.

The smallest length scale that we will cover is the size of individual atoms, but the movement of subatomic particles called electrons, can change atomic charge. Ions are atoms that carry either a positive or negative charge from altered numbers of electrons, and many atoms and molecules exist in the body as ions.

Ionic chemistry is important in human medicine and health. Ions play an essential role in physiological processes, particularly in cell membranes. Sodium, potassium and calcium ions are required for nerve impulses and heart beats, enable cell-to-cell communication and initiate cellular processes. For example, release of insulin by beta cells of the pancreas is mediated by ions. Transport of ions across membranes may occur by passive diffusion, through ion channels, or through pumps. Pumps often move ions against a concentration gradient. Ionic chemistry is important in human medicine. Anesthetic drugs such as Novocain block sodium channels. Neurotoxins from some snakes and puffer fish work by blocking ion movements in nerve transmission. Malfunctions in ionic channel or pump molecules can result in serious physiological ailments, including cystic fibrosis (mutation in a gene that codes for cell membrane chloride channel) and epilepsy.

Even subatomic particles, which are too small to see with the best microscopes in the world, play an extremely important role in maintaining proper physiology.

learn by doing

The key biologically relevant elements are hydrogen (H), carbon (C), nitrogen (N), oxygen (O), phosphorous (P) and sulfur (S). These elements represent more than 95 percent of the mass of a cell. Carbon is a major component of nearly all biological molecules.

Elements are characterized by their atomic structure. While the subatomic structure of the atom is a major topic of interest in chemistry, physics and biophysics, we will only discuss the basic structure that will provide sufficient information for the construction of molecules in the context of this course. Atoms have a central nucleus with positively charged protons and neutral neutrons; negatively charged electrons circle the nucleus. The electrons that are involved in chemical bonding are those electrons in the outermost orbit, referred to as valence electrons. On the periodic table below, you can view each of the atoms while hiding all but the outermost electrons.

Atomic mass, the sum of the number of protons and neutrons in the atomic structure, is a particularly useful measure of each element. By summing the atomic mass of all the atoms in a molecule, one can estimate the molecular mass of the molecule, which is then expressed in atomic mass units, or Daltons. This table shows the masses of the six atoms of the elements listed above, which can also be found in the upper right-hand corner of the box for each element in the periodic table.

To calculate the mass of a molecule, we find the mass of each individual atom in the molecule and add them together. For example, a water molecule (H2O) contains one oxygen atom that has a mass of 16 amu (atomic mass units) and two hydrogen atoms that each have a mass of one amu. Therefore, the mass of a water molecule is 16 amu + 2 X 1 amu = 18 amu.

The electronegativity of an element is the degree to which an atom will attract electrons in a chemical bond. Elements with higher electronegativities, such as N, O and F (fluorine), have a strong attraction for electrons in a chemical bond and will therefore “pull” electrons away from less electronegative atoms. Elements with low electronegativity, such as metals, tend to “give away” electrons easily.

Some atoms with important biological relevance are shown. Place the mouse pointer over an element to see its full name.
did I get this
learn by doing
did I get this

Chemical bonds result when atoms of the same element (e.g., C-C) or different elements (e.g., C-O, C-N, O-H) are attracted to one another. There are two major types of chemical bonds: ionic and covalent. A polar covalent bond is a type of covalent bond that results in unique interaction between molecules. Some moleculesA molecule is a group of at least two atoms in a specified arrangement held together by covalent chemical bonds. that contain polar bonds exhibit an intermolecular attraction or force known as a hydrogen bond. Both chemical bonds and intermolecular forces are important in the functioning of the cell.

## Ionic Bonds

IonsRecall, that an ion is an atom with a gain or loss of electrons, always valence electrons. The number of protons is not equal to the number of electrons. This occurs through addition or loss of electrons.There are many important ions in physiology including sodium (Na+), calcium (Ca2+) and chloride (Cl-). form when an atom or group of atoms gains or loses one or more electrons. When an atom gains electrons, it becomes a negatively charged ion, called an anion. When an atom loses electrons, it becomes a positively charged ion called a cation. Atoms with higher electronegativities tend to gain electrons and become anions, whereas those with lower electronegativities tend to lose electrons and become cations. The electrostatic attraction between a positively charged ion and a negatively charged ion is the basis of an ionic bond.

An ionic bond generally forms between an atom of low electronegativity and an atom of high electronegativity. In many cases this will be between a metal and a nonmetal. In this situation, one or more electrons is transferred from the atom with low electronegativity, which readily “gives away” its electrons, to the atom with high electronegativity, which strongly attracts those electrons.

Example

For example, as illustrated in the animation below, a sodium atom will transfer its one valence electron to a chlorine atom, resulting in the formation of a sodium cation, Na+, and a chloride anion, Cl-. Because these are oppositely charged particles, they are attracted to each other and form table salt.

Test My System

When an ionic compound, like table salt, is put into water, it dissolves. This happens because the polar water molecule pulls these oppositely charged ions apart, as will be discussed further in the next module.

## Covalent Bonds

After single elemental atoms, we can think of small molecules as the next level in chemistry’s hierarchy. Molecules result from the covalent bonding of two or more elements’ atoms.

Covalent bonds are strong bonds in which electrons circling the atomic nucleus are shared. The nature of the covalent bond is determined by the number of electrons shared and the nature of the two elements sharing the bond. Two or more atoms held together by covalent bonds in a specified arrangement is called a molecule. The diagram below illustrates the covalent bond that forms between two hydrogen atoms to form a molecule of hydrogen. Covalent bonds form between atoms of the same or similar electronegativities, most often two nonmetals.

Each atom will most often form a specific number of covalent bonds when in a molecule with other atoms. The number of bonds that a particular atom will form is based on the atom’s valence electrons. Carbon for instance, which has four valence electrons, will form four bonds when it is in a molecule, as you can see from the diagram of methane below. Nitrogen, which has five valence electrons, will form three bonds, as seen in the ammonia molecule. The number of covalent bonds that a nonmetal will most commonly form is given in this table for the biologically important elements.

The number of bonds between two atoms, such as single bonds, double bonds or triple bonds, helps determine the stability of the atomic interactions. Double bonds, which share two pairs of valence electrons between two atoms, are very strong. The strong bond of carbon double bonded to oxygen is found in amino acids (these will be discussed later). The number of valence electrons shared also controls the "shape" of the atomic interactions. Carbon double bonded to oxygen forms a "flat" (planar) bond that does not rotate. This limits the shapes that the larger macromolecule, with repetitive double bonds, can form.

##### Formation of Hydrogen Molecule
A covalent bond is formed between two hydrogen atoms.

## Polar Covalent Bonds

In a molecule such as hydrogen, the electrons are shared equally because each atom has the same electronegativity. However, in some molecules one atom is more electronegative than another, in which case the electrons are not shared equally. For example, in a water molecule, one oxygen atom is covalently bonded to two hydrogen atoms. Because an oxygen atom is more electronegative than a hydrogen atom, the oxygen atom draws the electrons being shared toward itself and away from the less electronegative hydrogen. We say that the bond between the oxygen and hydrogen is polar because the electrons are shared unequally. This unequal sharing of electrons results in the more electronegative element, in this example the oxygen atom, having a slightly negative charge and the less electronegative element, in this example the hydrogen atom, having a slightly positive charge. Molecules with polar bonds have characteristics of both ionic and covalent bonds. Whether or not a molecule is polar has significant implications on how that molecule interacts with other molecules and ions in biological systems.

learn by doing

Water is the basis of life. Without it, life is not possible. Water accounts for up to 75 percent of the weight of the human body. Water provides a relatively stable medium in which chemical reactions can take place. Water’s unique chemical properties (as a solvent with a high boiling point and high heat capacity) make it essential for homeostasis. The body’s thermoregulation relies on water’s high heat capacity to buffer it against swings in external temperature. Cooling of the body is carried out by evaporative water loss—perspiration. Water is also vital as a transport medium. Oxygen is carried by red blood cells suspended in serum, which is mostly water. Nutritional substances are dissolved in water and transported to cells. Water is used to dissolve and dilute waste molecules. If the body is deprived of water for very long, death will result.

Water has several properties that contribute to its suitability to support life as we know it. One of these properties is that water is a polar molecule. Oxygen is more electronegative than hydrogen and draws the electrons that it shares in the covalent bond towards itself. Because water is polar, the partial positive end of one water molecule will be attracted to the partial negative end of a neighboring water molecule. This attraction is called a hydrogen bond. Hydrogen bondingThe attraction of an atom with high electronegativity for a hydrogen atom that is covalently bonded to another highly electronegative atom. This involves the attraction of a hydrogen atom with a partial positive charge to an atom with a partial negative charge. Only hydrogen atoms covalently bonded to a highly electronegative atom can participate in hydrogen bonding. occurs between partially negatively charged atoms with high electronegativity—oxygen, nitrogen or fluorine—and partially positively charged hydrogen atoms that are bonded to oxygen, nitrogen or fluorine atoms.

Hydrogen bonding, which is referred to as an intermolecular attraction, is a critical interaction within the cell. It is the principal force that holds the tertiary structure of proteins, carbohydrates and nucleic acids together and the overall stability of these molecules is due in part to the cumulative effect of the large number of hydrogen bonds found in the functional structures. Hydrogen bonds are found in and between a variety of molecules. For example, the enormous number of hydrogen bonds between strands of plant cellulose provide the strength and structure of the plant cell wall. As another example, wool (sheep hair) has lots of proteins with an enormous number of hydrogen bonds that provide the curly structure of individual wool fibers. These curly fibers trap air spaces which makes wool such a good insulator. When washed at high temperatures, these hydrogen bonds are broken and the wool fibers will lose their shape, probably damaging any wool clothing.

The electronegative oxygen (red) draws electrons to it, creating the partial negative charge on oxygen and partial positive charge on hydrogen.
Adjust the volume on your computer and click the play button. Click on topic (partial charges) to see other animation choices.

A water molecule attracts four other water molecules towards itself. One molecule to each of the two free pairs of electrons in the oxygen atom valence shell, and one to each of the hydrogen atoms covalently bonded to the oxygen. As the water molecules associate with each other they have a defined structure dictated by the tetrahedral geometry of the electrons around the oxygen atom as seen in the figure below. The partially positive hydrogen atoms are attracted to the free electron pairs from other water molecules while the partially negative charge on the oxygen's free electron pairs are attracted to the partially positive hydrogen atoms from another water molecule.

learn by doing
Example
Click and drag to rotate the ice lattice. Use the right mouse button on the PC, or control click inside the FlashMol to control zooming to get a better look.

One excellent illustration of the hydrogen bonding is the change in hydrogen bonding of water in ice. These stabilized bonds give ice its crystal-like appearance. Use your mouse on the ice lattice above to explore the network-like formation of weak bonds between molecules. This type of hydrogen bonding also helps large protein structures stabilize.

did I get this

## Water and Ions

The attraction between oppositely charged ions in an ionic compound is strong. However, because of the polarity of water, when many ionic compounds are in aqueous solutions they become dissociated into ions. For instance, when an ionic compound such as table salt (NaCl) is dissolved in water, it separates into Na+ and Cl- ions. The water molecules surround the ions to form polar interactions such that the positive ends of the water molecules are arranged around negative ions and the negative ends of the water molecules surround positive ions. Thus the ions become encapsulated by water spheres, which are called spheres of hydration. The biological world is very ionic, and spheres of hydration are important in a cell because they maintain the separation of the many ions of the cell from each other. The sphere of hydration must be broken in order for binding to take place with a specific binding partner.

## Hydrophilic Interaction

The nature of polar molecules is that they contain highly electronegative atoms. Consequently, many are capable of hydrogen bonding with aqueous or polar solvents. Because polar molecules are generally water soluble, they are referred to as being hydrophilic, or water-loving. The one-carbon alcohol, methanol, is an example of a polar molecule.

## Hydrophobic Interaction

The final type of interaction occurs between neutral hydrophobic, or water-fearing, molecules. These nonpolar molecules do not interact with water and are characterized by atoms with the same or nearly the same electronegativities. In aqueous solutions, the hydrophobic molecules are driven together to the exclusion of water. For example, shaking a bottle of oil and vinegar (acetic acid in water), such as in a salad dressing, results in the oil being dispersed as tiny droplets in the vinegar. As the mixture settles, the oil collects in larger and larger drops until it only exists as a layer, or phase, above the vinegar.

A similar effect occurs in biological systems. As a protein folds to its final three-dimensional structure, the hydrophobic parts of the protein are forced together and away from the aqueous environment of the cell. Similarly, biological membranes are stabilized by the exclusion of water between layers of lipids as we will see later.

Amphipathic molecules are molecules that have a distinct nonpolar, or hydrophobic, region, and a distinct polar region. These molecules do not form true solutions in water. Rather, the nonpolar parts are forced together into a nonpolar aggregate, leaving the polar part of the molecule to interact with the aqueous phase. Detergents and long-chain carboxylic acids are examples of amphipathic molecules.

learn by doing
did I get this

## Energy Associated with the Bonds

Each of the bond types represents a measurable amount of energy. To break a bond, the equivalent amount of energy must be expended. In metabolism, bonds are broken in molecules, such as glucose, to "release" the energy. The cell utilizes this energy to drive other energy-consuming reactions. The covalent bond has the most energy associated with it, on average approximately 100 kilocalories/mole (kcal/mol). The noncovalent bonds, ionic and hydrogen, and hydrophobic interactions, have approximately five kcal/mol associated with each of them.

It should be noted here that throughout the presentation of this course approximations will be used for certain values so that estimations can be made as we move to more complex systems. It is to be acknowledged that very precise values for each of the measurements are not available.

Thus the noncovalent bonds that have been introduced have approximately 20 times less energy associated with them and, thus, are more easily broken individually. However, hydrogen bonds generally form extensive networks, and the total energy associated with the network is the sum of the individual interactions (van der Waals force). As anyone who has done a "belly flop" into a swimming pool knows, breaking a large surface area of water is extremely difficult (and painful).

Energy associated with the different bonds
Bond Energy, kcal/mol
Covalent 100
Ionic 5
Hydrogen 5
Hydrophobic interactions 5
van der Waals 5 (depends on surface area)

When NaCl dissolves in water, each ion becomes surrounded by at least 20 water molecules. As NaCl there is 5 kcal/mol of energy associated with the ionic attraction of the cation and anion, but when a Na ion is surrounded by 20 water molecules, there is 100 kcal/mol of energy associated with just the Na ion. Thus, NaCl in an aqueous solution is energetically more favored than NaCl as the ionically bonded molecule due to the resulting hydrated state. You will explore what happens to molecules that only partially dissociate in water, or weak electrolytes, in the next module.

learn by doing
did I get this

## Electrolytes

An electrolyte is any fluid that contains free ions. You have already learned about ions and ionic properties. Important ions in physiology include sodium, potassium, calcium, chloride and phosphate. These ions are used in maintaining protein structure and in cell communication, and generally can help maintain water balances throughout the body. We get electrolytes through ingestion. Drinks with “electrolytes” have salts (sodium and potassium) that help maintain ion homeostasis for athletes that sweat and lose salt. Electrolytes are essential for life, but many people get too much (like too much sodium from salt in processed food), which can also disrupt proper physiological function.

## pH

The hydrogen ion concentration (H+) of a solution is an important property, because biological systems contain functional groups whose properties are changed by changes in the hydrogen ion concentration.

Since the hydrogen ion concentrations are usually much less than one, and can vary over many orders of magnitude, a different scale is used to describe the hydrogen ion concentration—the pH scale. The pH is the negative logarithm (-log) of the proton concentration:

 pH = - log (H+).
The log conversion reduces a tenfold change in hydrogen ion concentration to a one unit change in pH. The minus sign changes the negative numbers that would be obtained from log(H+) to positive ones. Since the pH scale is an inverse scale, the concentration of protons is high at low pH and low at high pH. A solution is said to be acidic if the pH is less than 7.0, and basic if the pH is more than 7.0. A solution is neutral if its pH is equal to 7.0.

The image below shows the pH of a number of common fluids.

##### pH of various compounds
On the left are biological compounds and on the right are some foods and cleaning products.
learn by doing

## Acid Dissociation and pH

For our studies, the Bronsted definition of an acid will be used. Here, we will define an acid as a proton donor and a base as a proton acceptor. Hydrochloric acid, like sodium chloride, is a strong electrolyte because it completely dissociates in aqueous solution into charged ions. Hydrochloric acid is also a strong acid, because when it completely dissociates it also completely donates all of its protons.

Many molecules are weak electrolytes and exist in an equilibrium (indicated by $⇌$ in the general equation below) between the starting molecule and its dissociated parts. Thus dissociation can be seen as an acid (HA) in equilibrium with a proton (H+) and the corresponding conjugate base (A-).

In general:

 HA $⇌$ A- + H+

Specifically for acetic acid:

 CH3COOH $⇌$CH3COO- + H+
learn by doing
did I get this

The simplest of the macromolecules are carbohydrates, also called saccharides. The name is descriptive of the character of this class of molecules, since they all have the general formula of a hydrated carbon.

 (C(H2O))n

This represents a 2:1 ratio of hydrogen to oxygen atoms(as in water). But the constituent atoms of carbohydrates can be configured in virtually endless configurations, so carbohydrate molecules come in a multitude of different shapes and sizes.

Monosaccharides are the most basic units of carbohydrates. These are simple sugars, including glucose, fructose, and others. They contain between three and seven carbon atoms, have a sweet taste and are used by the body for energy.

Polysaccharides are long polymers of monosaccharide sugars that are covalently bonded together. Polysaccharides are often used to store the energy of the monosaccharide. These include starch and glycogen. Polysaccharides can also be used for structure in plants and other lower organisms. For example, cellulose is a large polysaccharide that is found in plant cell walls. People can't digest cellulose into monosaccharides, but it is important in our diets as "roughage" or "insoluble fiber."

Polysaccharides can be conjugated with other macromolecules. For example, complex carbohydrates can be linked with proteins or lipids to form glycoproteins and glycolipids, respectively. Very different structures can be made from a few monosaccharides arranged in different patterns and with different bonding. This flexibility in structure can therefore be used for identification of individual cell types, since the structure of each cell type is unique. More than half of the proteins in the body, which we will discuss later in this module, have glycosylations or carbohydrate modifications. The outside of cells are covered in carbohydrates from modifications of lipids that make up the membrane; we will cover lipids in the last chapter of this section.

Carbohydrates are best know as energy storage molecules. Their primary function is as a source of energy. Cells readily convert carbohydrates to usable energy. You will recall that molecules are a collection of atoms connected by covalent bonds. In general, single covalent bonds can be represented as having approximately 100 kcal/mol of energy associated with the force that holds the two atoms together. Table sugar, or sucrose, is the best-known carbohydrate. The most common carbohydrate in nature is glucose, which has the general formula

 (C(H2O))6
and which is a common source of energy for many living organisms. If glucose is completely metabolized or burned for its energy in a cell, the complete breakdown of the molecule follows the following equation:

 (C(H2O))6 + 6 O2 <-------------> 6 CO2 + 6 H2O + 673 kcal (energy)

While the overall reaction represents a coupled oxidation/reduction process, on balance this process involves the breaking of five carbon-to-carbon bonds with the release of 673 kcal/mol of energy.

However, the body does not need dietary carbohydrates for energy. Proteins and fats can meet the body's needs, and the body can convert molecules into carbohydrates needed for other cellular functions. But carbohydrates require minimal processing for use as energy. For example, a simple enzymatic reaction converts sucrose into blood sugar, which can be used directly as a source of cellular energy. The trick for the cell is to convert the 673 kcal of energy to a useful form so that it can do work for the cell or organism. The metabolic fate of the carbohydrate will be discussed later in the course.

learn by doing
did I get this

A second function performed by carbohydrates is structure. In this case, structure is not only what a polymer of carbohydrates has, but also what that structure contributes to the cell. For example, cellulose is a linear polymer of glucose that interacts with other cellulose polymers to form fibers that interact to form the basic structure of the cell wall of plants. These cellulose polymers are undigestable and constitute the roughage

Another example is the peptidoglycan that makes up the cell wall structure of a bacterium. "Peptido" refers to a peptide, which is a fragment of a protein or a short polymer of amino acids, and "glycan" refers to a polysaccharide, a polymer of carbohydrates. In this case, the polymer of carbohydrates includes building blocks other than glucose, but the end result is the formation of a matrix. In both cases, the resulting fibers and matrices provide scaffolding that gives rigidity (structure) and protection to the bacteria. Gram staining used to identify bacteria is based on the staining property of this peptidoglycan and some antibiotics work by destroying this protective layer so bacteria are killed by water rushing into the cell by osmosis.

Carbohydrates are also the structural basis for nucleic acids, which we will cover later.

A third function of carbohydrates is cell recognition and signaling. Just as a peptidoglycan is a conjunction (conjugation) of a peptide with a polysaccharide, other complex carbohydrates are conjugated to other molecules to form glycoproteins (carbohydrates linked to proteins) and glycolipids (carbohydrates linked to lipids). Because a very large number of structures can be made from a few monosaccharides (simple carbohydrates), a very large number of different structures can also be made from a few simple carbohydrates, as will be seen later. This large number of different structures can therefore be used for identification of individual cell types.

Carbohydrate modifications (called glycosylations) are present on lipid membranes and proteins for specialized function and recognition. Unique carbohydrate formations allow even more specificity to a protein, beyond just the amino acid code. The outer membrane of the cell is dotted with carbohydrate chains, which differ according to cell type. These carbohydrate glycosylations provide a "signature" of the cell and can also act as a signal. Thus, glycosylations are important in immune response and general cell-to-cell communication.

After nucleic acids, proteins are the most important macromolecules. Structurally, proteins are the most complex macromolecules. A protein is a linear molecule comprised of amino acids. Twenty different amino acids are found in proteins. The sequence of a protein's amino acids is determined by the sequence of bases in the DNA coding for the synthesis of this protein. A single protein molecule may be comprised of hundreds of amino acids. This sequence of amino acids is a protein's primary structure. The protein's size, shape and reactive properties depend on the number, type and sequence of amino acids. The amino acid chain can remain in its primary linear structure, but often it folds up and in on itself to form a shape. This Secondary structure forms from localized interactions (hydrogen bonding) of amino acid side chains. These include alpha helix and beta sheet structures. The alpha helix is dominant in hemoglobin, which facilitates transport of oxygen in blood. Secondary structures are integrated along with twists and kinks into a three-dimensional protein. This functional form is called the tertiary structure of the protein. An additional level of organization results when several separate proteins combine to form a protein complex—called quaternary structure.

Proteins perform numerous essential functions within the cell. Many proteins serve as enzymes, which control the rate of chemical reactions, and hence the responsiveness of cells to external stimuli. An enzyme can fast-forward a reaction that would take millions of years under normal conditions and make it happen in just a few milliseconds. Enzymes are important in DNA replication, transcription and repair. Digestive processes are also largely facilitated by enzymes, which break down molecules that would otherwise be too large to be absorbed by the intestines. Enzymatic proteins also play a role in generation and transmission of nerve impulses, for example helping to generate muscle contractions.

Other proteins are important in cell signaling and cell recognition. Receptor proteins recognize substances as foreign and initiate an immune response. Through cell signaling, proteins mediate cell growth and differentiation during development. Several important proteins provide mechanical support for the cell, scaffolding that helps the cell maintain its shape. Other proteins comprise much of the body’s connective tissue and structures such as hair and nails.

For protein production in cells the body needs amino acids, which we ingest. It seems a bit inefficient, but we eat proteins, break them down into amino acids, distribute the amino acids inside the body and then build up new proteins. Our cells can synthesize some amino acids from similar ones, but essential amino acids must be obtained from the diet, since they cannot be synthesized. Deficiencies of protein in the diet result in malnutrition diseases such as kwashiorkor, which is common in developing countries. In cases of kwashiorkor, protein deficiency causes edema (swelling) which leads to a distended abdomen. Excess protein is metabolized into ammonia and urea, which are typically excreted—up to a point. When too much urea accumulates it cannot be filtered by the kidneys. Urea accumulation can cause yellowing of the skin.

Unlike nucleic acids, which must remain unchanged in the body for the life of the organism, proteins are meant to be transient—they are produced, do their functions and then are recycled. Proteins are also readily broken down by extremes of heat or pH. When you boil an egg, the yolk and white stiffen and change color. When you cook meat, the flesh changes color and becomes firm. These changes arise because the constituent proteins are “denatured” and have lost their secondary and tertiary structures.

## Introduction

Amino acids are the building blocks of proteins. The sequence of amino acids in individual proteins is encoded in the DNA of the cell. The physical and chemical properties of the 20 different naturally occurring amino acids dictate the shape of the protein and its interactions with its environment. Certain short sequences of amino acids in the protein also dictate where the protein resides in the cell. Proteins are composed of hundreds to thousands of amino acids. As you can imagine, protein folding is a complicated process and there are many potential shapes due to the large number of combinations of amino acids. By understanding the properties of the amino acids you will gain an appreciation for the limits of protein folding and will learn how to predict the potential higher-order structure of the protein.

All amino acids have the same backbone structure, with an amino group (the $α$-amino, or alpha-amino, group), a carboxyl group, an $α$-hydrogen, and a variety of functional groupsThere are a number of functional groups used to describe the particular bonds and chemical reactions of molecules. (R) all attached to the $α$-carbon.

The general structure of an $α$-amino acid. The acidic group is a carboxylic acid. The carbon that is attached to the carboxylic acid is the $α$-carbon. If the R group were a carbon atom, it would be the $β$-carbon.

If all of the amino acids have the same basic structure with an amino, a carboxyl and a hydrogen fixed to the alpha-carbon, then the large variation in the properties and structure of the amino acids must come from the fourth group attached to the alpha carbon. This group is referred to as the side chain of the amino acid or the R group.

The structures of the 20 common amino acids are shown on the chart below. The simplest amino acid, glycine, is shown in the upper left. The main-chain atoms of glycine are highlighted in yellow and its side chain (H) is highlighted in green. All amino acids have the same main-chain atoms, but differ in the side chains. For clarity, the $α$-proton is omitted in the remaining drawings. Nonpolar amino acids are highlighted in gray, aromatic amino acids are highlighted in cyan, polar are highlighted in purple, amino acids with acidic side chains are highlighted in red, and amino acids with basic side chains are highlighted in blue. The amino acids cysteine and proline, which are shown at the bottom of the chart, have unique properties. Cysteine can form a covalent S-S disulfide bond, stabilizing the protein structure. In the case of proline, the side chain attaches to the nitrogen, making proline an imino acid (rather than an amino acid).

The side-chain groups of these amino acids contain many of the same functional groups that were discussed earlier in this unit and that can be found in the functional groups interactive chart, which can be accessed by clicking on the Learn by Doing link below.

did I get this

## Peptide Bonds

Proteins are polymers of amino acids. The amino acids are joined together by a condensation reaction. Each amino acid in the polymer is referred to as a "residue." Individual amino acids are joined together by the attachment of the nitrogen of an amino group of one amino acid to the carbonyl carbon (C=O) of the carboxyl group of another amino acid, to create a covalent peptide bond and yield a molecule of water, as shown below.

Peptide bond formation occurs by a dehydration reaction. The amino group of the second amino acid attaches to the carbonyl carbon of the first, forming the peptide bond and releasing water. The resultant dipeptide has an amino terminus (left) and a carboxy terminus (right). The main-chain atoms, which are the same for each residue in the peptide, include the nitrogen and its proton, the $α$-carbon and its hydrogen, and the C=O group. The R groups form the side-chain atoms.

The resulting peptide chain is linear with defined ends. Short polymers (less than 50 residues or amino acids) are usually referred to as peptides, and longer polymers or polypeptides. Several polypeptides together can form some large proteins. Because the synthesis takes place from the alpha-amino group of one amino acid to the carboxyl group of another amino acid, the result is that there will always be a free amino group on one end of the growing polymer (the N-terminus) and a free carboxyl group on the other end (the C-terminus). Note that the potential exists for the formation of amide (peptide) links involving the carboxyl and amino groups in the side chains, but bioselectivity directs the synthesis to be linear, involving only the alpha-amino and alpha-carboxyl groups.

Note that after the amino acid has been incorporated into the protein, the charges on the amino and carboxy termini have disappeared, thus the main-chain atoms have become polar functional groups. Since each residue in a protein has exactly the same main-chain atoms, the functional properties of a protein must arise from the different side-chain groups.

By convention, the sequences of peptides and proteins are written with the N-terminus on the left and the C-terminus on the right. The name of the N-terminal residue is always the first amino acid. The name of each amino acid then follows. The primary sequence of a protein refers to its amino acid sequence.

did I get this

Primarily located in the cell nucleus (hence the name) nucleic acidsOrganic, replicating macromolecules that include RNA and DNA. are replicating macromolecules. The most important are DNA and RNA. Without them, cells could not replicate; life would not be possible. These molecules store the cell’s “software”—the instructions that govern its function, processes and structure. The code is comprised of sequences of four bases—adenine, cytosine, guanine and thymine (uracil in RNA). These are arranged in sets of three called triplets. Each triplet specifies an amino acid, which in turn is a component of a protein macromolecule. All the intricate complexity of the human body arises from the information encoded by just four chemicals in a single long DNA macromolecule.

In humans, mistakes in the structures of DNA and RNA cause diseases, including sickle cell anemia, hemophilia, Huntingdon's chorea and some types of cancer. Even a small error can result in a dramatic effect. Sickle cell disease is caused when just one amino acid in the DNA base sequence is changed. Through directing chemical processes, nucleic acids instruct cells how to differentiate into various organs. During development, whole sets of DNA sequences are shut down or activated to drive specific processes. These processes lead to different kinds of cells that form organs such as the heart, liver, skin and brain.

Within the cell, nucleic acids are in turn organized into higher-level structures called chromosomes. You can see chromosomes with a light microscope, using an appropriate stain. Early study of chromosomes helped scientists discover and understand the role of nucleic acids in cellular reproduction. Errors in chromosomal structure lead to malfunctions of life processes. For example, in humans, an extra chromosome 21 results in Down Syndrome.

## The Backbone

Structure of RNA and DNA

Our genetic code is determined by only four bases in DNA (G, C, A, T), which are repeated and arranged in a special order. For example,

1 agccctccag gacaggctgc atcagaagag gccatcaagc agatcactgt ccttctgcca

61 tggccctgtg gatgcgcctc ctgcccctgc tggcgctgct ggccctctgg ggacctgacc

121 cagccgcagc ctttgtgaac caacacctgt gcggctcaca cctggtggaa gctctctacc

181 tagtgtgcgg ggaacgaggc ttcttctaca cacccaagac ccgccgggag gcagaggacc

241 tgcaggtggg gcaggtggag ctgggcgggg gccctggtgc aggcagcctg cagcccttgg

301 ccctggaggg gtccctgcag aagcgtggca ttgtggaaca atgctgtacc agcatctgct

361 ccctctacca gctggagaac tactgcaact agacgcagcc cgcaggcagc cccacacccg

421 ccgcctcctg caccgagaga gatggaataa agcccttgaa ccagcaaaa

This may seem like a random string of G, C, A, T, but this DNA codes for human insulin. DNA is organized into a linear polymer in a double helix and maintains the inherited order of bases or genetic code. The "steps" of the DNA ladder have the code that ultimately directs the synthesis of our proteins. This linear polymer of genetic code is maintained when double strand DNA is transcribed to single strand RNA.

Structure of a nucleotide

The fundamental unit of DNA is the nucleotide. The nucleotide contains a phosphate group (shown in orange), which will eventually give the DNA polymer its charge and interconnect nucleotides on the backbone. The furanose sugar group is a five-sided sugar (shown in purple). The nitrogenous base (shown in yellow) gives the DNA its specificity.

The numbering of the positions on the sugar furanose rings of DNA and RNA follow a convention that uses ' (the prime symbol) to denote the sugar positions. Thus, the ribose has a nitrogenous base connected to the 1' position and hydroxyl groups (OH) on the 2', 3' and 5' positions. Using this nomenclature, deoxyribose is formally called 2'-deoxyribose (2 prime deoxyribose) to denote the loss of the hydroxyl at the 2' position of ribose.

The major difference in the polymer backbones between DNA and RNA is the sugar used in the formation of the polymer. In DNA (DeoxyriboNucleic Acid) the 2' position of the furanose has a hydrogen. In RNA (RiboNucleic Acid), the 2' position of the furanose has an OH (hydroxyl) and the sugar is the monosaccharide ribose in the furanose conformation.

Furanose sugars

The linkage of individual nucleotides is made by a bridging phosphate molecule between two hydroxyl groups, one on each furanose ring. The resulting polymer is a string of furanose molecules linked by phosphodiester bonds in one very long macromolecule.

Backbone of DNA

The following is a list of structural characteristics of the DNA/RNA polymer backbone.

• Phosphate-ribose(deoxyribose)-phosphate-ribose(deoxyribose) sequence
• Linked by Phosphodiester covalent bonds
• 3' position on one ribose(deoxyribose) linked to 5' position of adjacent ribose(deoxyribose) through phosphodiester bridge
• Chain has 3' end and 5' end

## Hydrogen Bonding Between Bases

The DNA double helix is held in place with the hydrogen bonding of purines to pyrimidines. Recall that hydrogen bonds are weak interactions, not like the covalent bonds of the phosphate-furanose backbone. Thus, DNA is held together, but can be pulled apart for transcription to RNA or for DNA replication.

To maintain equal distance between the two strands of DNA, the larger purines must bind with the smaller pyrimidines. Specifically, A always binds with T and G always binds with C in DNA. A useful memory device is that A and T are angular letters and G and C are both curvy.

The following is an interactive simulation that allows you to form hydrogen bonding pairs between the appropriate bases in DNA and RNA that would be allowed in the formation of the double helical structure. You should apply the definition of the hydrogen bond to form all possible hydrogen bonds in any pair of bases you choose. All of the possible hydrogen bonds may be useful later as we explore multiple structures, especially for RNA. The focus of this exercise is to identify bonding partners that will be optimal in the formation of the DNA and RNA helical structures.

Select the proper base from the right to bond with the example on the left. Draw the hydrogen bonds between then and then click the Done when you have drawn all of the bonds and then identify the bases.
did I get this

## DNA Transcription

DNA replication: Every time a cell divides, all of the DNA of the genome is duplicated (called replication) so that each cell after the division (called a daughter cell) has the same DNA as the original cell (called the mother cell).

DNA transcription: For the genetic code to become a protein, it goes through a transcription step. DNA is transcribed into RNA (a single-strand nucleic acid). The RNA is then shuttled away from the DNA to the region of protein synthesis.

RNA translation: RNA is translated from a nucleic acid code into the amino acid sequence of a protein.

Thus, the DNA gene code is able to duplicate to maintain consistency throughout the person's body and throughout the person's life. DNA is also used to make proteins through the use of an RNA intermediate.

Lipids include fats and waxes. Several vitamins, such as A, D, E and K, are lipid soluble. Perhaps the most important role of lipids is in forming the membranes of cells and organelles. In this way, lipids enable isolation and control of chemical processes. They also play a role in energy storage and cell signaling.

Lipid molecules forming cell membranes are comprised of a hydrophilic “head” and hydrophobic “tail” (remember, "hydro" means water and "philos" means love; "hydro" means water, "phobic" means fear). A phospholipid bilayer is formed when the two layers of phospholipid molecules organize with the hydrophobic tails meeting in the middle. Scientists believe that the formation of cell-like globules of lipids was a vital precursor to the origin of cellular life, since membranes physically separate intracellular components from the extracellular environment. Thus, lipid membranes enclose other macromolecules, confine volumes to increase the possibility of reaction, and protect chemical processes. Proteins with hydrophobic regions float within the lipid bilayer. These molecules govern transport of charged or lipophobic molecules in and out of the cell, such as energy molecules and waste products. Carbohydrate molecules jutting out of the membrane are important for cell recognition as mentioned previously.

Lipids are also vital energy storage molecules. Carbohydrates can be used right away, and lipids provide long-term energy storage. Lipids accumulate in adipose cells (fat cells) in the body. As part of the catabolic process, from the days when humans had to forage for food, excess carbohydrates can be converted into lipids, which are then stored in fatty tissue. Ultimately, too many ingested carbohydrates and lipids lead to obesity.

learn by doing

Cells are the basis of life—the basic structural unit of living things. Molecules such as water and amino acids are not alive but cells are! All life is comprised of cells of one type or another.

One of the hallmarks of living systems is the ability to maintain homeostasis, or a relatively constant internal state. The cell is the first level of complexity able to maintain homeostasis, and it is the unique structure of the cell that enables this critical function.

In this section of the course, you will learn about the cell and all the parts that make it functional. You will also focus on the cell membrane, which is the structure that surrounds the cell and separates its internal environment from the external environment. It is a critical component because it controls what can enter and exit the cell. This section will also describe how cells reproduce to maintain homeostasis.

The current cell theory states that:

1. All known living things are composed of one or more cells.
2. All new cells are created by pre-existing cells dividing in two.
3. The cell is the most basic unit of structure and function in all living organisms.

Modern cell theorists assert that all functions essential to life occur within the cell; and that, during cell division, the cell contains and transmits to the next generation the information necessary to conduct and regulate cell functioning.

learn by doing

Let’s begin our study of the cell by investigating the basic anatomy of an animal cell. Each cell consists of three components shown in the image above.

1. A cell membrane which surrounds and protects the cell
2. The cytoplasm which is the watery interior of the cell which contains ions, proteins, and organelles
3. Organelles which carry out all activities necessary for the cell to live, grow, and reproduce

Within the body, cells represent a level of organization between organelles and tissues. Organelles in turn are comprised of specialized macromolecules and tissues are collections of specialized cells. Brain, kidney, liver, muscle and lung tissues differ from each other because of the structure and function of their constituent cells. Thus, the cells comprising each tissue type vary in shape, size and interior structure to permit their specific physiological function within the tissue.One important concept to keep in mind as you study anatomy and physiology is that structure determines function. When you look at the shape of a cell, it gives you a clue as to it’s function.

did I get this
did I get this

Observe the cells below and think about how the shape is necessary for its role. See if you can match the cell with its function.

did I get this

Each cell process is carried out in a specific location in the cell, often located in or around an organelle. Think of an organelle as a level of organization between macromolecules and the cell. Organelles carry out specialized tasks within the cell, localizing functions such as replication, energy production, protein synthesis, and processing of food and waste. The various cells differ in the arrangement and number of organelles, as well as structurally, giving rise to the hundreds of cell types found in the body.

The focus of this section is to understand the organelles of the cell, how they interact with each other, and how they function during transport, growth and division in the cell. You will learn about the controlled chemical environment a cell maintains and what restrictions this places on the types of chemical reactions it can perform. This background is vital to understanding key processes such as how a cell releases energy from glucose, makes and folds proteins, and goes through growth and cell division.

Think of a city and the various jobs within a city. A cell is similar with each organelle serving a specific purpose. There are organelles whose job is to provide shape and structure to the cell, much like the city streets and bridges. These protein rich organelles include intermediate filaments, microtubules, and microfilaments. Some of these actually move other organelles around the cell or change the shape of the cell. When a muscle cell contracts or shortens it does so by the microfilaments made up of the proteins actin and myosin. One special organelle composed of microtubules is located in an area near the nucleus, the centrosome. The centrosome contains a pair called of microtubule bundles known as the centrioles. Centrioles are important because they move chromosomes to opposite ends of the cell during cell replication termed mitosis. Neurons do not have centrioles and cannot replicate.

Other organelles help synthesize the proteins needed by the cell. These protein factories are called ribosomes. They can be scattered within the cell or attached to a membrane channel system called the endoplasmic reticulum or ER. When the ER has ribosomes attached to it, it is termed the rough ER (the ribosomes give it a rough or grainy appearance). When the ER lacks ribosomes it is termed the smooth ER and functions for lipid synthesis and storage of toxins. When a protein is manufactured it must be folded into a specific shape to work. Often additional side chains of carbohydrates must be attached. The protein is processed in the rough ER. Once it is formed it enters the golgi apparatus which is the distributing plant for the cell. It completes any protein processing and then packages it into a vesicle for transport to its destination. Some proteins are needed in the cell membrane and the vesicles make sure they reach the membrane. The golgi apparatus also makes a special type of vesicle termed a lysosome. The lysosome is the garbage man of the cell. It takes in cell debris and waste and destroys it. The lysosome contains very powerful hydrolytic enzymes to accomplish this. It is very important that the enzymes remain in the lysosome or they would destroy the cell.

The power plant of the cell is the mitochondria. This organelle generates the ATP or energy for the cell. Mitochondria even have their own DNA termed mitochondrial DNA (mDNA) and can replicate.

Finally there is the controller of the cell. This is the nucleus. Not all cells have a nucleus and are termed anucleate. If you look at the image of the red blood cells you will see a white dot in the center of the cell – that is where the nucleus used to be. The nucleus is ejected when they mature. Some cells have more than one nucleus and are termed multinucleate. Skeletal muscle cells are very large cells and are multinucleate. The nucleus contains the DNA of the cell and the nucleolus. The nucleolus is an organelle that makes ribosomes. The DNA is your genetic code. It contains the genes that contain the instructions for making every protein in your body. The nucleus is surrounded by it’s own membrane with tiny holes termed nuclear pores. The membrane is called the nuclear membrane or nuclear envelope.

The interactive diagram below shows a drawing of a eukaryotic cell. The cell components in the list link to images that highlight these same structures in a living cell.

learn by doing

Practice what you have learned by following the link and answering the questions in the interactive diagram.

The cell membrane is a dynamic structure composed of lipids, proteins, and carbohydrates. It protects the cell by preventing materials from leaking out, controls what can enter or leave through the membrane, provides a binding site for hormones and other chemicals, and serves as an identification card for the immune system to distinguish between “self” and “non-self” cells. We will first investigate the anatomy of the cell membrane and then continue on to study the physiology of membrane transport.

The phospholipid bilayer is the main fabric of the membrane. The bilayer's structure causes the membrane to be semi-permeable. Remember that phospholipid molecules are amphiphilic, which means that they contain both a nonpolar and polar region. Phospholipids have a polar head (it contains a charged phosphate group) with two nonpolar hydrophobic fatty acid tails. The tails of the phospholipids face each other in the core of the membrane while each polar head lies on the outside and inside of the cell. Having the polar heads oriented toward the external and internal sides of the membrane attracts other polar molecules to the cell membrane. The hydrophobic core blocks the diffusion of hydrophilic ions and polar molecules. Small hydrophobic molecules and gases, which can dissolve in the membrane's core, cross it with ease.

Other molecules require proteins to transport them across the membrane. Proteins determine most of the membrane's specific functions. The plasma membrane and the membranes of the various organelles each have unique collections of proteins. For example, to date more than 50 kinds of proteins have been found in the plasma membrane of red blood cells.

## Importance of Phospholipid Membrane Structure

What is important about the structure of a phospholipid membrane? First, it is fluid. This allows cells to change shape, permitting growth and movement. The fluidity of the membrane is regulated by the types of phospholipids and the presence of cholesterol. Second, the phospholipid membrane is selectively permeable.

The ability of a molecule to pass through the membrane depends on its polarity and to some extent its size. Many non-polar molecules such as oxygen, carbon dioxide, and small hydrocarbons can flow easily through cell membranes. This feature of membranes is very important because hemoglobin, the protein that carries oxygen in our blood, is contained within red blood cells. Oxygen must be able to freely cross the membrane so that hemoglobin can get fully loaded with oxygen in our lungs, and deliver it effectively to our tissues. Most polar substances are stopped by a cell membrane, except perhaps for small polar compounds like the one carbon alcohol, methanol. Glucose is too large to pass through the membrane unassisted and a special transporter protein ferries it across. One type of diabetes is caused by misregulation of the glucose transporter. This decreases the ability of glucose to enter the cell and results in high blood glucose levels. Charged ions, such as sodium (Na+) or potassium (K+) ions seldom go through a membrane, consequently they also need special transporter molecules to pass through the membrane. The inability of Na+ and K+ to pass through the membrane allows the cell to regulate the concentrations of these ions on the inside or outside of the cell. The conduction of electrical signals in your neurons is based on the ability of cells to control Na+ and K+ levels.

Selectively permeable membranes allow cells to keep the chemistry of the cytoplasm different from that of the external environment. It also allows them to maintain chemically unique conditions inside their organelles.

did I get this

The cell membrane is not a static structure. It is a dynamic structure that allows the movement of phospholipids and proteins. Fluidity is a term used to describe the ease of movement of molecules in the membrane and is an important characteristic for cell function. Fluidity is dependent on the temperature (increased temperatures it more fluid and decreased temperatures make it more solid), saturated fatty acids and unsaturated fatty acids. Saturated fatty acids make the membrane less fluid while unsaturated fatty acids make it more fluid. The correct ratio of saturated to unsaturated fatty acids keeps the membrane fluid at any temperature conducive to life. For example, winter wheat responds to decreasing temperatures by increasing the amount of unsaturated fatty acids in cell membranes to prevent the cell membrane from becoming too solid in the cold. In animal cells, cholesterol helps to prevent the packing of fatty acid tails and thus lowers the requirement of unsaturated fatty acids. This helps maintain the fluid nature of the cell membrane without it becoming too liquid at body temperature.

The fluidity of the membrane is demonstrated in the animation below. You will want to click the green arrow when the animation pauses to see all three parts. Select the magnifying glass to enlarge image.

learn by doing
Click the green arrow to play the animation.

Membranes also contain proteins, which carry out many of the functions of the membrane. Some functions of membrane proteins are:

• Transport. Because the plasma membrane is only semipermeable, the cell needs a way to transport larger materials into and out of the cell.
• Communication. Because the plasma membrane is the border of the cell, this is where the cell communicates with its environment. Membrane proteins are able to receive signals from outside the cell and begin a chain of events that cause the cell to respond to these signals.
• Metabolism. Membrane proteins can be enzymes that are involved in the chemical reactions of metabolism. These are the processes that allow the cell to grow, obtain energy, and eliminate wastes.
• Adhesion. Membrane proteins help cells bind to each other and form tissues. One example of this is skin cells, which must form a tight surface if the skin is to maintain proper integrity. Membrane proteins also bind to molecules inside and outside the cell which help the cell maintain its structure.

Membrane proteins are classified into two major categories: integral proteins and peripheral proteins. Integral membrane proteins are those proteins that are embedded in the lipid bilayer and are generally characterized by their solubility in nonpolar, hydrophobic solvents. Transmembrane proteins are examples of integral proteins with hydrophobic regions that completely span the hydrophobic interior of the membrane. The parts of the protein exposed to the interior and exterior of the cell are hydrophilic. Integral proteins can serve as pores that selectively allow ions or nutrients and wastes into or out of the cell. They can also transmit signals across the membrane.

Unlike integral proteins that span the membrane, peripheral proteins reside on only one side of the membrane and are often attached to integral proteins. Some peripheral proteins serve as anchor points for the cytoskeleton or extracellular fibers. Proteins are much larger than lipids and move more slowly. Some move in a seemingly directed manner, while others drift. Some are glycoproteins which have a carbohydrate group attached to the protein. These are on the outside of the membrane and important for cell recognition, they work like a cellular identification card.

Test My System

learn by doing
did I get this

The extracellular surface of the cell membrane is decorated with carbohydrate groups attached to lipids and proteins. Carbohydrates are added to lipids and proteins by a process called glycosylation, and are called glycolipids or glycoproteins. These short carbohydrates, or oligosaccharides, are usually chains of 15 or fewer sugar molecules. Oligosaccharides give a cell identity (i.e., distinguishing "self" from "nonself") and are the distinguishing factor in human blood types and transplant rejection.

## Membranes are Asymmetric

As discussed above and seen in the picture, the cell membrane is asymmetric. The extracellular face of the membrane is in contact with the extracellular matrix. The extracellular side of the membrane contains oligosaccharides that distinguish the cell as "self." It also contains the end of integral proteins that interact with signals from other cells and sense the extracellular environment. The inner membrane is in contact with the contents of the cell. This side of the membrane anchors to the cytoskeleton and contains the end of integral proteins that relay signals received on the external side.

## Summary: Membranes as Mosaics of Structure and Function

The biological membrane is a collage of many different proteins embedded in the fluid matrix of the lipid bilayer. The lipid bilayer is the main fabric of the membrane, and its structure creates a semipermeable membrane. The hydrophobic core impedes the diffusion of hydrophilic structures such as ions and polar molecules, but allows hydrophobic molecules, which can dissolve in the membrane, to cross it with ease.

did I get this

Diffusion relies on kinetic energy and a concentration gradient. Kinetic energy is affected by temperature, size of molecules, steepness of the gradient, and the medium the molecules are in. Anything that increases the kinetic energy of the molecules will increase the rate of diffusion.

Diffusion is the movement of molecules from an area of high concentration to an area of lower concentration. There are different types of diffusion: simple in which the molecule passes directly through the phospholipid bilayer and facilitated which uses the integral membrane proteins as channels. Simple diffusion occurs when the molecules are either very small or lipid soluble and pass through the phospholipid bilayer of the cell membrane. Some examples of substances that use this process are oxygen (O2), carbon dioxide (CO2), and lipids.

The molecules will move from an area of high concentration down its diffusion (or concentration) gradient to the lower concentration until equilibrium is reached. Once the concentration is the same on both sides of the membrane, the molecules continue to move but they maintain the same levels at equilibrium.

Have you ever had the pleasant surprise of waking up to the smell of coffee or bacon? It’s the diffusion of the chemicals (odorants) moving from the higher concentration in your kitchen to you! In the human body the diffusion of O2 and CO2 are critical for gas exchange. O2 levels are higher in your arterial blood than your tissue cells so O2 will diffuse out of the blood into your cells. CO2 has the opposite concentration gradient. CO2 levels are highest in your cells (your mitochondria produce CO2 as a waste product from cellular respiration) and CO2 diffuses out of the cell into the blood. These molecules are small enough to pass through the phospholipid bilayer and are examples of simple diffusion. Remember that anything that increases kinetic energy will also increase the rate of diffusion.

The following animation depicts this simple diffusion process.

learn by doing

## Diffusion Across the Membrane

Molecules can be divided into four categories with regard to their ability to cross the plasma membrane. The first category is nonpolar molecules. These hydrophobic molecules can easily cross the membrane because they interact favorably with the nonpolar lipids. Note that these molecules can accumulate in the membrane because they interact so well with the lipids. The second category is small polar molecules. Although they don’t interact with the lipids, their small size allows them to pass through small temporary holes in the membrane. The third category is large polar molecules. These have difficulty crossing the membrane because of their size and poor interaction with the lipids. The last category is ionic compounds. Their charge interacts very unfavorably with the lipids, making it very difficult for them to cross the membrane.

learn by doing

As three different molecules move, they encounter the lipid bilayer depicted by the horizontal membrane across the center of the stage in the preceding animation. Notice that one type of molecule passes freely through the lipid bilayer while the second type of molecule only occasionally passes through the membrane, and the lipid bilayer is totally impermeable to the third type of molecule.

The size, polarity, and charge of a substance will determine whether or not the substance can cross the cell membrane by diffusion. The cholesterol was an example of a lipid, and is highly soluble in the nonpolar environment of the lipid bilayer. You saw, in the animation above, the cholesterol freely passing into the hydrophobic environment of the membrane. The cholesterol distributes freely in the membrane and then some fraction will dissolve in the aqueous environment of the cytoplasm. Water, on the other hand, while polar, is small and because of this is able to freely cross the membrane. The lipid bilayer is much less permeable to the ion, because of its charge and larger size. As a general rule, charged molecules are much less permeable to the lipid bilayer.

did I get this

Cells must be able to move large polar and charged molecules across the lipid bilayer of the membrane in order to carry out life processes. To allow these molecules, which are not soluble in the lipid bilayer, to pass across the hydrophobic barrier it is necessary to provide ports, channels or holes through the membrane. The molecules will still move spontaneously down a concentration gradient from high to low concentration. Some of these channels can remain open at all times, allowing the molecules to move freely according to the concentration gradient. Others can be gated channels that open and close in response to the needs of the cell. In most cases these channels are very discriminatory and will only allow specific molecules to pass. The process of moving impermeable molecules across a membrane (down their concentration gradients) using channels or pores is referred to as facilitated diffusion. Because the molecules are moving down a concentration gradient, the process is driven by simple diffusion and does not require the input of additional energy from the cell. The following simulation depicts the facilitated diffusion of glucose across the membrane using the glucose permease transporter.

did I get this

Cells continually encounter changes in their external environment. Most cells have a similar blend of solutes within them, but interstitial or extracellular fluid can vary. What will happen if there is a strong concentration gradient between a cell's interior and the fluid outside? As you know, molecules will tend to move down their concentration gradients until equilibrium is reached. You might think that solutes will flow into our out of the cell until the solute concentrations are equal across the membrane. However, not all molecules can pass through the cell membrane. The plasma membrane (lipid bilayer) is significantly less permeable to most solutes than it is to water. Therefore the WATER tends to flow in a way that establishes an equal concentration of solutes on either side of the membrane. The water flows down its own concentration gradient, with a net movement toward the region that has a higher concentration of solutes. This movement of water across a semipermeable membrane in response to an imbalance of solute is called osmosis.

The relationship between the solute concentration and amount of water is an inverse relationship. The more concentrated a solution is, the less water it contains. The fewer solutes, the more water – i.e. it is more dilute. Water follows gradients and moves from an area of more water to less water but in reality water is moved to the area with the greater number of solutes. This creates a pressure termed osmotic pressure. Cells cannot actively move water, it must follow osmotic gradients. Solutions that have a greater solute concentration will pull water via osmotic pressure. This depends on the total number of solutes, not the type. Note that some water can pass through the cell membrane but most water passes through protein membrane channels termed aquaporins

learn by doing
did I get this

Cells may find themselves in three different sorts of solutions. The terms isotonic, hypertonic, and hypotonic refer to the concentration of solutes outside the cell relative to the solute concentration inside the cell. In an isotonic solution, solutes and water are equally concentrated within and outside the cell. 0.9% NaCl (physiologic saline) and 5% dextrose are two common isotonic solutions used.The cell is bathed in a solution with a solute concentration that is similar to its own cytoplasm. Many medical preparations (saline solutions for nasal sprays, eye drops, and intravenous drugs) are designed to be isotonic to our cells. A hypotonic solution has a low solute concentration and a high concentration of water compared to the cell's cytoplasm. Distilled (pure) water is the ultimate hypotonic solution. If a cell is placed in a hypotonic solution, it will tend to gain water. The solutes will "stay put" within the cell, but water molecules will diffuse such that their net flow is toward the area with a higher concentration of solutes. A hypertonic solution has a high solute concentration (lower water concentration) compared to the cell cytoplasm. Very salty or sugary solutions (brines or syrups) are hypertonic to living cells. If a cell is placed in such a solution, water tends to flow spontaneously out of the cell.

learn by doing
did I get this

Filtration is another passive process of moving material through a cell membrane. While diffusion and osmosis rely on concentration gradients, filtration uses a pressure gradient. Molecules will move from an area of higher pressure to an area of lower pressure. Filtration is non-specific. This means that it doesn’t sort the molecules, they pass due to pressure gradients and their size. If molecules are small enough to pass through the membrane, they will. The force that pushes the molecules is termed hydrostatic pressure.

Example

One example of filtration is making coffee. Think of the coffee filter as the cell membrane and the coffee grounds, flavor and caffeine as the molecules. The pressure is exerted by the water from the machine. It forces materials through the coffee filter into the coffee pot. Small molecules like caffeine, water, and flavor pass through the filter but the coffee grounds do not. They are too big. If you poked holes in the filter, the coffee grounds would end up in your coffee! The coffee filter represents the filtration membrane which is typically a layer of cells.

Filtration is one of the main methods used for capillary exchange. Blood pressure provides the driving force or hydrostatic pressure to force materials out of capillaries to cells or to form the filtrate (fluid in the nephron of the kidney). Hydrostatic pressure is countered by osmotic pressure. Remember osmotic pressure is created due to increased solute concentration and will pull water toward the area of higher solutes. These two pressures must be in balance for homeostasis of fluid volumes. In our body large molecules such as plasma proteins and red blood cells should not pass out of the blood through the cell membranes lining the capillaries. If they pass through and end up in in the tissues or in the kidney and later the urine it is abnormal and a sign of disease.

learn by doing
did I get this

You have just finished investigating the passive methods of transport, now let’s look at active methods. In active methods the cell must expend energy (ATP) to do the work of moving molecules. Active transport often occurs when the molecule is being moved against its concentration gradient or when moving very large molecules into our out of the cell. There are 3 main types of active processes.

1. Primary Active Transport or Solute Pumps
2. Endocytosis and Exocytosis

## Primary Active Transport or Solute Pumps

One form of active transport involves moving ions from an area of low concentration to an area of higher concentration. If you need to roll a rock it’s much easier to roll it downhill rather than uphill right? Active transport is moving the rock uphill and requires energy to do so. The best example of this involves the sodium (Na+)/potassium (K+) exchange pump. The interior of a cell contains a low Na+ concentration compared to the extracellular fluid. The interior of the cell (intracellular fluid or ICF) contains more K+ than the extracellular fluid (ECF). This creates an imbalance in these ions. Na+ has a concentration gradient to enter the cell since there is more Na+ in the ECF. K+ has a concentration gradient for it to leave the cell. The cell membrane is not impermeable to these ions and some of them escape following their concentration or diffusion gradients. You will later study why it is important to maintain these ion concentrations. The Na+/K+ pump is an active transport pump that moves Na+ “uphill” back out of the cell against it’s concentration gradient and at the same time moves K+ back into the cell against it’s concentration gradient. This pump requires ATP, a membrane protein transporter, and enzymes to function.

learn by doing

Another form of active transport is termed secondary active transport. While primary active transport directly uses ATP, secondary active transport relies on the energy from electrochemical gradients to move molecules against their gradients. Primary active transport sets this up because it actively pumps ions such as Na+ out of the cell thereby creating an electrochemical gradient for Na+ across the cell membrane. Protein transporters in the cell membrane use the energy from electrochemical gradients to transport molecules. If the molecules move in the same direction this is known as cotransport or symport. If they are moved in opposite directions this is known as countertransport or antiport. One common occurrence in the human body is the Na+/glucose transport protein known as SGLT1 which cotransports 1 glucose and 2 sodium ions into a cell. The electrochemical gradient for Na+ into the cell allows glucose to ride with it. When glucose moves into a cell, it rides the energy from the “coat tails of sodium ions”.

Facilitated diffusion and active transport are not the only ways that materials can enter or leave cells. Through the processes of endocytosis and exocytosis, materials can be taken up or ejected in bulk, without passing through the cell's plasma membrane.

In endocytosis, material is engulfed within an infolding of the plasma membrane and then brought into the cell within a cytoplasmic vesicle. To begin endocytosis, a particle encounters the cell surface and produces a dimple or pit in the membrane. The pit deepens, invaginates further, and finally pinches off to form a vesicle in the cytoplasm of the cell. Note that during the process the inside surface of the newly formed vesicle is the same as the exterior surface of the cell. Thus the integrity of the cytoplasm and the orientation of the plasma membrane are preserved. Once internalized, this new vesicle containing extracellular materials may fuse with a lysosome so that its solid contents are digested. The resulting molecules may be released to the cytoplasm for use within the cell.

There are two general forms of endocytosis: phagocytosis and pinocytosis. Phagocytosis is the uptake of large solid particles such as bacteria or cellular debris. Pinocytosis is the uptake of fluid and any small molecules dissolved within it. Cells are also capable of recognizing specific particles and engulfing them in a more targeted way, a process called receptor-mediated endocytosis. In this case, the particle first binds to a membrane protein receptor on the surface of the cell. Binding of the target particle induces the cell to engulf it.

Exocytosis is just the reverse of endocytosis. In exocytosis, an internal vesicle fuses with the plasma membrane and releases its contents to the outside. The balance of exocytosis and endocytosis preserves the size of the plasma membrane and keeps the cell's size constant. The following animation depicts endocytosis.

You can use the magnifier in the lower righ-hand corner to zoom the animation

How are endocytosis and exocytosis important to everyday life? Immune cells protect animals by recognizing and destroying foreign objects such as bacteria. Disease-causing bacteria are recognized by proteins called receptors on the surface of the immune cell. The phagocytic immune cell will then engulf the bacterial cells (phagocytosis). The vesicle that contains these bacterial cells is called a phagosome ("phago" means "eating" and "-some" refers to "body"). The phagosome next fuses with lysosomes. Finally, the digested bacterial products are excreted through the process of exocytosis.

##### Phagocytosis of a Bacterium
did I get this

Even though we may not feel any changes from day to day, we are constantly repairing and replacing cells within our bodies. It’s estimated that approximately 300 million cells die every minute in our body! These cells must be replaced by identical functional cells for us to survive and maintain homeostasis. The process of cell proliferation or cell division is termed mitosis. Mitosis produces two daughter cells that are identical (clones) to the parent cell.

Cell division is a carefully regulated process. There are “check-points” between phases, in which the cell “self-checks.” Through molecular interactions, the cell makes sure that it is ready to divide; for example, it checks to see that its DNA has not been damaged. If all criteria are met, the cell moves forward through the cell cycle. Normal cells usually divide only a limited number of times, and usually do so when stimulated by certain molecular signals. For example, if you move to higher altitude, your body will produce more red blood cells in order to supply enough oxygen despite the thinner air.

Mitosis is also regulated by genes. Some genes become active to stimulate mitosis and other genes act as the brakes to turn it off (suppressor genes). If our body loses control over mitosis the result would be the production of too many (hyperplasia) abnormal cells and would form a tumor. If the tumor is encapsulated it is termed benign. If not, the mutated cells can spread and it is known as cancer. Cancer cells, on the other hand, have lost the normal cell cycle controls, and therefore can divide indefinitely.

When a cell is performing its normal day-to-day functions it is in a state termed interphase. When it is time for that cell to replicate, genes become active and stimulate it to begin mitosis. Mitosis is characterized by four phases. Remember if a cell is going to form 2 new identical cells it must first replicate it’s DNA and organelles. It is during interphase that the DNA is replicated to form 2 identical strands. These strands of identical DNA are termed chromatids and are held together with a centromere.

The stages of mitosis occur in sequence with specific events in each one. It is only during mitosis that chromosomes are visible. Usually DNA is in its threadlike chromatin form. You can identify the stages of mitosis by observing the chromosomes. Remember that the DNA is in the nucleus which is surrounded by the nuclear membrane. The DNA needs to be free from the nucleus so it can be evenly distributed to two daughter cells. The events of mitosis describe the processes of splitting and moving nuclear DNA to opposite ends of the parent cell where the nuclear membranes will reform. Then the cell membrane can split the cytoplasm and organelles (termed cytokinesis). The two daughter cells will each have the same genetic code. When you studied the cell you learned about the microtubules of the centrioles. They are the organelles that will move the DNA during mitosis.

The major stages of mitosis are:

1. Prophase
2. Metaphase
3. Anaphase
4. Telophase

## Prophase

Mitosis begins when DNA condenses into chromosomes visible under a light microscope. This packaging of the chromosomes into condensed bundles makes them easier to sort, but it inhibits protein synthesis. Therefore, it is essential that the cell has produced all necessary proteins prior to the start of this process.

The nucleoli disappear and the nuclear envelope begins to disintegrate. This allows cellular components to act upon the chromosomes (the chromosomes are no longer tucked away inside the nucleus).

Centrioles, contained in the centrosomes formed during interphase, are areas where microtubules originate in order to help sort and organize the sister chromatids. The centrioles begin to move to the opposite poles of the cell. This will determine where the chromosomes go when they are sorted.

Microtubules are disassembled from the cytoplasm and reassembled into the mitotic spindle. This structure will move the chromosomes to the proper location.

This stage is called “prophase,” because it is a preparatory stage. “Pro-” means "before;" “phase” means “stage.” So, this is the stage before the process gets into full swing.

did I get this

## Prometaphase

Prometaphase is the stage between prophase and metaphase. During this stage, the nuclear envelope is fully broken down. This allows the microtubules to attach to the centromeres of the chromosomes.

The centromere is the region in the center of the X-shaped chromosomes. Each half of the X is a copy of the same DNA strand. The centromere contains proteins that hold together these two copies and can bind to the microtubules. The proteins on the centromere are called the kinetochore, and the microtubules that attach to them are called kinetochore microtubules. The microtubules that are not attached to the kinetochores are called nonkinetochore microtubules.

learn by doing

## Metaphase

Metaphase is so named because the chromosomes line up in the middle of the cell. The root “meta-” means “middle.”

The kinetochore microtubules are used to orient the chromosomes in the center of the cell. Each chromosome will be attached to two kinetochore microtubules. Each of these kinetochore microtubules will be attached to one of the two centrioles.

learn by doing

## Anaphase

During anaphase, the kinetochore proteins break down the microtubules attached to them and the connections between each copy of the chromosome will be broken down. This causes the individual chromosomes to move to opposite poles of the cell. The root “ana-” refers to “apart”; the chromosomes are moving apart from each other.

The nonkinetochore microtubules from one pole also push on the nonkinetochore microtubules from the other pole. This causes the cell to elongate. By the end of anaphase, each pole of the cell contains an identical set of chromosomes.

did I get this

## Telophase

In telophase, the nuclei at each pole form again. The chromosomes are now separated into two identical nuclei. This is the end of mitosis.

However, the two nuclei are still in a single cell. The next step will separate the cytoplasm into two cells. “Telo” comes from the Greek word for “end.”

did I get this

## Cytokinesis

Cytokinesis is the separation of the cytoplasm into two new daughter cells. Animal cells divide when proteins pinch in the center of the cell until it separates into two. This region is called the cleavage furrow.

Plant cells divide when new cell wall components are laid down in the center of the cell. This is called the cell plate.

learn by doing

## Apoptosis

How does a single fertilized cell develop into something as marvelous and intricate as the human body? Part of the answer is apoptosis, or programmed cell death. For example, the early hand of an embryo is a stubby appendage. As cells between the fingers selectively die off, they sculpt the hand, leaving behind the separate fingers. In adults, apoptosis is one way that tissues maintain their integrity. Cells selectively die off to allow renewal of tissues such as the stomach, lungs, liver and so on. If apoptosis ceases in the tissue’s cells, a tumor can form, perhaps becoming cancerous. Apoptosis is distinguished from necrosis, which is cell death as a result of injury. Much like proliferation, there is a series of tightly regulated events that lead to apoptosis. Apoptosis is a cellular program that is internally determined, and billions of cells die this way every day. However, external trauma, toxins or infection cause a different type of cell death called necrosis. Even though both mechanisms lead to dead cells, apoptosis is a program to maintain cell number whereas necrosis is a consequence of intense cell damage.

In the body's organizational hierarchy, tissues occupy a place between cells and organs. That is, a tissue is a group of cells with a similar shape and function. In turn, organs (which make up the body) are comprised of various tissues.

The component cells of a tissue are a specific cell type. A tissue’s cells may be identical, but are not necessarily so. Several tissues will comprise an organ. For example, the contractile cells of skeletal muscle are bundled together to make muscle fiber tissue. In turn, endomysium cells form enclosing tissue that wraps around bundles of muscle fibers, like a tortilla around the filling of a burrito. Several of these structures are in turn wrapped by another tissue, perimysium. Finally, bundles of these are surrounded by a sheath of yet another tissue, epimysium, which covers the outside of the whole muscle. Yet more tissue is necessary for the muscle to function in the body. Connective tissue comprising ligaments attaches the muscle to the skeleton, and nerve tissue conducts impulses from the nervous system to signal the muscle to contract.

Skeletal muscle is only one kind of tissue. The body is made of dozens of different tissues, but broadly speaking there are four types of tissues.

• Muscle tissue (in turn divided into skeletal, smooth and cardiac) is contractile. It allows locomotion of the body. It also allows necessary contractions of various organs such as the heart and of respiratory and digestive systems.
• Nerve tissue comprises the body’s wiring system. It conducts signals between the nervous system and various organs.
• Connective tissue holds the body together. It is found in most organs, anchoring them to the skeleton and other organs. Types of connective tissue include fibrous tissue, fatty tissue, loose tissue and cartilage. Connective tissue also includes bone, blood and lymph.
• Epithelial tissue is the body’s protection against the outside environment. Skin tissue helps to maintain homeostasis. It helps monitor and control temperature, and resists abrasion, foreign bodies and damaging chemicals. Internally, epithelial tissue lines most internal cavities, secreting or absorbing nutrients.

Tissues form during development. Stem cells in the embryo differentiate into various cell types. The necessary genes in the cells turn on or off, resulting in the production of proteins that characterize a cell’s structure and function. Early in embryonic growth, the cells migrate to the appropriate location in the body. Once there, they proliferate so that the tissue can perform its needed function.

Different tissues arise from the source cells in each of the three primary germ cell layers. For example, the epithelium is derived from the ectoderm and endoderm. Connective tissue arises largely from the mesoderm. Gastrointestinal and respiratory tissues arise mostly from the endoderm. Programmed cell death, or apoptosis, may take place to eliminate transitory tissues in the embryo, such as the pronephros, a simple excretory organ that is later replaced by the kidney.

learn by doing
did I get this

The organ level of organization in the body may be the most familiar to us from our everyday experiences. Many of the common ailments we hear about—an upset stomach, a broken bone, lung disease, skin cancer—are named for the organs they affect.

An organ is made up of tissues that work together to perform a specific function for the body as a whole. Groups of organs that perform related functions are organized into organ systems, which perform more general functions. The table below describes the structures and functions of some common organs.

Organ Primary function(s) Tissues it contains Organ system(s) it is a part of
brain control of body systems and behavior; cognition nervous, connective, epithelial nervous system; endocrine system
skin protection; support and containment; temperature and fluid regulation epithelial, nervous, connective, muscular integumentary system
stomach chemical and mechanical digestion of food epithelial, connective, muscular, nervous digestive system
sternum (breastbone) support; protection; blood cell production epithelial, connective, nervous skeletal system; immune system; cardiovascular system
kidney waste removal; fluid regulation epithelial, connective, nervous urinary system

Organ systems are made up of organs that work together to perform a specific function for the body as a whole. The table below describes the organ systems and their primary organs and physiological functions.

Organ system Key organ(s) Primary function(s)
integumentary skin support; protection; regulation of fluid levels and temperature
skeletal bones, cartilage support; protection; movement; blood cell production
muscular muscles, tendons support; movement
urinary kidneys, bladder, urethra waste removal; regulation of fluid levels
digestive tongue, esophagus, stomach, small intestine, large intestine, gallbladder, rectum digestion of food; waste removal
respiratory trachea, lungs gas exchange; regulation of temperature
cardiovascular heart, blood vessels transport of materials through the body; regulation of temperature
nervous brain, spinal cord control of behavior and body systems; cognition
endocrine glands control of body systems and development
immune thymus, tonsils, spleen defense against infection
lymphatic lymph nodes, lymphatic vessels immunity; regulating fluid balance
reproductive penis, testes, prostate (males); uterus, ovaries, vagina (females) reproduction

## The Whole Body

The organ systems of the body all work together to maintain proper physiological functions. Many times in the arena of anatomy and physiology, including in this course, we closely examine the molecules, cells, tissues and organs of the body to learn their forms and functions. However, it is important to consider that every molecule works as part of the entire system. Endocrine disorders such as diabetes affect glucose levels in the body. Altered blood glucose levels can affect many organ systems. For example, the immune system may not heal as well, the urinary system may experience kidney damage, and the cardiovascular system can experience vascular damage, even to the point of causing blindness. In the body, everything is interconnected.

## Populations

Beyond the body, populations and environment can impact physiology and health. Some diseases and disorders are common to certain populations, most likely because of genetic connections. Also, environmental conditions can impact health. Particulates in the air can impact respiratory function. We are also affected by foods, exercise, sun exposure and other environmental conditions.

Homeostasis relates to dynamic physiological processes that help us maintain a stable internal environment. Homeostasis is not the same as equilibrium. Equilibrium occurs when everything is equal: add milk to the coffee and eventually, when equilibrium is achieved, all of the coffee will be the same color. Homeostasis, however, is the mechanism by which internal variables are kept at or near values appropriate to the system.

Consider that when the temperature drops, the body does not just "equilibrate" with (become the same as) the environment. Multiple systems work together to help maintain the body’s temperature: we shiver, blood flow is altered, and our brain says “get out of the cold.”

Many conditions and diseases result from altered homeostasis. This section will review the terminology, and explain the physiological mechanisms, that are associated with homeostasis. We will discuss homeostasis in every subsequent system. Many aspects of the body are in a constant state of change—blood flows, that rate at which substances are exchanged between cells and the environment, and the rate at which cells are growing, dividing, and dying are all examples. But these changes actually contribute to keeping many of the body's variables, and thus the body's overall internal conditions, within relatively narrow ranges. For example, blood flow will increase to a tissue when it becomes more active. This is done to ensure that the tissue will have enough oxygen to support its higher level of metabolism. Maintaining internal conditions in the body is called homeostasis (from homeo-, meaning similar, and stasis, meaning standing still). The root "stasis" of the term "homeostasis" may seem to imply that nothing is happening. But if you think about anatomy and physiology, even standing still requires a lot of effort. Stabilizing muscles hold you upright, and your brain incorporates information from your tendons, inner ear and eyes to maintain balance. If you think that it’s easy to stand still, look at a baby who is just learning to stand. Similarly, the process of homeostasis is an active process to maintain the ‘same-ness’ of our body processes.

homeostasis
(Definition)
Homeostasis is the tendency of biological systems to maintain relatively constant conditions in the internal environment while continuously interacting with and adjusting to changes originating within or outside the system.
Example
##### Exercise

We can consider the maintenance of homeostasis on a number of different levels. For example, consider what happens when you exercise. At the whole-body level, you notice some specific changes: your breathing and heart rate increase, your skin may flush, and you may sweat. If you continue to exercise, you may feel thirsty. These effects are all the result of your body trying to maintain its internal balance:

• Your muscle cells use oxygen to convert the energy stored in glucose into the energy stored in ATP (adenosine triphosphate), which they then use to drive muscle contractions. When you exercise, your muscles need more oxygen. Therefore, to maintain an adequate oxygen level in all of the tissues in your body, you breathe more deeply and at a higher rate when you exercise. This allows you to take in more oxygen. Your heart also pumps faster and harder, which allows it to bring more oxygenated blood to your muscles and other organs that will need more oxygen.
• As your muscles carry out cellular respiration to release the energy from glucose, they produce carbon dioxide and water as waste products. These wastes must be eliminated to help your body maintain its fluid and pH balance. Your increased breathing and heart rates also help eliminate a great deal of carbon dioxide and some of the excess water.
• Your muscles use the energy stored in ATP molecules to generate the force they need to contract. A byproduct of releasing that energy is heat, so exercising increases your body temperature. To maintain temperature balance, your body compensates for the extra heat by causing blood vessels near your skin to dilate and by causing sweat glands in your skin to release sweat. These actions allow heat to more easily dissipate into the air through evaporation of the water in sweat into the air.
• As you exercise for longer periods of time, you lose more and more water and salts to sweat (and, to a smaller extent, from breathing more). If you exercise too long, your body may lose enough water and salt that its other functions begin to be affected. Low concentrations of water in the blood prompt the release of hormones that make you feel thirsty. Your kidneys also remove less water from urine if your fluid levels are low. These actions help you maintain fluid balance.

The maintenance of homeostasis in the body requires feedback loops that control the body's internal conditions. We use the following terminology to describe feedback loops:

• Variables are parameters that are controlled or affected by the feedback system.
• Receptors detect changes in the variable.
• Control centers (integrators) compare the variable in relation to a set point and signal the effector to generate a corrective response.
• Effectors execute the necessary changes to adjust the variable.

## Air Conditioning

Air conditioning is a technological system that uses feedback. The thermostat senses the temperature, an electronic interface compares the temperature against a set point (the temperature that you want it to be). If the temperature matches or is cooler, then nothing happens. If the temperature is too hot, then the electronic interface triggers the air-conditioning unit to turn on. Once the temperature is lowered sufficiently to reach the set point, the electronic interface shuts the air-conditioning unit off. For this example, identify the steps of the feedback loop.

learn by doing

## Cruise Control

Cruise control is another technological feedback system. The idea of cruise control is to maintain a constant speed in your car. The car's speed is determined by the speedometer and an electronic interface measures the car's speed against a set point chosen by the driver. If the speed is too slow, the interface stimulates the engine; if the speed is too fast, the interface reduces the power to the tires.

Example
##### Terms applied to temperature

Consider one of the feedback loops that controls body temperature.

• Variable

In this instance, the variable is body temperature.

• Receptors

Thermoreceptors detect changes in body temperature. For example, thermoreceptors in your internal organs can detect a lowered body temperature and produce nerve impulses that travel to the control center, the hypothalamus.

• Control Center

The hypothalamus controls a variety of effectors that respond to a decrease in body temperature.

• Effectors

There are several effectors controlled by the hypothalamus.

• blood vessels near the skin constrict, reducing blood flow (and the resultant heat loss) to the skin.
• Skeletal muscles are also effectors in this feedback loop: they contract rapidly in response to a decrease in body temperature. This shivering helps to generate heat, which increases body temperature.
did I get this

Remember that homeostasis is the maintenance of a relatively stable internal environment. When a stimulus, or change in the environment, is present, feedback loops respond to keep systems functioning near a set point, or ideal level.

feedback
(Definition)
Feedback is a situation when the output or response of a loop impacts or influences the input or stimulus.

Typically, we divide feedback loops into two main types:

• positive feedback loops, in which a change in a given direction causes additional change in the same direction.
• For example, an increase in the concentration of a substance causes feedback that produces continued increases in concentration.
• negative feedback loops, in which a change in a given direction causes change in the opposite direction.
• For example, an increase in the concentration of a substance causes feedback that ultimately causes the concentration of the substance to decrease.

Positive feedback loops are inherently unstable systems. Because a change in an input causes responses that produce continued changes in the same direction, positive feedback loops can lead to runaway conditions. Some positive feedback loops can be harmful. However, there are a few instances in which positive feedback helps to maintain homeostasis. One such example is blood clotting. When a blood vessel is broken, a clot begins to form and clotting factors are activated at the site. The activation of clotting factors continues into a chain reaction until bleeding within the vessel stops. In this instance, the set point is the point at which no blood leaves the site. The release of clotting factors stimulates further release of clotting factors, until the blood is so heavily clotted that no blood leaves the vessels. Some positive feedback loops are part of normal physiology. Some endocrine and reproductive functions, particularly in women, are part of positive feedback loops.

Negative feedback loops are inherently stable systems. Negative feedback loops typically produce conditions that oscillate around the set point. For example, negative feedback loops involving insulin and glucagon help to keep blood glucose levels within a narrow range of concentrations. If glucose levels get too high, the body releases insulin into the bloodstream. Insulin causes the body's cells to take in and store glucose, lowering the blood glucose concentration. If blood glucose gets too low, the body releases glucagon, which causes the release of glucose from the body's cells.

did I get this

In a positive feedback mechanism, the output of the system stimulates the system in such a way as to further increase the output. Common terms that could describe positive feedback loops include "snowballing" and "chain reaction". Without a counter-balancing or "shut-down" reaction or process, a positive feedback mechanism has the potential to produce a runaway process. Some physiological processes mediated by positive feedback help maintain homeostasis. In these cases, the positive feedback loop always ends with counter-signaling that suppresses the original stimulus.

Example
##### Blood clotting

Because of its ability to generate an amplifying process, beneficial positive feedback is often seen where a rapid response is needed. For example, blood clotting (or coagulation) starts with a wound that causes release of blood from damaged blood vessels. When the lining of the blood vessels (endothelium) is ruptured, proteins in the lining are exposed to collagen and other clotting factors. Platelets (small cell fragments) in the blood stick to the edges of the blood vessels and form an initial clot to plug the wound.

After they stick to the damaged blood vessels, the platelets release granules. The granules contain additional stimulatory molecules including serotonin, adenosine diphosphate (ADP), and thromboxane. The ADP attracts other platelets to the wound site. When they arrive, the thromboxane prompts them to aggregate and to release more granules in turn. The ADP and thromboxane thus promote the release of more ADP and more thromboxane in a positive feedback cascade. The result is a platelet plug that closes the wound.

Following this first line of defense, multiple proteins called clotting factors act together in a coagulation cascade to form a secondary clot. Once the bleeding stops, the stimuli promoting clotting processes are no longer present, so the cascading processes cease.

Example
##### Lactation

Another example of positive feedback occurs in lactation, during which a mother produces milk for her infant. During pregnancy, levels of the hormone prolactin increase. Prolactin normally stimulates milk production, but during pregnancy, progesterone inhibits milk production. At birth, when the placenta is released from the uterus, progesterone levels drop. As a result, milk production surges. As the baby feeds, its suckling stimulates the breast, promoting further release of prolactin, resulting in yet more milk production. This positive feedback ensures the baby has sufficient milk during feeding. When the baby is weaned and no longer nurses from the mother, stimulation ceases and prolactin in the mother’s blood reverts to pre-breastfeeding levels.

learn by doing
did I get this
Example
##### Heart failure

The above provide examples of beneficial positive feedback mechanisms. However, in many instances, positive feedback can be potentially damaging to life processes. For example, a myocardial infarction (heart attack) begins when a small portion of heart tissue dies off (usually due to inadequate blood supply). The loss of tissue then results in too little blood being pumped to the body tissues and cardiac muscle tissue, so the heart must work harder and more heart tissue can become damaged and decrease heart function further.

Most biological feedback systems are negative feedback systems. Negative feedback occurs when a system's output acts to reduce or dampen the processes that lead to the output of that system, resulting in less output. In general, negative feedback loops allow systems to self-stabilize.

Example
##### Insulin

An important example is the control of blood sugar levels following a meal.

1. After a meal, the small intestine absorbs glucose from digested food. Blood glucose levels rise.
2. Increased blood glucose levels stimulate beta cells in the pancreas to produce insulin.
3. Insulin triggers liver, muscle, and fat tissue cells to absorb glucose, where it is stored. As glucose is absorbed, blood glucose levels fall.
4. Once glucose levels drop below a threshold, there is no longer a sufficient stimulus for insulin release, and the beta cells stop releasing insulin.

Due to synchronization of insulin release among the beta cells, basal insulin concentration oscillates in the blood following a meal. The oscillations are clinically important, since they are believed to help maintain sensitivity of insulin receptors in target cells. This loss of sensitivity is the basis for insulin resistance. Thus, failure of the negative feedback mechanism can result in high blood glucose levels, which have a variety of negative health effects.

Example
##### Temperature

Negative feedback is a vital control mechanism for the body’s homeostasis. One important example of how a negative feedback loop maintains homeostasis is the body’s thermoregulation mechanism. The body maintains a relatively constant internal temperature to optimize chemical processes. The hypothalamus, located in the brain, monitors body temperature. Neural impulses from heat-sensitive thermoreceptors in the skin signal the hypothalamus. As skin temperature rises, the hypothalamus initiates release of water (sweat) from sweat glands. Evaporation cools the skin until its temperature returns to normal. Once its temperature returns to normal, the thermoreceptors in the skin cease to signal the hypothalamus, and sweating stops. Likewise, when body temperature drops, the hypothalamus initiates several physiological responses to increase heat production and conserve heat:

• Narrowing of surface blood vessels (vasoconstriction) decreases the flow of heat to the skin.
• Shivering commences, increasing production of heat by the muscles.
• Adrenal glands secrete stimulatory hormones such as norepinephrine and epinephrine to increase metabolic rates and hence heat production.

These effects cause body temperature to increase. When it returns to normal, the hypothalamus is no longer stimulated, and these effects cease.

Example
##### Blood Pressure Homeostasis

Many homeostatic mechanisms, like temperature, have different responses if the variable is above or below the set point. When temperature increases, we sweat, when it decreases, we shiver. These responses use different effectors to adjust the variable. In other cases, a feedback loop will use the same effector to adjust the variable back toward the set point, whether the initial change of the variable was either above or below the set point. For example, pupillary diameter is adjusted to make sure an appropriate amount of light is entering the eye. If the amount of light is too low, the pupil dilates, if it is too high, the pupil constricts.

This might be compared to driving. If your speed is above the set point (the value you want it to be), you can either just decrease the level of the accelerator (i.e. coast), or you can active a second system -- the brake. In both cases you slow, but it can be done by either just "backing" off on one system, or adding a second system.

Let’s look at how these two examples work related to normal blood pressure homeostasis.

learn by doing

Let's take a closer look at diabetes. In particular, we will discuss diabetes type 1 and type 2. Diabetes can be caused by too little insulin, resistance to insulin, or both.

Diabetes Type 1 is usually diagnosed in childhood. However, many patients are diagnosed when they are older than age 20. In this disease, the body makes little or no insulin. Daily injections of insulin are needed. The exact cause is unknown. Genetics, viruses, and autoimmune problems may play a role.

Also affected are those who lose their pancreas. Once the pancreas has been removed (because of cancer, for example), diabetes type 1 is always present.

Diabetes Type 2 is far more common than type 1. It makes up most of diabetes cases. It usually occurs in adulthood, but young people are increasingly being diagnosed with this disease. The pancreas does not make enough insulin to keep blood glucose levels normal, often because the body does not respond well to insulin. Many people with type 2 diabetes do not know they have it, although it is a serious condition. Type 2 diabetes is becoming more common due to increasing obesity and failure to exercise.

did I get this

You have read about general and specific examples of homeostasis, including positive and negative feedback loops, and have learned the terminology that is used to describe parts of the feedback loops. It is important to become comfortable with the terminology, since it will be used to introduce new concepts in upcoming sections of this course.

Maintaining homeostasis within the body is important for proper physiological function, growth and remodeling. It is important to recognize the mechanisms of homeostasis in the body, as well as the consequences of homeostasis dysfunction.

In the following examples, you will learn to identify homeostasis at different levels of organization, such as how the body maintains tight control over small molecules, and the importance of maintaining cell number with regard to tissue homeostasis.

Body functions such as regulation of the heartbeat, contraction of muscles, activation of enzymes, and cellular communication require tightly regulated calcium levels. Normally, we get a lot of calcium from our diet. The small intestine absorbs calcium from digested food.

The endocrine system is the control center for regulating blood calcium homeostasis. The parathyroid and thyroid glands contain receptors that respond to levels of calcium in the blood. In this feedback system, blood calcium level is the variable, because it changes in response to the environment. Changes in blood calcium level have the following effects:

• When blood calcium is low, the parathyroid gland secretes parathyroid hormone . This hormone causes effector organs (the kidneys and bones) to respond to increase calcium levels. The kidneys prevent calcium from being excreted in the urine. Osteoclasts in bones reabsorb bone tissue and release calcium.
• When blood calcium levels are high, the thyroid gland releases calcitonin .Calcitonin causes the kidneys to reabsorb less calcium from the filtrate, allowing excess calcium to be removed from the body in urine. Calcitonin also suppresses the formation of active vitamin D in the kidneys; without vitamin D the small intestines don't absorb as much dietary calcium. Osteoblasts, stimulated by calcitonin, use calcium in the blood to add to bone tissue.
learn by doing

Calcium imbalance in the blood can lead to disease or even death. Hypocalcemia refers to low blood calcium levels. Signs of hypocalcemia include muscle spasms and heart malfunctions. Hypercalcemia occurs when blood calcium levels are higher than normal. Hypercalcemia can also cause heart malfunction as well as muscle weakness and kidney stones.

did I get this

Glucose is an important energy source used by most cells in the body, especially muscles. Without glucose, the body "starves," but if there is too much glucose, problems occur in the kidneys, eyes, and even with the immune response. Insulin, a hormone produced by the pancreas in response to increased blood glucose levels. When the pancreas releases insulin, it acts as a key to open glucose passageways to enter cells. Glucose enters the cells where it is used for energy production. Excess glucose is used to synthesize glycogen for storage. The pancreas also produces the hormone glucagon. Glucagon is released with blood glucose levels decrease and breaks down glycogen back to glucose which is released into the blood to bring blood glucose levels back up.

learn by doing
did I get this

Tissues have an optimal number of cells for function. Cells are able to interact with their neighbors using cell-to-cell connections or cell-to-cell signaling to maintain homeostasis of cell number. Normally cells will stop dividing when there is an appropriate number of cells in a tissue or space. If a neighboring cell is lost or if there is an inadequate number of cells, cells may be stimulated to divide. Cells with too many neighbors trigger an internal response to die in a regulated programmed way called apoptosis. When cells sense they have no neighbors, signals in the nucleus cause division of the cell.

learn by doing
learn by doing

Each organ system performs specific functions for the body, and each organ system is typically studied independently. However, the organ systems also work together to help the body maintain homeostasis.

Example
##### Water Levels

For example, the cardiovascular, urinary, and lymphatic systems all help the body control water balance. The cardiovascular and lymphatic systems transport fluids throughout the body and help sense both solute and water levels and regulate pressure. If the water level gets too high, the urinary system produces more dilute urine (urine with a higher water content) to help eliminate the excess water. If the water level gets too low, more concentrated urine is produced so that water is conserved.

Example
##### Internal Temperatures

Similarly, the cardiovascular, integumentary, respiratory, and muscular systems work together to help the body maintain a stable internal temperature. If body temperature rises, blood vessels in the skin dilate, allowing more blood to flow near the skin's surface. This allows heat to dissipate through the skin and into the surrounding air. The skin may also produce sweat if the body gets too hot; when the sweat evaporates, it helps to cool the body. Rapid breathing can also help the body eliminate excess heat. Together, these responses to increased body temperature explain why you sweat, pant, and become red in the face when you exercise hard. (Heavy breathing during exercise is also one way the body gets more oxygen to your muscles, and gets rid of the extra carbon dioxide produced by the muscles.)

Conversely, if your body is too cold, blood vessels in the skin contract, and blood flow to the extremities (arms and legs) slows. Muscles contract and relax rapidly, which generates heat to keep you warm. The hair on your skin rises, trapping more air, which is a good insulator, near your skin. These responses to decreased body temperature explain why you shiver, get "goose bumps," and have cold, pale extremities when you are cold.

learn by doing
did I get this

As you have learned, proper calcium levels are important to maintain whole body homeostasis. Calcium ions are used for the heartbeat, the contraction of muscles, the activation of enzymes, and cellular communication. The parathyroid and thyroid glands of the endocrine system detect changes in blood calcium levels. When the parathyroid glands detect low blood calcium levels, several organ systems alter their function to restore blood calcium levels back to normal. The skeletal, urinary, and digestive systems all act as effectors to achieve this goal through negative feedback.

The release of parathyroid hormone from the endocrine system triggers osteoclasts of the skeletal system to resorb bone and release calcium into the blood. Similarly, this hormone causes the kidneys of the urinary system to reabsorb calcium and return it to the blood instead of excreting calcium into the urine. Through altered function of the kidneys to form active vitamin D, the small intestine of the digestive system increases the absorption of calcium.

When the thyroid gland detects elevated blood calcium levels, the skeletal, urinary, and digestive systems contribute to lower blood calcium levels back to normal. Release of the hormone calcitonin from the thyroid gland of the endocrine system triggers a series of responses. The osteoblasts of the skeletal system use excess calcium in the blood to deposit new bone. The kidneys of the urinary system excrete excess calcium into the urine instead of reclaiming calcium through reabsorption. Lastly, the kidneys stop forming active vitamin D, which causes decreased intestinal absorption of calcium through the digestive system.

learn by doing

The endocrine functions of the pancreas and liver coordinate efforts to maintain normal blood glucose levels. When pancreatic cells detect low blood glucose levels, the pancreas synthesizes and secretes the hormone glucagon. Glucagon causes the liver to convert the polymerized sugar glycogen into glucose through a process known as glycogenolysis. Glucose then travels through the blood to allow all cells of the body to use it.

If pancreatic cells detect high blood glucose levels, the pancreas synthesizes and releases the hormone insulin. Insulin causes polymerization of glucose into glycogen, which is then stored in the liver through a process known as glycogenesis.

The nervous and digestive systems also play a role in maintaining blood glucose levels. When the stomach is empty and blood glucose levels are low, the digestive system and the brain respond by making you feel hungry—your stomach may "growl," and you may feel pain or discomfort in your midsection. These sensations prompt you to eat, which raises blood glucose levels.

did I get this

All organ systems require a balance of cell division and apoptosis during development, growth, and repair to maintain tissue structure and function. The endocrine and immune systems are important regulators for cell populations. The endocrine system delivers steroids and growth hormones that send survival signals to specific tissues so that apoptosis is prevented. Additionally, the endocrine system delivers some hormones that work to induce apoptosis under some physiological conditions.

The cells of the immune system screen the blood for cells that divide at inappropriate times. Immune cells produce antibodies to mark these out-of-control cells for destruction. A breakdown in these processes can lead to the formation of tumors.

learn by doing

Like all body systems, the skeletal system can be affected by disease and injury. By studying the responses of the skeletal system to these conditions, we can learn about how the components of the skeletal system interact and how the skeletal system interacts with the rest of the body. We will consider six common dysfunctions of the skeletal system:

• Fractures: Breakage of the solid bones.
• Osteoarthritis: a chronic inflammation and damage of the articular cartilage.
• Osteogenesis imperfecta: A genetic condition leading to small bones.
• Osteomalacia ("rickets"): A bone disorder caused by a lack of vitamin D.
• Osteoporosis: A bone weakening condition, most common in women, caused by hormonal changes.
• Rheumatoid arthritis: An autoimmune disease that can damage the articular cartilage.

While the skeletal system primarily supports the body and allows movement, it also performs a variety of important functions and impacts many other organ systems.

## Bones

Bones are the primary organs in the skeletal system. Their functions include:

• protection of vital structures, such as the spinal cord, brain, heart, and lungs.
• support of body structures.
• body locomotion through coordination with the muscular system.
• hematopoiesis, or generation of blood cells, within the red marrow spaces of bones.
• storage and release of the inorganic minerals calcium and phosphorous, which are needed for functions such as muscle contraction and neural signal conduction.

It's common to think of the skeletal system as being made up of only bones, but the skeletal system contains many types of structures. In addition to localizing blood cell formation and storing calcium, bones come together at locations called articulations (or joints) to allow for locomotion and work. In any complex system that moves (such as a bicycle or car), allowing functional, repetitive motion requires a lot of control and support.

## Connective Tissues

In addition to bones, the skeletal system contains several other important connective tissues: cartilage , ligaments , and tendons .

Cartilage is a firm yet pliable substance that performs a variety of functions: protection, shape maintenance and support, lubrication, and shock absorption. Its primary function is to coat the end of the bones where they articulate with one another, providing a smooth, cushioned surface. Furthermore, cartilage can serve as a template for bone formation during development and bone healing (this will be further discussed in the section about bone homeostasis).

Ligaments and tendons support articulations and control the muscle attachment to the bones. Ligaments connect bones to one another and stabilize articulations. Tendons connect bones to muscles.

The structures of ligaments and tendons are similar, in that both tissues are made of fibrous proteins aligned in the direction of force. The types of proteins and differences in stretch and recoil distinguish the mechanical behavior of ligaments and tendons. Ligaments are stiffer, but deform more, since they stabilize articulations. Tendons are wrapped with a continuation of the fascia that surrounds muscle cells to help transmit and dissipate force.

learn by doing

The adult human skeletal system is composed of 206 bones. The skeleton is divided into two functional groupings—the axial skeleton and the appendicular skeleton .

## The Axial Skeleton

The axial skeleton is composed of the skull, hyoid bone, vertebral column, and the thorax (ribs and sternum). The axial skeleton functions to protect and support organs of the head, neck, and trunk.

The skull consists of 22 facial and cranial bones that interlock to form openings for the eyes and protection for the brain. The cranium, a collection of bones that protect the brain, and the mandible are the two major parts of the skull.

The hyoid bone is not attached to any other bone and is located in the neck, and it supports tongue movement.

The vertebral column consists of individual vertebrae separated by cartilage disks. The vertebral column forms the middle axis of the skeleton.

The thoracic cage protects the internal organs of the upper abdomen. The thoracic cage consists of the ribs and the sternum. The ribs articulate anteriorly with the sternum and posteriorly with the vertebrae of the thorax.

The table below lists the location and function of the major bones of the axial skeleton:

Bone(s) Location Function Major grouping of axial skeleton
Cranium Head Supports facial structures, encloses and protects the brain, provides muscle attachments for chewing and moving the head Skull
Mandible Lower jaw Permits chewing Skull
Vertebrae Spine Permit mechanical stability for the body and protect the spinal cord Vertebral column
Ribs Chest wall Provide protection for the organs of the upper body Thoracic cage
Sternum Center of the chest Provides attachment for many (not all) ribs Thoracic cage
learn by doing
did I get this

The appendicular skeleton is composed of the upper limbs, lower limbs, pectoral girdle, and pelvic girdle. The appendicular skeleton functions to anchor the limbs to the axial skeleton.

The pectoral girdle consists of a scapula and clavicle on each side of the body. The pectoral (shoulder) girdle permits movement of the upper limbs by connecting the upper limbs to the axial skeleton.

The upper limbs of the appendicular skeleton are composed of the humerus or upper arm bone, the radius and ulna, which complement each other to form the forearm, and the wrist. The hand subdivides into smaller bones of the palm and fingers.

The pelvic girdle of the appendicular skeleton is composed of two coxal bones (fused ilium, ischium and pubis bones), which attach to the vertebral column and the lower limbs.

The lower limbs each consist of the femur, or thigh bone; the tibia, or shinbone and the fibula, or calf bone; and the foot. The patella is the bone located at the point where the femur and tibia articulate with each other. The foot subdivides into smaller bones of the ankle, instep, and toes.

The table below lists the location and function of the major bones of the appendicular skeleton:

Bone(s) Location Function Major grouping of appendicular skeleton
Scapula Flat, triangular bone located on the posterior side of each shoulder Articulates with the clavicle and humerus Pectoral girdle
Clavicle Located in each shoulder at the base of the neck Helps to keep the shoulders in place; connects upper arm to the body Pectoral girdle
Humerus Extends from the scapula to the elbow Provides attachments for muscles that move the shoulder and upper arm at the proximal end; articulates with the radius and ulna at the distal end Upper limbs
Radius Located on the lateral side of the forearm between the elbow and wrist Provides attachment for muscles that bend the arm at the elbow and muscles that allow movement of the wrist Upper limbs
Ulna Located on the medial side of the forearm between the elbow and wrist Provides attachment for muscles that bend and straighten the arm at the elbow and muscles that allow movement of the wrist Upper limbs
Ilium Located on the superior portion of the coxal bone Connects the bones of the lower limbs to the axial skeleton Pelvic girdle
Femur Extends from the hip to the knee Provides attachment for muscles of the lower limbs and buttocks; distal end articulates with the tibia and patella Lower limbs
Tibia Located on the medial side of the leg between the knee and the ankle Articulates with the femur, on its superior side, to form the knee joint; articulates with the fibula on the lateral side; articulates with the patella on the anterior side; and the tarsels to form the ankle joint Lower limbs
Fibula Located on the lateral side of the tibia between the knee and ankle Forms the lateral part of the ankle joint Lower limbs
Patella Located on the anterior surface of the articulation between the femur and tibia Supports movement of the knee joint Lower limbs
learn by doing
did I get this

The bones of your body are mineralized structures that make up a major portion of your skeleton. In the broad sense, a bone is composed of bone tissue, cartilage, ligaments, tendons, vasculature, and nervous tissue. Bone tissue is a collection of specialized cells (osteoblasts, osteoclasts, osteocytes), organic extracellular matrix proteins (collagen and proteoglycans) and inorganic salt crystals that work together to provide strength and flexibility.

Although all bones have a similar composition, their large-scale structures and functions differ. One way to classify bone tissue is based on their microscopic structure.

• Bone tissue with a tightly packed microstructure arranged into rings is called compact bone (also called cortical or lamellar bone). Compact bone structure gives bones their stiffness. However, if bone structures were made only of compact bone, they would be very heavy and brittle.
• Bone tissue with a porous microstructure is spongy bone (also called cancellous or trabecular bone). Spongy bone consists of branching bone structures called trabeculae . Spongy bone helps to reduce the weight and brittleness of bone, and is found at the ends of bone where forces are high. Spongy bone allows bones to bend a slight amount without cracking.

Most bones of the body are composed of both spongy and compact bone tissues, so that they are stiff, resilient and lightweight.

learn by doing
did I get this

A common way to classify individual bones of the skeletal system is based on their shapes. The table below describes the four main shapes of bones.

Shape Description Examples
long bones significantly longer in one direction than in either of the other two directions humerus (upper arm); femur (thigh)
short bones similar length in all directions most carpal (wrist) and tarsal (ankle) bones
flat bones flat and plate-like skull
irregular bones not regular or systematic in shape vertebrae; hip bones

## Components of Long Bones

A typical long bone, such as the femur, has three main components:

• the diaphysis or shaft;
• the epiphyses (singular, epiphysis ), found at the bone ends;
• and the metaphyses (singular, metaphysis), transitional areas between the diaphysis and epiphyses.

The diaphysis or shaft is the longest part of a long bone. The epiphyses (epiphysis if singular) are the ends of a long bone that articulate (connect) with other bones at articulations or joints. The transitional area between the diaphysis and epiphysis is the metaphysis (meta- means "in between"). The medullary cavity, which houses yellow bone marrow, begins at the boundary between the metaphysis and diaphysis of each bone end and runs throughout the shaft or diaphysis of the bone. This marrow is rich in fat which is why it is termed yellow bone marrow. The epiphyses contain mainly spongy (cancellous) bone and red bone marrow. In children, the junction between the epiphysis and metaphysis contains a layer of hyaline cartilage,termed the epiphyseal plate. You have most probably heard of this as the growth plate. This layer of cartilage is what allows bone to continue to lengthen. The cartilage cells undero mitosis and move away from the center of the bone toward the epiphyses while the bone grows into it and takes over. In adult bone, this cartilage has become calcified and hard, the bone has caught up and replaced all of the cartilage with bone. Now this area is termed the epiphyseal line. The only area of hyaline cartilage left is on the outer edge of each epiphysis. This cartilage is termed articular cartilage and functions to cushion and reduce friction between bones at articulations.

We can also use a bone's location within the axial or appendicular skeleton to classify it. In addition to classifying bones based on their shape, we divide the skeleton into axial and appendicular segments. The axial skeleton is composed of the skull, the hyoid bone in the throat, the vertebral column, and the thoracic cage. The appendicular skeleton is composed of the upper limbs, lower limbs, pectoral girdle, and pelvic girdle.

learn by doing
did I get this

It's common to think of the skeletal system as being made up of only bones, and performing only the function of supporting the body. However, the skeletal system also contains other structures, and performs a variety of functions for the body.

While the bones of the skeletal system are fascinating, it is our ability to move segments of the skeleton in relation to one another that allows us to move around. Each connection of bones is called an articulation or a joint. Articulations are classified based on material at the joint and the movement allowed at the joint.

## Synarthrosis Articulations

Immovable articulations are synarthrosis articulations ("syn" means together and "arthrosis" means joint); immovable articulations sounds like a contradiction, but all regions where bones come together are called articulations, so there are articulations that don't move, including in the skull, where bones have fused, and where your teeth meet your jaw. Synarthroses are often joined with fibrous connective tissue.

## Amphiarthrosis Articulations

There are some articulations which have limited motion called amphiarthrosis articulations, that are held in place with cartilage or ligaments. Some amphiarthroses are permanent such as the articulation between the ribs and the sternum (via costal cartilage). Some are temporary such as the epiphyseal plate. Ribs connected to the sternum (except the first rib) and the two parallel bones in the arms and legs are considered amphiarthrosis articulations.

The articulations that people are most familiar with are diarthrosis articulations, which have wide ranges of motion. Diarthrotic articulations are said to be freely moveable and have a joint cavity. A joint cavity is a structure that consists of a joint capsule which surrounds the joint, and a synovial membrane which is inside the joint and produces a fluid known as synovial fluid. These joints are known as synovial joints and are further classified according to the type of movement allowed at the joint.

## Nonaxial Joints

Nonaxial joints do not have a pivot or axis of movement. An example are gliding joints, also known as plane joints. These joints do not allow much movement other than sliding and twisting. These are often found in certain articulations in the wrist and ankle.

Test My System

## Uniaxial or Monoaxial Joints

These joints have one axis of movement and are more moveable than gliding joints. Examples of uniaxial joints are hinge and pivot joints.

These joints have protrusions that fit into a corresponding depression; hinge joints, such as the elbow, allow the movement of flexion and extension. The pivot joint of the atlanto-axial joint (the atlas or C-1 on the axis or C-2) rotation of the head and neck. For example, when you shake your head "no" you are using this joint to rotate your head.

Test My System

Test My System

## Biaxial Joints

Biaxial joints have two axes of movement and therefore allow more movements than uniaxial joints. One example of a biaxial joint are saddle joints, such as the thumb. These joints were appropriately named because they look like saddles; there are two curved surfaces that meet and allow limited motion in many directions.

##### thumb joint

Test My System

Another example of a biaxial joint is an ellipsoid or condlyar joint. Ellipsoid articulations, also called condyloid articulations, have oddly shaped or elliptical interactions that articulate to allow movement in two planes with no rotation. These are present in the fingers and toes.

Test My System

## Triaxial Joints

As you can guess, triaxial joints are the most moveable with three axes of movement. The ball and socket joints such as the shoulder and hip, have the widest range of motion. They are aptly named as the head of the bone resembles a "ball" and the articulating bone of the joint (either the scapula or coxal bone) has a deep pit for the "socket".

##### Hip joint

Test My System

learn by doing
did I get this

The skeletal system is organized into the following structural hierarchy, from microstructure to gross anatomy:

• Chemistry and molecular scale - Water, minerals, collagen, and other proteins.
• Nanoscale - Mineral crystals are embedded within collagen to form composite fibers.
• Submicron scale - Mineralized fibrils are organized into a lamella (plural is "lamellae").
• Micron (micrometer) scale - Lamellae form osteons in compact bone or trabeculae in spongy bone.
• Macroscale - Compact and spongy bone combine together to form whole bones, and bones combine at articulations to form the skeletal system.

Bones constantly store and release calcium, phosphate, proteins, and other matrix components of bone. Within the matrix, the mineral crystals resist compression but are very brittle. The organic components, such as the collagen fibers and the cells, help give the bone some flexibility. The hierarchical organization of the skeletal system at different scales is important for its mechanical, biological, and chemical functions.

learn by doing
did I get this

The major components of bone tissue at the molecular scale are minerals, water, collagen, and other proteins. At the next level of organization, small crystals of hydroxyapatite made of calcium and phosphate are embedded within collagen fibers to produce a composite (blended) material with high compressive and tensile strength.

The skeletal system protects and supports vital organs, allows our body to move, stores important minerals, and produces blood cells. There are several chemical elements and molecules required to maintain the many functions of the skeletal system. The chemical properties of these components support bone structure and function. On a chemical level, bone is divided into inorganic and organic (carbon-containing) components.

The primary inorganic components of bone are:

• calcium, which is required for many functions throughout the body;
• phosphorus (in the form of phosphate ions), which is a component of buffer systems and energy-rich molecules; and
• water, which contributes to the compressive resistance of bone and contributes to the fluid matrix of bone.

The primary organic components of bone are:

• collagen, the major structural protein (type I in bone and type II in cartilage); and
• proteoglycans , which are negatively charged glycosylated proteins (glycosylated means having carbohydrate sugar groups modifying the protein).

Bone is approximately 60 to 70 percent inorganic mineral and 10 percent water by weight. The remaining 20 to 30 percent of bone is organic matrix (osteoid), such as collagen and proteoglycans. Your body contains 1 to 2 kilograms of calcium and nearly 600 grams of phosphorous. Nearly 99 percent of the calcium and 86 percent of the phosphorous is stored in your bones.

Calcium ions (Ca2+) are stored in bone tissue, but can be released into the bloodstream when blood levels fall below optimal. Blood calcium is important for muscle contractions, nerve impulses, and blood clotting.

In bone, phosphorous (P) is found in the form of phosphate ions (H2PO4-). Outside of bone, phosphorous plays roles in energy storage (such as in ATP), and is required for the formation of DNA and RNA. Therefore, it is required for cellular growth, maintenance, and tissue repair.

When combined with hydrogen, phosphorous forms dihydrogen phosphate ions (H2PO4-). Dihydrogen phosphate acts as a buffer to maintain a constant pH balance by acting as either a hydrogen ion donor (acid) or a hydrogen ion acceptor (base). In all cells, a constant pH must be maintained to carry out cell functions.

As mentioned in previous sections, hydroxyapatite is an inorganic calcium phosphate mineral that is a primary component of bone. Crystal hydroxyapatite has the chemical formula: Ca10(PO4)6(OH)2.

During bone formation, the collagen fiber matrix is formed. Next, mineralization of the matrix occurs when calcium, phosphate, and water from the extracellular fluids combine to form insoluble hydroxyapatite. The hydroxyapatite incorporates into the small pores within collagen fibrils and crystallizes into long, thin, nanosized plates within the collagen network. The incorporation of hydroxyapatite within the collagen fibers contributes to the overall compressive strength of bone. Because the crystals are nanosized, they have a large surface area. The large surface area of the crystals makes it easy to release ions into the extracellular fluids when blood levels decrease.

Sometimes bones contain fluoride. Fluoride is similar to the hydroxyl ion in charge and size. When fluoride replaces the hydroxyl ion in hydroxyapatite crystals, it forms fluoroapatite. Fluoroapatite is a more compact and less soluble crystal than hydroxyapatite. Therefore, ion exchange at the crystal surface is slower. The primary role of fluoride in bone is to strengthen bone mineral.

Water is an important molecular component of bone matrix. Water is initially present in the spaces within the collagen matrix of the unmineralized bone extracellular matrix (osteoid). As crystals fill in the spaces between collagen fibrils, the bone is mineralized and the water is displaced. The water that remains in bone after this process is complete forms hydrogen bonds with polar, hydrophilic components of collagen. Water also assists with the compressive resistance of bone due to osmotic interactions caused by negatively charged proteoglycans.

In addition to calcium, phosphorous, water, and fluoride, the inorganic parts of bone also contain sodium, potassium, carbonate, and magnesium. Although these molecules do not form their own crystals, they are bound to hydroxyapatite crystals within bone mineral.

learn by doing
did I get this

You can think of the hydroxyapatite in bones as being similar to concrete. The chemical structure of hydroxyapatite gives it a high mechanical strength under compression (squeezing force), but little strength under tension (pulling force). If our bones were made only of hydroxyapatite, they would be very fragile, like concrete. They would break easily under tension. The organic components of bone help to give it additional strength and flexibility.

Collagen, a ropelike, fibrous protein, is the major organic component of bone. Like rope, collagen has significant mechanical strength under tension. Therefore, collagen provides tensile strength to the bones. The spiral arrangement of collagen in combination with its ECM (extracellular matrix) components, such as water and specialized proteins, also makes bone more elastic and less brittle, so that it can absorb shock more easily.

Bone matrix is a network of collagen fibers and hydroxyapatite. It is strong under both tension and compression. Furthermore, the collagen contributes to its ability to absorb sudden forces without breaking.

learn by doing

Collagens are a class of fibrous proteins found in bone, cartilage, and other connective tissues. The primary structure of collagen has repeats of glycine-proline-X, where X can be any other amino acid. This repeated arrangement gives collagen a unique helical secondary structure. The tertiary structure of collagen is a triple helix fibril, which further twists into a quaternary structure of a collagen fiber. The resulting "twisted, twisted, twist" is similar to the higher-ordered structures in rope.

Type I collagen is the primary form of collagen found in bone. The collagen fibers in bone are approximately 300 nanometers long, and are arranged in a staggered pattern. During bone formation, the collagen fiber matrix is deposited first. Proteoglycans are a second class of organic components found in bone. Proteoglycans are macromolecules composed of proteins with negatively charged glycosylated modifications. There are a number of proteoglycans, which are classified by the type of side chains on the core protein. The side chains on the proteoglycans are linear carbohydrates. As with cartilage, the presence of the negatively charged proteoglycans contributes to the resilience of the tissue and retention of water within the matrix. Proteoglycans also bind and release molecules for cell signaling.

did I get this

Mineralization of the bone matrix occurs when calcium, phosphate, and water from the extracellular fluids combine to form insoluble hydroxyapatite. The hydroxyapatite incorporates into the small pores within collagen fibrils and crystallizes into long, thin, nanosized plates within the collagen network. The incorporation of hydroxyapatite within the collagen fibers contributes to the overall compressive strength of bone. Within the bone matrix, the minerals, water, collagens, and proteoglycans function together to provide strength in tension and compression. Additionally, this unique environment binds and releases chemicals into the extracellular fluids for use throughout the body.

learn by doing
did I get this
Example

Osteogenesis imperfecta (from osteo-, meaning bone, and genesis, meaning production or beginning) is a congenital (genetic) disorder that affects the structure and strength of bones. The condition is primarily caused by genetic mutations that affect the structure and/or quantity of type I collagen produced by the body. Remember that collagen is an important component of the extracellular matrix of bone tissue. In people with osteogenesis imperfecta, the lack of collagen (or presence of defective collagen) prevents the extracellular matrix from forming correctly. The mineral structure of the bone is weakened, and as a result, the bones are unusually brittle.

The bones of people with osteogenesis imperfecta break extremely easily, sometimes with only small amounts of pressure. The bones' brittleness reduces their ability to support and protect the body. They also typically take longer to heal and may be more prone to infection.

Bones become stronger and thicker when they are exposed to regular stress. Conversely, bones that do not experience regular stress may lose extracellular matrix and become less dense. In a person with osteogenesis imperfecta, bones that break often (and therefore spend a lot of time immobilized in casts or restraints) are exposed to much less stress. As a result, they may lose even more extracellular matrix and become even more brittle.

did I get this

You have already learned about the hydroxyapatite and collagen combination, which is responsible for giving bones their rigidity. The skeletal system is an excellent example of a system that is primarily composed of extracellular matrix. Generally, cells of the body function within a matrix to hold them together. In the case of bone, the extracellular matrix (ECM) is composed of crystals of hydroxyapatite and long collagen proteins. The hydroxyapatite and collagen work together to give bone its unique properties of strength, compressive resistance, and flexibility.

## Cells in Bone

The previous section described the importance of the bone matrix components calcium and hydroxyapatite in maintaining bone rigidity. However, bone remodeling is equally important to maintaining bone health. Throughout your lifetime, your bones are constantly remodeled and repaired. There are three main cell types in bone, which maintain bone balance and strength:

• osteoclasts , which break down and reabsorb bone;
• osteoblasts , which deposit and build new bone; and
• osteocytes , which are mature bone cells that act as sensors for repair.

Think of the bones of your body as a rapidly expanding city. When the old buildings get outdated, they are either remodeled to make enhancements or knocked down to make room for the new ones. As soon as a building is knocked down, a new one is erected in its place. The construction crew recycles the old building materials. Many city planners constantly monitor the building progress and talk with one another about which sections of the city will get the available resources.

Osteoclasts secrete an acid that dissolves the inorganic components of bone: calcium and phosphate. Osteoclasts also contain enzymes that digest the organic components of the bone matrix, such as the proteins and proteoglycans. Bone resorption (osteolysis) is complete when small cavities remain on the bone surface. Osteoclast activity is important for creating the medullary cavities of diaphyses, which house bone marrow. (Remember that the diaphysis is the main shaft of a long bone.) Osteoclasts are important for removing calcium from bones if the blood calcium levels fall, such as when a diet is deficient in calcium. Remember calcium is critical for life and if levels fall, it could be fatal if it wasn't taken from the bones.

Osteoblasts build bone and fill in the cavities created by osteoclasts. Osteoblast cells secrete osteoid (the organic portion of the bone matrix) around them, and then mineralize the matrix to generate rigid bone tissue. Bone mineralization occurs through osteoblast secretion of an enzyme called alkaline phosphatase. Alkaline phosphatase cleaves phosphate groups to provide the necessary phosphate for building hydroxyapatite. Osteoblasts are stimulated when blood calcium levels increase. The excess calcium is deposited into the bones for storage.

After bone mineralization, osteoblasts trapped within the matrix differentiate into osteocytes. Osteocytes have long processes (outgrowths or protrusions) for connection to other osteocytes within the bone. This arrangement allows osteocytes to act as mechanical sensors. Osteocytes sense mechanical strain within bone and regulate the activity of osteoblasts or osteoclasts, depending on needs for calcium and phosphate. To maintain bone strength, bone resorption and bone deposition must be in constant balance with each other.

learn by doing
did I get this

You have learned that bone tissue is classified into two types based on structure: compact bone and spongy bone. The parallel arrays of lamellae are organized into different arrangements depending on the bone structure. The lamellae in compact bone form tubular structures, called osteons. The osteons of compact bone are oriented in the direction of the load-bearing axis. The osteons also create a central canal for the passage of blood vessels. Osteocytes in the osteons are embedded in small cavities called lacunae (singular is lacuna ), and are oriented around the central canal parallel with the lamellae on the load-bearing axis. The diaphyses of long bones are stronger on their long axis than in any other direction, because of the parallel array of osteons and osteocytes.

The lamellae in spongy bone form a random mesh-like structure of interconnecting plates called trabeculae . Likewise, osteocytes within spongy bone are randomly arranged. The strongest trabeculae in spongy bone are arranged on the bone axis that undergoes the most stress. Flat bones of the skull are primarily made of spongy bone and are good at resisting forces from many directions because of the trabecular arrangement.

In both types of bone tissue, the mineral components, calcium and phosphate, combine with collagen to provide the compressive and tensile strength of bone. Spongy and compact bone tissues are combined to create bones, which store and release calcium and phosphate into the blood through constant resorption and deposition. Many bones then articulate with each other to form the skeletal system.

learn by doing
did I get this

Bones form in two ways. A process known as intramembranous ossification forms bones that develop from layers of connective tissue. Flat bones such as those found in the skull develop through this process. Endochondral ossification (from the word roots endo-, meaning "within," and chondral, meaning "cartilage") is bone formation from a hyaline cartilage blueprint or template, which determines the future bone shape. Bones of the limbs and extremities develop through endochondral ossification. For example, an infant's arm and leg bones contain only small amounts of actual hard bone material; they are primarily made of cartilage. As the child grows, bone replaces the cartilage.

Ossification is the process of forming bone. You learned that there are two types of ossification:

• intramembranous ossification, which is direct synthesis of bone by specialized stem cells (mesenchymal cells) from fibrous connective tissue; and
• endochondral ossification, which is synthesis of bone from a (hyaline) cartilage template.

## Intramembranous Ossification

Intramembranous ossification is the process that forms and repairs the flat bones of the skull, clavicles and other irregularly shaped bones. In some situations of bone repair and adaptation to excessive force, intramembranous ossification generates new bone.

The process of intramembranous ossification involves multiple steps:

1. Increased vascularization.
2. Recruitment of mesenchymal stem cells
3. Differentiation
4. Secretion of osteoid
5. Mineralization
6. Formation of trabeculae
7. Formation of outer compact bone

First, the site for future bone formation increases in vascularization—new blood vessels form near the site where the bones will grow. Mesenchymal stem cells, which originate in the embryonic mesoderm, become active and travel through the blood vessels to the future site of bone formation. Chemical messages then cause the mesenchymal stem cells to differentiate: they change into osteoprogenitor cells, which may divide and differentiate into osteoblasts. The osteoblasts deposit osteoid (the unmineralized bone extracellular matrix) and are then trapped in the matrix, where they differentiate into osteocytes. Inorganic salts in the blood travel through the blood vessels to mineralize the bone matrix. As a result, hydroxyapatite crystals form within the osteoid. On the interior of the tissue, small clusters of bone begin to connect with other clusters to form trabeculae. Osteoblasts near the surface of the bone deposit matrix in organized lamellae and form a thin outer layer of compact bone. The periosteum ("peri-" means "surrounding" and "osteum" means "bone") is living membrane composed of fibrous connective tissue that forms on the outside of the compact bone. Its inside layer has osteoblasts for bone growth and repair.

## Endochondral Ossification

Most bones of the skeleton below the skull develop through endochondral ossification.

This process involves the following steps:

1. Formation of a cartilage template
2. Growth of the template
3. Differentiation
4. Vascularization
5. Calcification
6. Bone formation

The first step is formation of a hyaline cartilage template, which is the shape of the desired new bone. The cartilage template grows in size and thickens through the production of new chondroblasts at the perichondrium. The perichondrium is the cartilage equivalent of the periosteum. Chondroblasts differentiate into chondrocytes, which produce chemical messages that stimulate the increase of vascular supply at the perichondrium. This increase in vascular supply brings in inorganic salts, which mineralize the central cartilage matrix.

Cartilage is laid down as a template that provides some mechanical stability. This is like when designers and architects build a template out of balsa wood, clay or foam because it is easy to quickly remodel and manipulate those substances. Then, once the template is worked out, they will remodel it using a stronger material. In bone, the 'model' cartilage is remodeled over time and osteoblasts produce a full bone matrix with new collagen and hydroxyapatite. In this way, biology works more efficiently than any engineered tissue graft.

learn by doing
did I get this

After bone formation, bone resorption and bone deposition occur continually in a process called bone remodeling to allow for skeletal response to mechanical use, nutritional status and as part of the bone repair and healing process. In the absence of malnutrition or disease, this process maintains homeostasis of both total bone mass and inorganic substances such as calcium and phosphate.

As bones age, they tend to decrease in density and, as a consequence, decrease in strength. In some people, especially women, the bones become very brittle and easily broken. The result is a disorder called osteoporosis . Within bones affected by osteoporosis, bone mass and mineral content decrease. As a result, the bones develop canals filled with fibrous and fatty tissues. This leads to an increased risk of bone fracture because the bone organization that is important to weight bearing is lost.

learn by doing
did I get this

The microscale structure of a bone gives it significant strength and rigidity, but extreme forces can cause bones to break, or fracture. The table below describes the most common types of fractures.

Common Types of Fractures
Type of fracture Description
Simple fracture (also called a closed fracture) A fracture in which a bone breaks completely, but the broken ends do not penetrate the skin
Compound fracture (also called an open fracture) A fracture in which the ends of the broken bone break through the skin
Comminuted fracture A fracture in which the bone is shattered or broken into several pieces
Greenstick fracture A fracture that occurs in children when one side of a bone breaks, and the other side bends
Impacted fracture A fracture in which one end of the fractured bone is forced into the interior of the other end
Stress fracture A set of tiny fractures or fissures in a bone caused by repeated stress on the bone

A bone fracture affects the bone on several levels of organization. A fracture involves a physical break in the mineral structure of the bone. Fractures typically cause blood vessels in the bone to rupture, reducing the blood flow to the bone tissue. As a result, some of the cells in the surrounding bone die. These dead cells and the related cellular debris are removed by immune cells and osteoclasts. Over time, various cell types—fibroblasts, chondroblasts, and osteoblasts—work together to repair the mineralized bone tissue.

Fractures weaken bone, making it less able to perform its functions of support and protection, although once healed, the site of the fracture is stronger than the remaining bone. A fracture may cause a change in the shape of the bone. If that happens, then the way the bone responds to a contracted muscle may change. As a result, fractures can prevent bones from moving correctly when muscles pull on them.

There are pain receptors and nerves in the bone. The pain experienced when a fractured bone moves is one way the body reacts to help itself heal. Bones heal more quickly and thoroughly if they are kept immobilized (which is why the typical treatment for a broken bone is to put it in a cast or other restraint). Because we instinctively avoid actions that cause pain, the pain that occurs when a broken bone is moved causes us to minimize the movement of that bone. This, in turn, helps keep the bone stable while it heals.

Severe fractures, such as compound fractures or comminuted fractures, can cause long-term or permanent disruptions to the body's homeostasis. Because a compound fracture breaks through the skin, bacteria and other pathogens can enter the body after a compound fracture. Those pathogens can enter the bone, blood, muscles, or other tissues or organs, causing severe infection. Severe fractures are also less likely to heal correctly without medical (typically surgical) intervention. Improperly healed fractures can cause changes in the bone's reaction to force, leading to changes in body motion (such as a limp).

did I get this

The skeletal system provides an excellent example of homeostasis. From the time that we are born, our skeleton must be sufficiently robust to provide stature, protect our soft internal organs and provide a mechanical resistance for our muscles to pull on. However, in addition to the constant need for the skeleton to maintain its function, it must also constantly remodel, otherwise we could not grow. Even in adulthood we constantly develop microfractures that need to be repaired.

The body uses the bones not only for structure and protection, but also for calcium storage. Approximately 99 percent of the body's calcium is stored in the bone, and calcium plays an important role in most of the body's functions. Free calcium levels must remain at a set point for proper body functions. The extracellular levels of calcium are affected by calcium intake from foods, excretion of calcium as waste, and the storage and release of calcium from the bones. Hormones regulate these processes to maintain balanced calcium levels in the extracellular fluid, which is necessary to maintain homeostasis.

Small changes in blood calcium levels can have significant effects on body function. For example, if extracellular calcium levels are too low, the nervous system becomes overexcited, resulting in tetany (rigid, locked muscles). On the other hand, if calcium levels in the body are above normal, the nervous system becomes sluggish. Muscle activity of the heart and gastrointestinal tract slows down.

Milk and dark green vegetables are rich in calcium, and an adequate supply of calcium helps maintain healthy bones. When we eat calcium-rich foods, some calcium is absorbed into the small intestinal wall, and some of the calcium becomes soluble in the blood stream. However, calcium and other divalent cations (ions that are missing two electrons) are poorly absorbed by the small intestine. For this reason, vitamin D is an important dietary supplement. Vitamin D increases calcium absorption in the small intestine.

By altering the function of the osteoblasts and osteoclasts, hormones help regulate calcium levels in the blood. There are three hormones that control osteoblast and osteoclast activity:

• parathyroid hormone or PTH, which increases bone resorption by stimulating osteoblasts, leading to increased calcium release from bone.
• calcitonin, which acts in children to decrease bone resorption, leading to less calcium entering the blood.
• calcitriol, which increases absorption of dietary calcium.
• calcitonin, which acts to decrease bone resorption and increase bone deposition by stimulating osteoblasts.

Parathyroid hormone (produced in the parathyroid glands) controls extracellular calcium by regulating how calcium is reabsorbed in the intestines, excreted from the body, and exchanged between the extracellular fluid and the bone. The cells of the parathyroid gland synthesize and release parathyroid hormone in response to low blood calcium levels. To bring blood calcium levels into the normal range, the release of parathyroid hormone stimulates osteoclasts to reabsorb bone mineral, therefore releasing calcium into the blood. Parathyroid hormone also enhances calcium absorption by the intestines, and prevents calcium loss in urine to increase calcium levels in the blood. When parathyroid cells sense that blood calcium levels are above normal, cellular receptors are activated and the synthesis and release of parathyroid hormone is inhibited.

Calcitonin is produced in the thyroid gland. The function of this hormone is to decrease bone resorption and retain calcium in the bones. Therefore, the effects of calcitonin counteract the effects of parathyroid hormone. When blood calcium levels are high, the thyroid releases calcitonin into the blood. Calcitonin decreases bone resorption by decreasing the activity of osteoclasts and decreasing the formation of new osteoclasts. In this way, calcitonin shifts the bone balance in favor of bone deposition, which requires the removal of calcium from the blood and into the bone. Calcitonin also has minor effects on how the intestines and kidney tubules handle calcium. In adult humans, calcitonin has weak effects on the regulation of calcium levels. We know this because if the thyroid gland is removed, calcium levels are not adversely affected.

learn by doing

Vitamin D is a group of lipid soluble compounds involved in calcium regulation. Vitamin D can be made in the skin through exposure to sunlight, or acquired from the diet and dietary supplements. Under the influence of the parathyroid hormone, vitamin D is converted to an active molecule, calcitriol. Calcitriol circulates through the blood to maintain normal blood calcium levels. When your body does not have sufficient levels of calcitriol, the intestines do not absorb as much calcium, and blood calcium levels decrease. Vitamin D also inhibits calcium loss in urine.

The activity of osteoblasts and osteoclasts in the bone is tightly regulated by the activity of the parathyroid hormone, calcitonin and vitamin D. Nutritional deficiencies in vitamin D, calcium or phosphate lead to a disease called osteomalacia.

Osteomalacia (from osteo-, meaning "bone," and mal-, meaning "bad"), also known as rickets when it occurs in children, is a disease that is most commonly caused by a lack of vitamin D in the body. Remember that vitamin D helps to increase the amount of calcium that the body absorbs and, as a result, helps the body build the mineralized extracellular matrix in bone tissue. If a person lacks sufficient vitamin D, calcium absorption is slowed, and bone growth is affected.

In children, the lack of calcium absorption prevents new bone tissue from ossifying properly. As a result, the bones become weak and rubbery. Because their bones are less able to support the body and withstand the pressure of the body's weight, children with rickets may develop bowed legs and deformed skeletons.

In adults, osteomalacia prevents bones from healing and remodeling properly. Recall that bone tissue is being continually formed and broken down by osteoblasts and osteoclasts. If insufficient calcium is available, the new bone that forms may not calcify properly. As a result, the bones may become painful and brittle.

learn by doing

Osteoporosis is a condition in which the balance between calcium deposition and calcium loss in bones is disrupted. In people with osteoporosis, the bones lose more calcium than they deposit. As a result, the bones become brittle and break easily.

Osteoporosis is most common in post-menopausal women. As a woman goes through menopause, her levels of estrogen decrease significantly. Estrogen and testosterone are important hormones that affect the reproductive system, but they also can stimulate osteoblast activity. As concentrations of these hormones decrease, osteoblasts become less active, and less calcium is deposited in the extracellular matrix. In addition to resulting in weak bones, this is also an issue because there is a reduced reserve of calcium in the body for other tissues.

Osteoporosis can be affected by diet and lifestyle. People who consume very little calcium and vitamin D are at increased risk of osteoporosis. (For example, women with anorexia nervosa, who eat very little, may develop osteoporosis in their late twenties and thirties.) Weight-bearing exercise, such as running, helps to build bone mass and can reduce the chances of developing osteoporosis.

learn by doing
did I get this

You learned that osteocytes become embedded within bone matrix during mineralization. Within bone lamellae, osteocytes interact with each other through a network of cellular extensions. These extensions, found in a network of canals referred to as canaliculi, allow external mechanical information to be rapidly transmitted to many osteocytes. The response of osteocytes to mechanical force allows our skeletal system to maintain itself.

When bone experiences a mechanical force, this force is transmitted to the fluids and cells within the bone. The forces on the fluids are then transferred through the spaces of the canaliculi down to the osteocytes. In response to the received forces, osteocytes generate a force on the bone tissue. Therefore, the cells and bone matrix constantly respond to each other’s mechanical force input.

Osteocytes in bone tissue act as mechanical strain sensors to convert information about mechanical force into chemical messages. These chemical messages control osteoblast and osteoclast activity and can result in either bone deposition or bone resorption, also known as osteolysis. In response to mechanical force, a two-step process occurs. First, mechanically sensitive membrane proteins on the surface of the osteocytes are activated. Second, chemical pathways within the osteocytes are activated. Activation of these intracellular pathways stimulates osteoblast activity and inhibits osteoclast activity.

As you learned earlier, bone ECM (extracellular matrix) maintains the mechanical structure and functional properties of bone tissue. The collagen fibers of bone ECM are under constant tension so that the bone ECM is always ready to respond to mechanical force. Because osteocytes are attached to the ECM, the tension felt by the collagen fibers is balanced by the tension that osteocytes place on the ECM. Therefore, osteocytes sense mechanical force and transmit this force to the surrounding ECM. Bone ECM is constantly remodeled to maintain optimal strength for applied mechanical force.

Mechanical forces control osteoblast and osteoclast activity through feedback from the osteocytes and the ECM. One common type of mechanical force is physical activity. Another force that is not as obvious is body mass. With increased mechanical force, such as physical activity or weight gain, bone ECM increases to support the force. When the mechanical force applied to bone is too high, osteocytes within bone matrix signal for remodeling through bone resorption and bone deposition.

People who routinely lift heavy loads have very strong bones, but the body spends a lot of energy to maintain these stronger bones. On the other hand, sedentary individuals may lose bone density and strength. However, that can be a problem: a lack of exercise, extended bed rest and space travel (for astronauts), during which there is little or no force on bones because of inactivity or weightlessness, can cause a significant loss of bone mass.

learn by doing
did I get this

You have learned in relation to ossification how cartilage and bone are inherently integrated. Both tissue types are also some of the most force-responsive in the body. This is necessary to maintain stature. Chondrocytes sense force and changes in water movement—associated with the force-induced movement of water—and secrete the appropriate collagen and proteoglycan extracellular matrix proteins.

Recall that cartilage is composed primarily of a network of elastic type II collagen fibers embedded in gel-like proteoglycans. Water, electrolytes, and chondrocytes are interspersed within the network. The physical properties of collagen and proteoglycans are largely responsible for the ability of cartilage to respond flexibly to force.

Collagen fibers have significant tensile strength, which means that they can withstand a lot of tension (pulling) without damage. However, collagen fibers have very little compressive strength—that is, under compression (squeezing), they bend easily. You can think of a collagen fiber as a rubber band or string. If you pull on a rubber band, it stretches easily, and then returns to its original shape when you stop pulling. However, if you push on the ends of the rubber band, it folds up easily—it has minimal strength.

Collagen fibers are what give cartilage its strength. The cartilage in different areas of the body contains fibers that are arranged in different ways. The orientation and arrangement of the collagen fibers helps to give each region of cartilage strength to withstand specific types of stress. For example, articular cartilage—the cartilage that forms the articulating surfaces of joints, such as the knee—contains two main regions of collagen fiber orientation. At the surface of the cartilage, the fibers are arranged primarily parallel to the surface. Further from the surface, the fibers are arranged primarily perpendicular to the surface.

Proteoglycans are gel-like, elastic substances. They are highly resilient, which means that they deform easily under stress, but return to their original shape when the stress is removed. Proteoglycans give cartilage its resiliency and elasticity.

The combination of strength and elasticity allows cartilage to respond flexibly and quickly to forces placed on it. For example, the cartilage in your knee can support up to eight to 10 times your body weight for short periods without being damaged. As more force acts on the cartilage, it compresses. Its elasticity allows it to distribute the force evenly, and its strength allows it to withstand the stress without breaking or collapsing. When the stress is removed, the cartilage returns to its original shape. The physical movement of the water in the cartilage also helps to distribute the force of compression.

Cartilage is less complex in response to force than bone, which has multiple integrated cell types. Cartilage is less regulated by hormones, is difficult to overgrow, and grows extremely slowly. Part of the reason for slow growth is a limited amount of nutrients. Cartilage is avascular (a- means "none"), so there are no blood vessels or blood supply to the interior of the cartilage, so nutrient travel is limited to diffusion, and growth is limited.

learn by doing

Arthritis (from arthro-, meaning "joint," and itis, meaning "inflammation") is any inflammation of the cartilage and/or bone tissue within a joint. The most common form of arthritis is osteoarthritis, which is caused primarily by physical damage to the cartilage that cushions many joints. The damage may be caused by a decrease in cartilage flexibility and water content as a person ages, but it may also be a secondary result of a variety of other conditions (including diabetes and mechanical injury to the joint). Osteoarthritis is most common in the elderly, but can affect younger people as well.

Osteoarthritis begins with physical damage to cartilage tissue in the joints. The damage may be cellular (such as damage cause by an infection), or it may occur at the tissue level. The damage causes the cartilage to break down. As the cartilage breaks down, friction within the joint increases; in severe cases, the ends of the bones themselves may rub together, causing severe pain. Loss of cartilage can also reduce the flexibility of the joint. Pain and loss of flexibility typically cause a person to move the joint less; as a result, the muscles, tendons, and ligaments near the joint may weaken. This in turn can cause additional difficulty moving the joint.

A different form of arthritis that also causes joint pain, rheumatoid arthritis, is caused by inflammation of the membranes of the synovial capsule, not the articular cartilage.

learn by doing
did I get this

The homeostatic control of blood (plasma) calcium levels requires interactions between several body systems. Roughly 1000 mg of calcium per day is taken into the body by ingestion, 350 mg of calcium per day is absorbed into the digestive system and the rest is excreted. Of the calcium absorbed by the digestive system and from there into the cardiovascular system, some is processed through the urinary system. Calcium exchange between cells, extracellular fluid and the bones is partly regulated by the endocrine system, which directs bone degradation if more calcium is needed in other parts of the body. The endocrine system also stimulates osteoclasts, which are cells derived from the precursor cells of the immune system. The calcium liberated by the bones is used by the nervous system and the muscular system to keep many of their functions working appropriately.

Systems within the body are integrated with respect to dysfunction as well. Osteoarthritis is the most common form of arthritis, and as you have learned, it is caused by mechanical damage to the cartilage. Rheumatoid arthritis, in contrast, is an autoimmune disease—that is, a disease in which the body's immune system attacks normal tissue. In rheumatoid arthritis, the immune system attacks healthy cartilage and synovial membranes.

Immune cells attack the synovial membranes in synovial joints, causing inflammation. As the membrane becomes inflamed and thickened, synovial fluid begins to accumulate in the joints. The joints can become swollen and painful, and it becomes more difficult for the bones in the joint to slide past one another. Over time, fibrous tissue forms in the joint. Eventually, the fibrous tissue fuses the two bones together, preventing the joint from moving.

learn by doing
did I get this

When you think of muscles you probably have a picture in your mind of some muscular people who are pleasing to the eye. Did you know that you have over 650 muscles in your body? That sounds like a lot but a caterpillar has even more, around 4000 muscles! Without muscles we would never be able to move. The main function of the muscular system is movement. But did you know that muscle contractions generate 85% of our body heat? Muscles also protect our organs. Your abdominal muscles keep your “guts” and internal organs in place. Some muscles are circular, such as the one that encircles your mouth for kissing or puckering. Other circular muscles form sphincters which control when you defecate or urinate. One important muscle, known as your diaphragm, is necessary for breathing. If your diaphragm stopped working you would die in minutes because you would not breathe.

Let’s test your knowledge on some common facts and myths of the muscular system.

did I get this

Let’s check out the muscular system in action in the following case study.

Seymour is a nineteen year old power lifter and college student. You sit next to Seymour in psychology class and have gotten to know him this semester. On Monday, he sits down next to you and lets out a wince of pain as he takes his seat. You ask him, “What’s wrong?”

He replies, “Oh, it’s probably nothing, but my stomach has been hurting especially when I lift something heavy.”

“Don’t you work at The Dark Horse Tavern? And work out a lot? I bet that must be tough on you. Do you think you pulled a muscle?” you ask him.

Seymour answers, “I don’t know, I’ve never felt this kind of pain before, it hurt a lot at work and I haven’t been able to lift as much at the gym.”

“Why don’t we check this out on my iPhone, we still have 5 minutes before class begins” you reply.

Seymour suggests going to WebMD.com for a quick look. “Hmm, I don’t see anything specific for stomach pain while exercising,” you tell him. “What other symptoms do you have?”

“Well, it’s kind of embarrassing but I have noticed this lump in my navel especially while lifting.”

“My cousin had something like that before, I think it was called a hernia, let’s Google that. Oh – man, it sounds like something called an umbilical hernia, it says that the bulge might be your intestines!” you whisper to him. “Seymour, you better get to your doctor right away, this can’t be good.”

Seymour goes a little pale and says, “I’m going to call my mom right after class.”

learn by doing

The muscular system is mainly composed of skeletal muscle, such as those that cover the anterior portion of your abdomen and help compress the abdominopelvic cavity and digestive organs. As we saw with Seymour, if these muscles are weakened, they might separate and allow the underlying organs to protrude. Seymour’s constant exposure to high intra-abdominal pressure has weakened the muscle. If a piece of Seymour’s intestine is bulging through his abdominal muscles this can have serious consequences. The small intestine is a critical component of the digestive system and if it is pinched off that section could become necrotic and die.

There are two other types of muscle tissue that are necessary for life: cardiac and smooth muscle. Cardiac muscle is found in the heart and its rhythmic contraction is responsible for your heart beat, while smooth muscle is found in many organs and blood vessels. Smooth muscle is a significant part of your cardiovascular system (blood vessels), respiratory system (bronchioles), digestive system (esophagus, stomach, small and large intestines), urinary system (ureters and urinary bladder), and your reproductive system (uterus, vas deferens).

As stated earlier, skeletal muscle has many important functions in maintaining our homeostasis. Skeletal muscle contractions are critical in producing heat for our body. In fact, when you are very cold your skeletal muscles increase contractions to generate more heat to warm you – this is known as shivering. When you exercise and your skeletal muscles are more active you produce more body heat and your body temperature increases. Your body will sweat to help cool itself.

The diaphragm is a skeletal muscle that contracts to allow us to inhale, we exhale when it relaxes. Any disruption in this important muscle’s function can be fatal. The diaphragm is a critical organ of the respiratory system.

Clearly, skeletal muscle and muscle tissue is much more important than just giving us a “buff” body!

learn by doing

The muscular system consists of skeletal muscle connected to bones via tendons. Tendons are a type of dense regular connective tissue that joins muscles to bone. The abdominal muscles are also held with broad tendon sheaths termed aponeuroses. In Seymour’s case either the muscle separated or pulled away from its aponeurosis that helped to anchor the muscle fibers together.

As mentioned, there are three types of muscle tissue. Skeletal muscle attaches to bones, is voluntary, and has a striped (striated) appearance. Cardiac muscle is found in the heart, is involuntary and is striated. Smooth, sometimes known as visceral muscle, is found in many organs and blood vessels, is not striated but is involuntary.

All muscle tissue is composed of muscle cells known as muscle fibers. These fibers are bundled and held together with connective tissue. The basic unit of the muscle cell is the sarcomere. Muscles contract because sarcomeres shorten. Calcium is essential for all types of muscle tissue to function properly. You will investigate the role of calcium in muscle contraction in this module.

Muscle contains many proteins, mainly myosin and actin. Skeletal muscle is under control of the nervous system and will not contract unless a neural command reaches the muscle and instructs it to do so. The nervous system communicates with skeletal muscle via chemical messengers known as neurotransmitters. The neurotransmitter, acetylcholine, is responsible to stimulating skeletal muscle so it contracts. The process of muscle contraction occurs at the cellular level and will be studied in this unit.

Muscle fibers or cells are not all alike. There are cells that are specialized for endurance events, these are known as slow-twitch fibers. There are also cells or fibers that are better suited for power and sprinting. These fatigue a lot faster and are known as fast-twitch fibers.

When you study the muscular system you will need to understand the microscopic anatomy and physiology so you can learn how muscle contracts. You will also study the gross anatomy of muscles, their names, locations, and functions in the human body. The muscular system is a fascinating system. Enjoy your journey as you discover it!

learn by doing

Skeletal muscles (organs) are almost never completely relaxed. Even if a muscle is not producing movement, some of the muscle fibers (cells) in the organ contract to produce muscle tone muscle tone low levels of muscle contraction . The tension produced by muscle tone prevents the muscle from becoming weak, allowing the muscle to stabilize joints and maintain posture. Muscle tone is accomplished by the contraction of a small fraction of muscle cells so muscles won't fatigue completely; some cells can recover while others are active. This can help with stronger movements, as the motor units being used to maintain tone can produce a quicker, stronger contraction than the motor units that are resting, avoiding the treppe stepwise increase in contraction tension that occurs with muscle fibers that are stimulated from a state of rest.

The absence of the low-level contractions that lead to muscle tone is referred to as hypotonia. Hypotonia can be caused by nervous system dysfunction or imbalances in certain ions in the blood stream. Hypotonic muscles have a flaccid appearance and display functional impairments. Conversely, excessive muscle tone is referred to as hypertonia. This takes two forms: spasticity, which is a type of stiffness related to uncontrolled reflexes, and rigidity, a stiffness not associated with reflexes.

learn by doing

## Isometric and Isotonic

There are two main types of skeletal muscle contractions: isotonic and isometric. When a muscle exerts a force, it exerts this force on a load. At the molecular level, cross-bridge formation occurs in both isotonic and isometric contractions, but the whole muscle acts differently depending on the load and the outcome to be achieved. In isotonic (iso- same, tonic - tension) contractions, a load is moved as the length of the muscle changes.

There are two types of isotonic contraction: concentric and eccentric. Concentric contractions involve the muscle shortening to move a load. An example of this is the biceps muscle shortening as a hand weight is brought upward and the angle of the elbow decreases. Eccentric contractions occur as the muscle lengthens. Eccentric contractions do not produce adequate force to move a load but are used for movement, balance, and resisting movement. An example of an eccentric contraction is the movement of a bicep as it performs the lowering portion of a biceps curl. A concentric contraction brings the arm upward, reducing the angle of the elbow, and then an eccentric contraction lowers the arm, resisting gravity and increasing the elbow angle slowly. The same muscle tension is required whether the muscle is shortening or lengthening.

Isometric (iso- same, metric- length) contractions occur as the muscle produces tension without changing length. Isometric contractions do not produce movement or lift loads; these contractions maintain posture and joint stability. For example, pushing against a wall produces no movement because the muscle simply cannot produce enough force and thus does not result in changes in muscle length. Conversely, holding your head in an upright position occurs not because the muscles cannot move the head, but because the goal is to remain stationary and not produce movement. In both of these cases, cross-bridge cycling occurs in the same manner as it would if the load had been moved. Most actions are the result of a combination of isotonic and isometric contractions working together to produce a wide range of outcomes.

All of the contraction that occurs before a load is lifted is isometric. Even when muscles carry no load, they must still develop a tension equal to the muscles' own weight before they can shorten. When contractile forces exceed the weight of the load, muscles begin shortening. Shortening stops when active tension falls to the point that it can no longer overcome and move the load. This converts it back to an isometric contraction.

learn by doing

It is relatively easy for someone to lift a glass of water. However, holding a glass of water at arm’s length for one full minute is difficult.

did I get this

Skeletal muscles, which are the organs of the skeletal muscle system, include three layers of connective tissue that enclose and provide structure to the muscle as a whole. The outer layer of each muscle fiber is wrapped with a layer of connective tissue called the epimysium ("epi-" means "outside" or "over," and "-mysium" refers to "muscle"). The epimysium allows muscle to contract and move powerfully while maintaining its structural integrity; it also separates muscle from other tissues and organs. It is composed of a thick layer of collagen fibers. The epimysium is surrounded by fascia, which is a type of connective tissue that is found around body organs. Deep fascia surrounds groups of muscles, sometimes joining with tendons to strengthen the bone attachment, whereas superficial fascia lies between muscle and skin. Some fascia contain adipose tissue that insulates and protects muscle.

Inside each skeletal muscle, muscle fibers (a single muscle cell is called a muscle fiber; not to be confused with fibers found in connective tissue) are organized into groups called fascicles, or bundles of muscle fibers (cells). Some of these fascicles can be seen without a microscope when a muscle is cut open. Each fascicle contains many long muscle fibers bound by a middle layer of connective tissue called the perimysium ("peri-" means "around"). Similar to the epimysium, the perimysium contains collagen fibers, but the perimysium also contains elastic fibers.

Inside each fascicle, each individual muscle fiber is encased in a connective tissue layer called the endomysium ("endo-" means "inside"). The endomysium forms a thinner layer than the dense epimysium and perimysium, and contains areolar and reticular tissues which form loose, delicate networks. The endomysium of muscle fibers connect to each other to form a loose complex within a fascicle. Small blood vessels and motor neurons pass through the endomysium to support and activate each muscle fiber.

The plasma membrane, or sarcolemma, of a skeletal muscle fiber is located just under the endomysium. The sarcolemma is the site of action potential conduction, which triggers muscle contraction. Within the sarcolemma is the sarcoplasm, the cytoplasm of the muscle cell.

Example

Muscular Dystrophy (MD) is a progressive weakening of skeletal muscles. Duchenne’s Muscular Dystrophy (DMD), the most common type of MD, is caused by a mutation in the dystrophin gene. Dystrophin helps the thin filaments of myofibrils bind to the sarcolemma and maintains equal force transmission through the muscle tissue. Without sufficient dystrophin, muscle contractions cause the sarcolemma to tear, causing an influx of Ca2+, leading to cellular damage and muscle fiber degradation. Over time, muscles are damaged and functional impairments develop.

DMD is an inherited disorder caused by an abnormal gene found on the X chromosome. It is one of many genetic diseases which are referred to as X-linked; X-linked disorders affect males since they only carry one copy of the X chromosome, which they inherited from their mother. Girls inherit one X chromosome from their mother and one from their father, so they are usually not affected. DMD is usually diagnosed in early childhood. It usually first appears as difficulty with balance and motion, and then progresses to an inability to walk. It continues progressing upwards in the body from the lower extremities to the upper body, where it affects the muscles responsible for breathing. It ultimately causes death due to respiratory failure, and those afflicted do not usually live past their twenties.

learn by doing
did I get this

The fascicles of parallel muscles are arranged parallel to the long axis of the muscle. They are equidistant and run in the same direction. The majority of skeletal muscles in the body follow this type of organization. With muscles that seem to be plump, the large mass of tissue located in the middle of the muscle is known as the central body, but its more common name is the belly. When the muscle contracts, the contractile fibers shorten into a large bulge. To see this, extend and then flex your biceps muscle. The large mass of the muscle is called the belly; tendons emerge from both ends of the muscle. When a muscle contracts, it is the pulling on the tendon by the muscle that actually produces the movement.

The fascicles of circular muscles, also called sphincters, are arranged around an opening in rings. When the muscle contracts, the size of the sphincter opening decreases. The orbicularis oris muscle is a circular muscle around the mouth under the lips. Another example is the orbicularis oculi ("ocular" means "eye"), which surrounds each eye. The circular muscles expand and contract in a circular way. The circular muscles contract and relax in a circular way. Think about how you can contract and shape your lips to whistle or pucker.

In convergent muscle, the fascicles extend from a broad, fan-shape area and converge on single attachment site where the muscle interacts with a tendon. .The large muscle on the chest, the pectoralis major, is an example of a convergent muscle. Because of the arrangement of motor units within a convergent muscle, it can be stimulated in different, smaller areas. This can change the direction of the muscle force slightly from when the entire muscle contracts at once.

Pennate muscles are feather-shaped and form different fascicle arrangements at an angle to the tendon. Contracting pennate muscles pull at an angle and can produce high tension, but don’t move tendons very far. There are three subtypes of pennate muscles: unipennate, bipennate, and multipennate muscles. In unipennate muscles, such as the extensor digitorum in the forearm, the fascicles are located on one side of the tendon. A bipennate muscle, such as the rectus femoris in the thigh, has fascicles on both sides of the tendon. If the tendon branches within a pennate muscle, as it does in the deltoid muscle of the shoulder, the muscle is referred to as multipennate.

Some parallel muscles are fusiform and have fascicles that are spindle-shaped to give the muscle a large belly, such as the biceps brachii, whereas triangular muscles can be convergent or multipennate to create triangular shapes. Triangular muscles include the trapezius, which extends from the head down the back and out to the shoulder.

did I get this

Skeletal muscles, which are the organs of the skeletal muscle system, generally act by pulling on bones to produce movement. To pull the bone, muscles need to attach to the bone, either directly or indirectly. The epimysium of a muscle can attach directly to bone or cartilage to form a direct attachment. An indirect attachment is formed when the connective tissue layers, the epimysium, perimysium, and endomysium form a complex at the end of the muscle.

For connections, muscles require either a tendon or a broader sheet of connective tissue called an aponeurosis. Muscles connect to muscles via aponeuroses, and muscles attach to bones via tendons or aponeuroses. Thus, when a muscle contracts, the force of movement is transmitted through the attachment, which pulls on the bone to produce skeletal movement.

Tendons also help to stabilize the joints. Tendons are a common form of attachment because the collagen fibers are more resistant to tearing than direct muscle tissue attachment to bone would be, and the compact form of the tendon requires a small amount of space. Tendons can be easily seen as the hand is flexed, causing the thick, cordlike tendons of the forearm to stand out prominently. The calcaneal (Achilles) tendon is visible from the heel to the calf. Some tendons are also surrounded by a connective tissue layer called a tendon sheath, which protects the tendon as it moves. Fluid-filled sacs called bursae also join to tendons to reduce friction as the tendon moves. Bursae are present in connective tissue near bone, where tendons experience friction, but they occasionally arise in other areas due to stress caused by movement.

Example

Bursae can become inflamed, a condition known as bursitis. This is usually caused by overuse of a joint or by other mechanical stress, which can result in pain and swelling. Bursitis is common in knees, elbows, and shoulders.

Keep in mind that the range of motion produced by muscles is restricted by the anatomy of the bones and other support structures involved in a particular joint. Consider the movements of the hip and shoulder joints, both of which are freely moveable. The hip is the attachment point for the thigh and leg. The shoulder is the attachment point for the arm and forearm. The shoulder can produce movements that the hip cannot because of the anatomy of the bones involved and the ligaments (connective tissue) associated with the joint. Hold your arm out to the side and move your thumb around the axis of the arm in a 360-degree circle. Can you do that with your hip and leg? No, you can’t. There are some people who appear to be “double-jointed"; they are able to push their joints past the normal limits of movement. The reason they can do this is because the ligaments of their joints are “loose” compared with someone who is not “double-jointed.” This ability appears to have a genetic basis.

For muscles attached to the bones of the skeleton, the location of the connection determines the force, speed, and type of movement. These characteristics depend on each other and can explain the general organization of the muscular and skeletal systems.

learn by doing
did I get this

We can consider the mechanisms by which muscles act on bones using descriptions based on levers. A lever is a rigid structure, in this case a bone, that moves on a fixed point called the fulcrum, in this case an articulation. A lever moves when an applied force or effort is sufficient to overcome any load or resistance that would otherwise oppose or prevent such movement. In the body, each bone is a lever and each joint is a fulcrum, and muscles supply the applied forces. Movement of the skeleton occurs at joints, so there has to be sufficient muscle power to move all the bones at these joints.

Levers can change the direction and effective strength of a force as well as the distance and speed of movement produced by the force. Imagine a seesaw in a playground. You and a friend could sit on opposite ends of it. You would then take turns pushing off the ground with your legs as you each went up in the air. A seesaw is an example of a first-class lever, and there are three classes of levers. The fulcrum (F) lies at the midpoint of the seesaw, between the applied force (AF) and the load (L). What this means is that the seesaw balances you and your friend, as you both provide the applied force with the push of your legs and the load with the weight of your bodies.

The body has only a few first-class levers. One is involved in head flexion (pulling the head down toward the chest) and head extension (pulling the head back up into normal position). The fulcrum is where the head moves in the sagittal plane on the first cervical vertebrae. The load is the weight of the head, and the applied force comes from the muscles. Extension occurs when the muscles pull the head back up. Moving your head forward and backward mirrors the action of a seesaw.

In a second-class lever, the load is located between the applied force and the fulcrum. When you move a load in a wheelbarrow, you lift upward on the handle and the wheel acts as the fulcrum. The force is further from the fulcrum than the load is, so you can move a larger weight with less effort. In the body, you achieve the same effect by standing on your toes. The fulcrum is on the ball of the foot, the load is your body weight, and the effort comes from the muscles in the back of the leg.

In third-class levers the force is applied between the load and the fulcrum. We don’t often see these types of levers in artificial machines, but they are the most common levers in the body. Speed and distance traveled are increased at the expense of force. For the biceps brachii in the arm, the load will be located in or around the hand. The biceps muscle applies the force, while the fulcrum is the elbow. For instance, when you pick up a full bag of groceries, you can lift it quickly using the third-class lever of the biceps brachii and the forearm. However, the location of fulcrum prevents great enhancements of load carrying.

did I get this

Skeletal muscles are arranged in pairs for balance and to work efficiently.

Some muscles function as agonists, or prime movers. An antagonist is a muscle that opposes the action of the agonist. When an agonist contracts to produce a movement, the corresponding antagonist will be stretched and contract with sufficient tension to control the movement. For instance, when your biceps muscle acts to flex your forearm, the triceps muscle contracts slightly to prevent you from flexing your forearm too quickly or too strongly.

Agonist and antagonist muscles work against one another to control and balance movements. Other muscles, called synergists (from synergy, to work together), improve the efficiency of an agonist muscle. Synergists may provide additional pull or stabilization, and their assistance to a particular movement may change throughout the progression of the movement.

This table provides examples of agonist-antagonist combinations.

Agonist Antagonist Movement
Biceps brachii—located on the anterior surface of the upper arm Triceps brachii—located on the posterior surface of the upper arm The biceps brachii flexes the forearm, while the triceps brachii extends it.
Hamstrings—group of three muscles located on the posterior of the thigh Quadriceps femoris—group of four muscles located on the anterior of the thigh The hamstrings flex the lower leg. The quadriceps femoris extend the lower leg.
Flexor digitorum superficialis and flexor digitorum profundus—located in and around the hand Extensor digitorum—located in and around the hand The flexor digitorum superficialis and flexor digitorum profundus flex the fingers and the hand at the wrist while the extensor digitorum extends the fingers and the hand at the wrist.
learn by doing

## Gross Anatomy of Muscles

Nomenclature for skeletal muscles is based on numerous criteria including: the location of the muscle, the shape, the orientation, the number of the muscle in a group, the action it generates and the location of its origin(s) and insertion(s). The origin is the unmoving, stable connection of the muscle to a structure, usually a bone. The insertion is the moveable end of the muscle, and it inserts onto various structures in the body.

Location: Some muscle names indicate the bones or body region with which the muscle is associated. For example, the frontalis muscle is located on top of the frontal bone of the skull. The rectus femoris (femur) and brachioradialis (arm and radius) are also good examples.

Shapes: Muscles with distinctive shapes are often named for the shape. The trapezius in the neck and back is similar to a trapezoid. You have already learned about muscles that have “orbicularis” in the name. The size of the muscle is the source of the names of the muscles of the buttocks: gluteus maximus (largest), gluteus medius (medium) and gluteus minimus (smallest). There are also muscles with names that contain brevis (short), longus (long), lateralis (lateral side or away from midline) and medialis (toward the midline). Some practice with the names of common muscles will help you with the descriptions that indicate muscle size or location.

Orientation: The direction of the muscle fibers and fascicles relative to the midline are also used to describe muscles, such as the rectus (straight) abdominis or the internal and external oblique (at an angle) muscles of the abdomen.

Numbers in a group: Some muscles are named according to the number of muscles in a “group.” One example of this is the quadriceps, a group of four muscles located on the anterior (front) of the thigh. Other muscle names can give you a clue as to how many origins a particular muscle has, such as the biceps brachii or triceps brachii. Bi- indicates that the muscle has two origins and tri- indicates three.

Action: When muscles are named for the movement they produce, you will find action words in their name. Some examples are flexor (decreases the angle at the joint), extensor (increases the angle at the joint), abductor (moves the bone away from the midline) or adductor (moves the bone toward the midline).

Attachments: The location of a muscle’s orientation and insertion can also be used in its name. For this classification, the origin is always named first. For instance, the sternocleidomastoid muscle of the neck has a dual origin on the sternum (sterno) and clavicle (cleido) and it inserts on the mastoid process of the temporal bone.

The following table lists important muscle terminology.

Name Definition Example
Direction Relative to the Midline of the Body
rectus straight rectus abdominis
transverse at right angle transverse abdominis
oblique diagonal external oblique
Relative Size
maximus largest gluteus maximus
medius medium gluteus medius
minimus smallest gluteus minimus
longus long longus capitis
brevis short extensor carpi radialis brevis
latissimus widest latissimus dorsi
longissimus longest longissimus thoracis
major larger rhomboid major
minor smaller rhomboid minor
vastus huge vastus medialis
Relative Shape
deltoid triangular deltoid
trapezius trapezoidal trapezius
serratus serrated serratus anterior
rhomboid diamond-shaped rhomboid minor
orbicularis circular orbicularis oris
pectinate comb-like pectineus
piriformis pear-shaped piriformis
platys flat platysma
gracilis slender gracilis
Action
flexor decreases the angle at a joint flexor digitorum superficialis
extensor increases the angle at a joint extensor digitorum
abductor moves the bone away from the midline abductor pollicis longus
levator elevates a body part levator scapulae
depressor lowers a body part depressor labii inferioris
supinator turns the palm anteriorly supinator
pronator turns the palm posteriorly pronator teres
sphincter decreases the size of an opening external anal sphincter
tensor tenses a body part tensor fasciae latae
rotator rotates a bone around its longitudinal axis rotator
Number of Origins
biceps two biceps brachii
triceps three triceps brachii
Example
##### Explicit Muscle Anatomy: Axial Muscles of the Face, Neck, and Head

There are more than 600 individually identified skeletal muscles in the human body. An entire course could be spent just learning the names, origins, insertions and actions of skeletal muscles and muscle groups of the body. This course presents an example of integrated muscle units, so that you can appreciate the complex integration of muscle anatomy and physiology.

Muscles can be classified either as axial or appendicular muscles, depending on whether they act on bones of the axial or appendicular skeleton, respectively. If we just look at the axial muscles, we can further divide them into groups on the basis of location, function, or both. Some of the axial muscles may seem to blur the boundaries due to the fact that they cross over to the appendicular skeleton. The muscles of the head and neck would be considered a subgroup of the axial muscles based on location.

This group can also be divided into those that insert into skin or those that insert on bones. The muscles in the face create facial expressions by inserting into the skin rather than onto bone. These muscles include the occipitofrontalis, orbicularis oris, buccinators, orbicularis oculi, and corrugator supercilii among others.

did I get this

The force generation required for skeletal muscle function occurs at the molecular level. You can develop a better understanding of the properties of cells and tissues by studying the molecular mechanisms common to the cells involved:

• Molecular level — actin and myosin
• Microscopic level — sarcomere and myofibrils
• Cell level — myoblasts and myofibers
• Tissue level — neuromuscular junctions and fascicles
• Organ level — major skeletal muscles of the body
did I get this
did I get this

Myosin is a protein that converts the chemical energy stored in the bonds of ATP into the kinetic energy of movement. Myosin is the force-generating protein in all muscle cells, and a coordinated effort among many myosin molecules pulling on actin, generates force for movement. Myosin molecules have two main structural parts. The tail of a myosin molecule consists of two polypeptide subunits wound together, whereas the head is composed of two globular subunits. The tail of a myosin molecule connects with other myosin molecules to form the central region of a thick filament, whereas the heads align on either end of the thick filament where thin filaments overlap with the thick filament. The point at which the head and tail of the molecule meet is flexible and allows the head to move back and forth. This allows myosin to “walk” and pull on actin filaments. Actin filaments are made of individual globular (spherical) protein subunits that assemble linearly into helical (twisted) filaments.

ATP binding to myosin causes it to release actin, allowing actin and myosin to detach from each other. After this occurs, ATP is converted to ADP and Pi. The binding site on myosin that hydrolyzes ATP to ADP is called ATPase. The energy released during ATP hydrolysis changes the angle of the myosin head into a “cocked” position. The myosin head is then in a position for further movement, possessing potential energy; however, ADP and Pi are still attached.

Cross-bridge formation occurs at this point, as actin binds while ADP and Pi are still bound to myosin. Pi is then released, causing myosin to form a stronger attachment to actin, and the myosin head moves toward the M line, pulling actin along with it. As actin is pulled, the filaments move approximately 10 nanometers toward the M line. This movement is called the power stroke, as the thin filament “slides” over the myosin and ADP is released during this step.

When the myosin head is “cocked,” myosin is in a high-energy configuration. This energy is expended as the myosin head moves through the power stroke. At the end of the power stroke, the myosin head is in a low-energy position. Each myosin molecule may form many cross-bridges during muscle contraction. The collection of power strokes and cross-bridges allows collections of individual molecules to generate large forces.

In skeletal muscle, tropomyosin and troponin regulate contraction by controlling the interaction between actin and myosin filaments. Tropomyosin acts to block myosin binding sites on the actin filament, preventing cross-bridge formation and thus preventing contraction in a relaxed muscle. Calcium triggers muscle contraction by binding to troponin and altering its shape so that tropomyosin does not block the myosin binding sites on actin, thus allowing muscle contraction to occur. Calcium is generally an important molecule in muscle function, as we will discuss later.

Titin, as the name implies, is a very large structural protein in muscle cells. Unlike actin and myosin, which bundle together to form a multiprotein complex, titin is a single protein that holds large structures together. Thus, titin is a large, multifunctional protein (hundreds of times bigger than these other proteins) that forms an elastic filament. Titin helps align the myosin proteins and allows the muscle cell to maintain structural integrity by resisting extreme stretching, preventing damage due to overstretching.

Dystrophin is a protein that helps bind actin to the muscle cell membrane. Insufficient dystrophin production results in an inability to transfer the force of the organized actin-myosin contraction to the muscle cell membrane and ultimately to the tendons. Loss or insufficient production of this molecule causes Duchenne muscular dystrophy (DMD).

learn by doing
Example
##### Rigor and Rigor Mortis

At the end of the power stroke, the actin-myosin cross-bridge is still in place (until ATP binds to the myosin head to change its shape). When energy is depleted, ATP is no longer available to bind to myosin; without ATP, actin remains bound to myosin, making both relaxation and further contraction impossible. This state, with an intact cross-bridge and depleted ATP, is called rigor.

This situation is exemplified during rigor mortis, which occurs after death. Dead cells can no longer produce ATP. Without ATP, the myosin heads can not detach from actin. Recall that ATP is required for the myosin to come off of the actin. Rigor mortis eventually subsides as proteins in the body, including actin and myosin, degrade.

did I get this

The fundamental functional unit of muscle is called a sarcomere. One muscle may contain as many as 100,000 of the repeating sarcomere units. In the sarcomere, the myofilaments (thick filaments and thin filaments) are organized into parallel units. Sarcomeres were first identified by imaging (histology), and the nomenclature described below reflects their microscopic "appearance."

## Molecular Organization of Muscle

Myofilaments are organized structures in muscle cells that contain the actin and myosin. The organized globular proteins of actin in muscle cells form a thin filament, and bundles of over 200 myosin proteins form a thick filament. The thick filament myosin heads “walk” along the actin thin filaments. A single thin filament is composed of 300-400 globular actins with 40-60 troponin and tropomyosin molecules. A single thick filament is composed of more than 200 myosin molecules.

Actin filaments are thin, causing the actin "rope" to appear skinny. The myosin filament contains many myosins bundled up with all of the head groups sticking out, so that it looks “fluffy.” That fluffiness makes it look thick.

learn by doing

## Sarcomere Anatomy—H Zone, M Line, Z Disc, I Band and A Band

Histological sections of muscle show the anatomical features of the sarcomeres. Thick filaments, composed of myosin, are visible as the A band of a sarcomere. Thin filaments, composed of actin, attach to a protein in the Z disc (or Z line) called alpha-actinin, and they are present across the entire length of the I band and a portion of the A band. The region where thick and thin filaments overlap has a dense appearance, as there is little space between the filaments. This zone where thin and thick filaments overlap is very important to muscle contraction, as it is the site where filament movement starts. Thin filaments do not extend completely into the A bands, leaving a central region of the A band that only contains thick filaments. This central region of the A band looks slightly lighter than the rest of the A band, and is called the H zone. The middle of the H zone has a vertical line called the M line, where accessory proteins hold together thick filaments.

Microscopically Visible Feature Composition
A band Region of thick-filament myosin proteins
H zone Central region of the A band with no overlapping actin proteins when muscle is relaxed
I band Region of thin-filament actin proteins, with no myosin
M line M line accessory proteins in center of myosin thick filament perpendicular to the sarcomere
Z disc Zig-zag line of Z line proteins and actin binding proteins perpendicular to the sarcomere
learn by doing

## Cellular Organelles and Structures

Muscle cells contain organelles found in all cells, including nuclei, the endoplasmic reticulum, mitochondria and the Golgi apparatus. The amount and organization of organelles and structures is slightly different in muscle cells. Actin is found inside every cell in the body, but actin is specially organized within the sarcomeres of muscle cells. Muscle cells also have extremely high numbers of mitochondria to produce ATP for force generation. Recall that an ATP molecule is required for one myosin to perform one power stroke.

Click here to review cells and organelles in the Levels of Organization unit.

## Organelles and Structures Specific to Muscle Cells

This image shows the internal organization of a muscle cell. The image is a light microscopic image of skeletal muscle in cross section showing a group muscle cells, each surrounded by epimysium and the group surrounded by perimysium. Blood vessels are seen passing through the image and in cross section on the right. The magnified image shows cross section of a single cell (fiber) at higher magnification with many myofibrils visible (small dark circles).

Each skeletal muscle fiber is a single cell produced from the fusion of many precursor cells. These fused cells are therefore functionally quite large, with diameters of up to 100 micrometers and lengths of up to 30 centimeters. Compare this with a cell of the skin which is a cube of 20 micrometers in nearly every diameter. In muscle fibers, sarcomeres arrange into parallel structures called myofibrils, so both the Z disc and the M line hold myofilaments in place to maintain the structural arrangement and layering. Myofibrils are connected to each other by intermediate, or desmin, filaments that attach to the Z disc.

There is some special nomenclature associated with these fused cells. Each skeletal muscle fiber cell has more than one nucleus, which is called multinucleate. The plasma membrane of this fused skeletal muscle cell is called the sarcolemma. The muscle interacts with the nerves that stimulate the muscle at the sarcolemma, and we will describe this interaction later. Within the sarcolemma is the sarcoplasm, which is the cytoplasm of the fused muscle fiber. The sarcoplasm has most of the same components as standard cytoplasm in addition to high levels of the protein myoglobin, which stores oxygen.

Also, the sarcolemma contains many structures similar to the plasma membrane of other cells, but it also possesses structures unique to muscle cells. The sarcolemma has transverse tubules, or T tubules, which are indentations of the sarcolemma into the interior of the cell along the length of the muscle cell. The T tubules are filled with extracellular fluid, and they conduct the action potential from the nerve deep into the interior of the muscle cells, which can be very large. With T-tubules, nerves can stimulate entire muscles and muscle groups quickly and effectively. Without T tubules, action potential conduction into the interior of the cell would happen much more slowly, causing delays between neural stimulation and muscle contraction, resulting in slower, weaker contractions.

Inside skeletal muscle fibers is a network of membranous tubules called the sarcoplasmic reticulum (SR), which is similar to the smooth endoplasmic reticulum found in other cells. SR tubules are filled with high-calcium fluid, and they surround each myofibril. Terminal cisternae are dilated regions of the SR that form on either side of each T tubule extending into the cell. A grouping consisting of a T tubule, from the outside of the muscle fiber, and two terminal cisternae, from the inside of the muscle fiber, is called a triad.

T tubules conduct an action potential along the surface of the muscle fiber into triads that trigger the release of Ca2+ ions from the nearby terminal cisternae. This, in turn, triggers muscle contraction when the calcium ions in the sarcoplasm can bind to the troponin of the sarcomeres.

did I get this

## Skeletal Myocytes—Myoblast Fusion, Myotube Organization in Skeletal Muscle Tissue and Satellite Cells

Each skeletal muscle fiber is a single skeletal muscle cell, also known as a skeletal myocyte ("myo-" refers to "muscle" and "-cyte" refers to "cell"), that is formed from the fusion of precursor cells. As described before, cell fusion leads to multinucleation of each mature muscle fiber. Each myoblast, the embryonic cell type that differentiates into muscle, contributes one nucleus when the muscle fiber is formed during development.

During development, individual myoblasts ("-blast" refers to "building" … like osteoblasts), migrate to different regions in the body and then fuse to form a myotube. A myotube is a type of syncytium, which is the term used for a group of fused cells. Skeletal muscle cells are multinucleate because the syncytium ("syn-" means "same" and "cyt" refers to "cytoplasm") fusion retains the nucleus of each contributing myoblast. This syncytium leads to the collective sarcoplasm and sarcolemma, described above.

Mature muscle does not grow by this process. Mature cells can change in size, but new cells are not formed when muscles grow. Instead, structural proteins are added to muscle fibers in a process called hypertrophy. The reverse, when structural proteins are lost and muscle mass decreases, is called atrophy. Cellular components of muscles can also undergo changes in response to changes in muscle use.

Although the number of muscle cells is set during development, satellite cells help to repair skeletal muscle fibers. Satellite cells are similar to myoblasts in that they are able to divide, fuse and differentiate. These satellite cells are located outside the muscle fibers and are stimulated to grow and fuse with muscle cells by growth factors that are released by muscle fibers under certain forms of stress. Satellite cells can regenerate muscle fibers to a very limited extent, but they primarily help to repair damage in living cells. Satellite cells facilitate the protein synthesis required for repair and growth. If a cell is damaged to a greater extent than can be repaired by satellite cells, the muscle fibers are replaced by scar tissue in a process called fibrosis. Because scar tissue cannot contract, muscle that has sustained significant damage loses strength and cannot produce the same amount of force or endurance as it could before being damaged.

learn by doing
did I get this

## Cardiac Myocytes

Cardiac tissue is only found in the walls of the heart chambers, where it provides the muscle contractions required to pump blood throughout the body. At the tissue level, cardiac muscle is striated (or striped) since, like skeletal muscle, it has organized sarcomeres. However, cardiac muscle fibers are shorter than skeletal muscle fibers and usually contain only one nucleus, which is located in the central region of the cell.

Cardiac muscle fibers are branched, whereas skeletal muscle fibers are unbranched. This branching allows individual cells to contact several adjacent cells at specialized cell junctions called intercalated discs. Intercalated discs are part of the sarcolemma and contain two structures important in cardiac muscle contraction: gap junctions and desmosomes. Gap junctions are tunnels or protein channels in the cell membrane connecting adjacent cardiac muscle cells, allowing ions involved in electric currents to move quickly from one cell to the next. This is called electric coupling, and in cardiac muscles, it allows the quick transmission of action potentials and synchronized contraction of the entire heart. Desmosomes are especially strong cell-to-cell junctions that help maintain structural integrity at the connections between these contractile cardiac muscle cells.

## Cardiac Cell Specialization

There are two specialized types of cardiac cells: the contractile cells and the pacemaker cells. The contractile cells that produce the force for the beating of the heart have the capability to beat on their own, but for useful organ level contractions, the cells must beat as a unit. The stimulus for contraction is normally provided by the pacemaker cells and this stimulus is passed through gap junctions to synchronize the signals. These electrically conductive pacemaker cells are important for electrical stimulation since cardiac muscle cells are not under voluntary control. Pacemaker cells are spontaneously depolarizing at set intervals (faster than contractile cells would do on their own), starting a wave of depolarization that then spreads throughout the heart and triggers contraction. Because the pacemaker cells are located in the heart, the heart is said to control its own contraction, which is called autorhythmicity (or automaticity). Pacemaker cells depolarize at set intervals, and the heart beats a steady, predictable 60 to 80 beats per minute at rest. These repetitive contractions ensure a constant blood supply to all body cells.

learn by doing
did I get this

Smooth muscle tissue is found in many different body systems, including as part of organs in the digestive, respiratory, and reproductive tracts and in the walls of blood vessels. Smooth muscle cells are approximately the same size as cardiac muscle cells and also have only one nucleus. However, smooth muscle cells are not branched and, unlike both cardiac and skeletal muscle, smooth muscle cells don't have sarcomeres. Smooth muscle cells form layers that are usually arranged so that one runs parallel to an organ and the other wraps around it. These two muscle layers then contract in turn, causing alternating dilation and contraction or lengthening and shortening of the organ, moving substances through internal passages. This is called peristalsis and is displayed in the process of digestion as food moves through the gastrointestinal tract.

Similar to skeletal and cardiac muscle cells, smooth muscle can undergo hypertrophy to increase in size. Unlike the other two muscle types, mature smooth muscle cells can also divide to produce more cells, a process called hyperplasia. This can be observed in the uterus, which responds to increased estrogen levels by producing more uterine muscle cells.

Smooth muscle cells also do not possess T tubules and do not have a very extensive sarcoplasmic reticulum. Smooth muscle has actin and myosin but they are not organized into sarcomeres, so there are no obvious bands or striations. Instead, actin and myosin is organized into dense bodies attached to the sarcolemma, shortening the muscle cell as thin filaments slide past thick filaments. Thin and thick filaments are aligned in a diagonal pattern across the cell so that contraction produces a twisting or corkscrew motion, rotating one way as it contracts and the other way as it relaxes. Cross-bridge formation and filament sliding processes are the same in smooth muscle as they are in skeletal and cardiac muscle. Actin, myosin, and tropomyosin are all present, but smooth muscle cells do not possess troponin as their regulatory protein. Instead, a molecule called calmodulin binds to calcium and activates myosin cross-bridge formation. There is also a greater ratio of actin to myosin in smooth muscle, meaning that there are more thin filaments for every thick filament.

Most smooth muscles must function for long periods without rest, so their power output is relatively low, but contractions can continue without utilizing large amounts of energy. This occurs because the ATPase in myosin works at a relatively slow rate, meaning that high levels of ATP are not available for powerful contractions but a steady supply is produced for sustained contractions. Smooth muscle can also maintain contractions through a latch state, during which actin and myosin remain locked together, or latched, in the absence of Ca2+ ions. This does not require ATP, thereby producing sustained contractions without using energy. This allows smooth muscles to keep your blood vessels partially contracted for your entire life without them fatiguing.

Similar to cardiac muscle, smooth muscle is not under voluntary control. In addition to spontaneous stimulation, smooth muscle can be stimulated by pacesetter cells that are similar to pacemaker cells and trigger waves of action potentials in smooth muscle. Smooth muscle can also be stimulated by the autonomic nervous system or hormones. Neuromuscular junctions are not present in smooth muscle, but varicosities, enlargements along autonomic nerves, release neurotransmitters into synaptic clefts. Smooth muscle can respond to a variety of neurotransmitters to produce different effects at different locations.

Smooth muscle can be divided into two types based on how depolarization and muscle contraction occur. Single-unit smooth muscle cells contain gap junctions, which allow the cells to be electrically coupled. Electric couplings allow action potentials to spread quickly from one cell to the next, permitting coordinated depolarization and contraction. In this manner, groups of muscle cells act as a single unit, contracting in unison. This type of smooth muscle is found in hollow organs, including the gastrointestinal tract, and in the walls of small blood vessels, and it is often stimulated spontaneously or by stretching, to produce an action potential.

Multiunit smooth muscle cells rarely possess gap junctions, so they are not electrically coupled. Stimuli for multiunit smooth muscles come from autonomic nerves or hormones but not from stretching. This type of tissue is found in the walls of large blood vessels, in the respiratory airways, and connected to hair follicles (to make your hair "stand up”), among other places.

learn by doing
did I get this

Skeletal muscle cell contraction occurs after a release of calcium ions from internal stores, which is initiated by a neural signal. Each skeletal muscle fiber is controlled by a motor neuron, which conducts signals from the brain or spinal cord to the muscle.

The following list presents an overview of the sequence of events involved in the contraction cycle of skeletal muscle:

1. The action potential travels down the neuron to the presynaptic axon terminal.
2. Voltage-dependent calcium channels open and Ca2+ ions flow from the extracellular fluid into the presynaptic neuron's cytosol.
3. The influx of Ca2+ causes neurotransmitter (acetylcholine)-containing vesicles to dock and fuse to the presynaptic neuron's cell membrane.
4. Vesicle membrane fusion with the nerve cell membrane results in the emptying of the neurotransmitter into the synaptic cleft; this process is called exocytosis.
5. Acetylcholine diffuses into the synaptic cleft and binds to the nicotinic acetylcholine receptors in the motor end-plate.
6. The nicotinic acetylcholine receptors are ligand-gated cation channels, and open when bound to acetylcholine.
7. The receptors open, allowing sodium ions to flow into the muscle's cytosol.
8. The electrochemical gradient across the muscle plasma membrane causes a local depolarization of the motor end-plate.
9. The receptors open, allowing sodium ions to flow into and potassium ions to flow out of the muscle's cytosol.
10. The electrochemical gradient across the muscle plasma membrane (more sodium moves in than potassium out) causes a local depolarization of the motor end-plate.
11. This depolarization initiates an action potential on the muscle fiber cell membrane (sarcolemma) that travels across the surface of the muscle fiber.
12. The action potentials travel from the surface of the muscle cell along the membrane of T tubules that penetrate into the cytosol of the cell.
13. Action potentials along the T tubules cause voltage-dependent calcium release channels in the sarcoplasmic reticulum to open, and release Ca2+ ions from their storage place in the cisternae.
14. Ca2+ ions diffuse through the cytoplasm where they bind to troponin, ultimately allowing myosin to interact with actin in the sarcomere; this sequence of events is called excitation-contraction coupling.
15. As long as ATP and some other nutrients are available, the mechanical events of contraction occur.
16. Meanwhile, back at the neuromuscular junction, acetylcholine has moved off of the acetylcholine receptor and is degraded by the enzyme acetylcholinesterase (into choline and acetate groups), causing termination of the signal.
17. The choline is recycled back into the presynaptic terminal, where it is used to synthesize new acetylcholine molecules.
did I get this

## Anatomy

We stimulate skeletal muscle contraction voluntarily. Electrical signals from the brain through the spinal cord travel through the axon of the motor neuron. The axon then branches through the muscle and connects to the individual muscle fibers at the neuromuscular junction. The folded sarcolemma of the muscle fiber that interacts with the neuron is called the motor end-plate; the folded sarcolemma increases surface area contact with receptors. The ends of the branches of the axon are called the synaptic terminals, and do not actually contact the motor end-plate. A synaptic cleft separates the synaptic terminal from the motor end-plate, but only by a few nanometers.

Communication occurs between a neuron and a muscle fiber through neurotransmitters. Neural excitation causes the release of neurotransmitters from the synaptic terminal into the synaptic cleft, where they can then bind to the appropriate receptors on the motor end-plate. The motor end-plate has folds in the sarcolemma, called junctional folds, that create a large surface area for the neurotransmitter to bind to receptors. Generally, there are many folds and invaginations that increase surface area including junctional folds at the motor endplate and the T-tubules throughout the cells.

did I get this

## Physiology

The neurotransmitter acetylcholine is released when an action potential travels down the axon of the motor neuron, resulting in altered permeability of the synaptic terminal and an influx of calcium into the neuron. The calcium influx triggers synaptic vesicles, which package neurotransmitters, to bind to the presynaptic membrane and to release acetylcholine into the synaptic cleft by exocytosis.

Review the section of this course about membranes if you need a refresher.

The balance of ions inside and outside a resting membrane creates an electric potential difference across the membrane. This means that the inside of the sarcolemma has an overall negative charge relative to the outside of the membrane, which has an overall positive charge, causing the membrane to be polarized. Once released from the synaptic terminal, acetylcholine diffuses across the synaptic cleft to the motor end-plate, where it binds to acetylcholine receptors, primarily the nicotinic acetylcholine receptors. This binding causes activation of ion channels in the motor end-plate, which increases permeability of ions via activation of ion channels: sodium ions flow into the muscle and potassium ions flow out. Both sodium and potassium ions contribute to the voltage difference while ion channels control their movement into and out of the cell. As a neurotransmitter binds, these ion channels open, and Na+ ions enter the membrane. This reduces the voltage difference between the inside and outside of the cell, which is called depolarization. As acetylcholine binds at the motor-end plate, this depolarization is called an end-plate potential. It then spreads along the sarcolemma, creating an action potential as voltage-dependent (voltage-gated) sodium channels adjacent to the initial depolarization site open. The action potential moves across the entire cell membrane, creating a wave of depolarization.

After depolarization, the membrane needs to be returned to its resting state. This is called repolarization, during which sodium channels close and potassium channels open. Because positive potassium ions (K+) move from the intracellular space to the extracellular space, this allows the inside of the cell to again become negatively charged relative to the outside. During repolarization, and for some time after, the cell enters a refractory period, during which the membrane cannot become depolarized again. This is because in order to have another action potential, sodium channels need to return to their resting state, which requires an intermediate step with a delay.

Propagation of an action potential and depolarization of the sarcolemma comprise the excitation portion of excitation-contraction coupling, the connection of electrical activity and mechanical contraction. The structures responsible for coupling this excitation to contraction are the T tubules and sarcoplasmic reticulum (SR). The T tubules are extensions of the sarcolemma and thus carry the action potential along their surface, conducting the wave of depolarization into the interior of the cell. T tubules form triads with the ends of two SR called terminal cisternae. SRs, and especially terminal cisternae, contain high concentrations of Ca2+ ions inside. As an action potential travels along the T tubule, the nearby terminal cisternae open their voltage-dependent calcium release channels, allowing Ca2+ to diffuse into the sarcoplasm. The influx of Ca2+ increases the amount of calcium available to bind to troponin. Troponin bound to Ca2+ undergoes a conformational change that results in tropomyosin moving on the actin filament. When tropomyosin moves, the myosin binding site on the actin is uncovered. This continues as long as excess Ca2+ is available in the sarcoplasm. When there is no more free Ca2+ available to bind to troponin, the contraction will stop. To restore Ca2+ levels back to a resting state, the excess Ca2+ is actively transported back into the SR. In a resting state, Ca2+ is retained inside the SR, keeping sarcoplasmic Ca2+ levels low. Low sarcoplasmic calcium levels prevent unwanted muscle contraction.

learn by doing
did I get this

Acetylcholine, often abbreviated as ACh, is a neurotransmitter released by motor neurons that binds to receptors in the motor end-plate. It is an extremely important small molecule in human physiology. On the neuron side of the synaptic cleft, there are typically 300,000 vesicles waiting to be exocytosed at any time and each vesicle contains up to 10,000 molecules of acetylcholine.

ACh is produced by the reaction of Acetyl coenzyme A (CoA) with a choline molecule in the neuron cell body. After it is packaged, transported, and released, it binds to the acetylcholine receptor on the motor end-plate; it is degraded in the synaptic cleft by the enzyme acetylcholinesterase (AChE) into acetate (and acetic acid) and choline. The choline is recycled back into the neuron. AChE resides in the synaptic cleft, breaking down ACh so that it does not remain bound to ACh receptors, which would interrupt normal control of muscle contraction. In some cases, insufficient amounts of ACh prevent normal muscle contraction and cause muscle weakness.

Example
##### Botulinum's Effect on ACh

Botulinum toxin prevents ACh from being released into the synaptic cleft. With no ACh binding to its receptors at the motor end-plate, no action potential is produced, and muscle contraction cannot occur. Botulinum toxin is produced by Clostridium botulinum, a bacterium sometimes found in improperly canned foods. Ingestion of very small amounts can cause botulism, which can cause death due to the paralysis of skeletal muscles, including those required for breathing.

learn by doing
did I get this

ATP supplies the energy for muscle contraction to take place. In addition to its direct role in the cross-bridge cycle, ATP also provides the energy for the active-transport Na+/K+ and Ca2+ pumps. Muscle contraction does not occur without sufficient amounts of ATP. The amount of ATP stored in muscle is very low, only sufficient to power a few seconds worth of contractions. As it is broken down, ATP must therefore be regenerated and replaced quickly to allow for sustained contraction.

did I get this

One ATP moves one myosin head one step. This can generate three picoNewtons (pN) of isometric force, or move 11 nanometers. Three pN is a very small force—a human bite, generated by muscle, can generate 500 trillion pN of force. And 11 nm is a very small distance— one inch has 25 million nanometers.

There are three mechanisms by which ATP can be regenerated: creatine phosphate metabolism, anaerobic glycolysis, and aerobic respiration.

Creatine phosphate is a phosphagen, which is a compound that can store energy in its phosphate bonds. In a resting muscle, excess ATP (adenosine triphosphate) transfers its energy to creatine, producing ADP (adenosine diphosphate) and creatine phosphate. When the muscle starts to contract and needs energy, creatine phosphate and ADP are converted into ATP and creatine by the enzyme creatine kinase. This reaction occurs very quickly; thus, phosphagen-derived ATP powers the first few seconds of muscle contraction. However, creatine phosphate can only provide approximately 15 seconds worth of energy, at which point another energy source has to be available.

After the available ATP from creatine phosphate is depleted, muscles generate ATP using glycolysis. Glycolysis is an anaerobic process that breaks down glucose (sugar) to produce ATP; however, glycolysis cannot generate ATP as quickly as creatine phosphate. The sugar used in glycolysis can be provided by blood glucose or by metabolizing glycogen that is stored in the muscle. Each glucose molecule produces two ATP and two molecules of pyruvate, which can be used in aerobic respiration or converted to lactic acid.

If oxygen is available, pyruvic acid is used in aerobic respiration. However, if oxygen is not available, pyruvic acid is converted into lactic acid, which may contribute to muscle fatigue and pain. This occurs during strenuous exercise when high amounts of energy are needed but oxygen cannot be delivered to muscle at a rate fast enough to meet the whole need. Anaerobic glycolysis cannot be sustained for very long (approximately one minute of muscle activity), but it is useful in facilitating short bursts of high-intensity output. Glycolysis does not utilize glucose very efficiently, producing only two ATP molecules per molecule of glucose, and the by-product lactic acid contributes to muscle fatigue as it accumulates. Lactic acid is transported out of the muscle into the bloodstream, but if this does not happen quickly enough, lactic acid can cause cellular pH levels to drop, affecting enzyme activity and interfering with muscle contraction.

Aerobic respiration is the breakdown of glucose in the presence of oxygen to produce carbon dioxide, water, and ATP. Aerobic respiration in the mitochondria of muscles uses glycogen from muscle stores, blood glucose, pyruvic acid, and fatty acids. Approximately 95 percent of the ATP required for resting or moderately active muscles is provided by aerobic respiration. Aerobic respiration is much more efficient than anaerobic glycolysis, producing approximately 38 ATP molecules per molecule of glucose. However, aerobic respiration does not synthesize ATP as quickly as anaerobic glycolysis, meaning that the power output of muscles declines, but lower-power contractions can be sustained for longer periods.

Phosphorylation of creatine phosphate Anaerobic glycolysis Aerobic metabolism
Energy source Creatine phosphate Glucose Glucose, pyruvic acid, fatty acids
Rate of ATP synthesis Very fast Fast Slow
Number of ATPs produced per unit 1 2 38
Oxygen required No No Yes

This combination of different energy sources is important for different types of muscle activity. As an analogy, a cup of coffee with lots of sugar provides a quick burst of energy but not for very long. A balanced meal with complex carbohydrates, protein and fats takes longer to impact us, but provides sustained energy.

Muscles require a large amount of energy, and thus require a constant supply of oxygen and nutrients. Blood vessels enter muscle at its surface, after which they are distributed through the entire muscle. Blood vessels and capillaries are found in the connective tissue that surrounds muscle fascicles and fibers, allowing oxygen and nutrients to be supplied to muscle cells and metabolic waste to be removed. Myoglobin, which binds oxygen similarly to hemoglobin and gives muscle its red color, is found in the sarcoplasm.

Example
##### Exercise and Energy

After the first few seconds of exercise, available ATP is used up. After the next few minutes, cellular glucose and glycogen are depleted. After the next 30 minutes, the body's supply of glucose and glycogen are depleted. After that time, fatty acids and other energy sources are used to make ATP. That’s why we should exercise for more than 30 minutes to lose weight (i.e. lose fat). Sometimes, time is important.

learn by doing

You have already learned about the anatomy of the sarcomere,with its coordinated actin thin filaments and myosin thick filaments. For a muscle cell to contract, the sarcomere must shorten in response to a nerve impulse. The thick and thin filaments do not shorten, but they slide by one another, causing the sarcomere to shorten while the filaments remain the same length. This process is known as the sliding filament model of muscle contraction. The mechanism of contraction is accomplished by the binding of myosin to actin, resulting in the formation of cross-bridges that generate filament movement.

When a sarcomere shortens, some regions shorten while others remain the same length. A sarcomere is defined as the distance between two consecutive Z discs or Z lines. When a muscle contracts, the distance between the Z discs is reduced. The H zone, the central region of the A zone, contains only thick filaments and shortens during contraction. The I band contains only thin filaments and also shortens. The A band does not shorten; it remains the same length, but A bands of adjacent sarcomeres move closer together during contraction. Thin filaments are pulled by the thick filaments towards the center of the sarcomere until the Z discs approach the thick filaments. The zone of overlap, where thin filaments and thick filaments occupy the same area, increases as the thin filaments move inward.

The ideal length of a sarcomere to produce maximal tension occurs when all of the thick and thin filaments overlap. If a sarcomere is stretched past this ideal length, some of the myosin heads in the thick filaments are not in contact with the actin in the thin filaments, and fewer cross-bridges can form. This results in fewer myosin heads pulling on actin, and less tension is produced. If a sarcomere is shortened, the zone of overlap is reduced as the thin filaments reach the H zone, which is composed of myosin tails. Because myosin heads form cross-bridges, actin will not bind to myosin in this zone, again reducing the tension produced by the muscle. If further shortening of the sarcomere occurs, thin filaments begin to overlap with each other, further reducing cross-bridge formation and the amount of tension produced. If the muscle were stretched to the point where thick and thin filaments do not overlap at all, no cross-bridges are formed, and no tension is produced. This amount of stretching does not usually occur, as accessory proteins and connective tissue oppose extreme stretching.

learn by doing

With large numbers of relatively weak molecular motors, we can more easily adjust the force to meet our needs. Otherwise, we would regularly be producing too little or too much force for most of our tasks. Also, molecules are only capable of generating small forces based on their molecular structure.

did I get this

You have already learned about how the information from a neuron ultimately leads to a muscle cell contraction.

Revisit previous material for a review of neuromuscular junctions.

One action potential in a motor neuron produces one contraction. This contraction is called a twitch. We think of "muscle twitches" as spasms that we can’t control, but in physiology, a twitch is a technical term describing a muscle response to stimulation. A single twitch does not produce any significant muscle contraction. Multiple action potentials (repeated stimulation) are needed to produce a muscle contraction that can produce work.

A twitch can last from a few milliseconds up to 100 milliseconds, depending on the muscle type. The tension produced by a single twitch can be measured by a myogram, which produces a graph illustrating the amount of tension produced over time. When combined with a plot of electrical signaling, the myogram shows three phases that each twitch undergoes. The first period is the latent period, during which the action potential is being propagated along the membrane and Ca2+ ions are released from the sarcoplasmic reticulum (SR). No tension or contraction is produced at this point, but the conditions for contraction are being established. This is the phase during which excitation and contraction are being coupled but contraction has yet to occur. The contraction phase occurs after the latent period when calcium is being used to trigger cross-bridge formation. This period lasts from the beginning of contraction to the point of peak tension. The last phase is the relaxation phase, when tension decreases as contraction stops. Calcium is pumped out of the sarcoplasm, back into the SR, and cross-bridge cycling stops. The muscle returns to a resting state. There is a very short refractory period after the relaxation phase (Review the previous material about the physiology of a neuromuscular junction)

A single twitch does not produce any significant muscle activity in a living body. Normal muscle contraction is more sustained, and it can be modified to produce varying amounts of force. This is called a graded muscle response. The tension produced in a skeletal muscle is a function of both the frequency of neural stimulation and the number of motor neurons involved.

The rate at which a motor neuron delivers action potentials affects the contraction produced in a muscle cell. If a muscle cell is stimulated while a previous twitch is still occurring, the second twitch will not have the same strength as the first; it will be stronger. This effect is called summation, or wave summation, because the effects of successive neural stimuli are summed, or added together. This occurs because the second stimulus releases more Ca2+ ions, which become available while the muscle is still contracting from the first stimulus (the first wave of calcium ions released). This allows for more cross-bridge formation and greater contraction. Because the second stimulus has to arrive before the first twitch has completed, the frequency of stimulus determines whether summation occurs or not.

If the frequency of stimulation increases to the point at which each successive stimulus sums with the force generated from the previous stimulus, muscle tension continues to rise until the tension generated reaches a peak point. The tension at this point is about three to four times higher than the tension of a single twitch; this is referred to as incomplete tetanus. Tetanus is defined as continuous fused contraction. During incomplete tetanus, the muscle goes through quick cycles of contraction with a short relaxation phase. If the stimulus frequency is so high that the relaxation phase disappears completely, contractions become continuous in a process called complete tetanus. This occurs when Ca2+ concentrations in the sarcoplasm reach a point at which contractions can continue uninterrupted. This contraction continues until the muscle fatigues and can no longer produce tension.

This type of tetanus is not the same as the disease of the same name that is distinguished by severe sustained contraction of skeletal muscles. The disease, which can be fatal if left untreated, is caused by the bacterium Clostridium tetani, which is present in most environments. The toxin from the bacterium affects how motor neurons communicate and control muscle contractions, resulting in muscle spasms or sustained contractions, also known as “lockjaw.”

Slightly different from incomplete tetanus is the phenomenon of treppe. Treppe (from the German term for step, referring to stepwise increases in contraction) is a condition in which successive stimuli produce a greater amount of tension, even though tension goes back to the resting state between stimuli (in tetanus, tension does not decrease to the resting state between stimuli). Treppe is similar to tetanus in that the first twitch releases calcium into the sarcoplasm, some of which will not be taken back up before the next contraction. Each stimulus afterward releases more calcium, but there is still some calcium present in the sarcoplasm from the previous stimulus. This extra calcium permits more cross-bridge formation and greater contraction with each additional stimulus up to the point where added calcium cannot be utilized. At this point, successive stimuli will produce a uniform amount of tension.

The strength of contractions is controlled not only by the frequency of stimuli but also by the number of motor units involved in a contraction. A motor unit is defined as a single motor neuron and the corresponding muscle fibers it controls. Increasing the frequency of neural stimulation can increase the tension produced by a single motor unit, but this can only produce a limited amount of tension in a skeletal muscle. To produce more tension in an entire skeletal muscle, the number of motor units involved in contraction must be increased. This process is called recruitment.

The size of motor units varies with the sizes of muscle. Small muscles contain smaller motor units and are most useful for fine motor movements. Larger muscles tend to have larger motor units because they are generally not involved in fine control. Even within a muscle, motor units vary in size. Generally, when a muscle contracts, small motor units will be the first ones recruited in a muscle, with larger motor units added as more force is needed.

All of the motor units in a muscle can be active simultaneously, producing a very powerful contraction. This cannot last for very long because of the energy requirements of muscle contraction. To prevent complete muscle fatigue, typically motor units in a given muscle are not all simultaneously active, but instead, some motor units rest, while others are active, allowing for longer muscle contractions by the muscle as a whole.

The action potentials produced by pacemaker cells in cardiac muscle are longer than those produced by motor neurons that stimulate skeletal muscle contraction. Thus, cardiac contractions are approximately ten times longer than skeletal muscle contractions. Because of long refractory periods, new action potential cannot reach a cardiac muscle cell before it has entered the relaxation phase, meaning that the sustained contractions of tetanus are impossible. If tetanus were to occur, the heart would not beat regularly, interrupting the flow of blood through the body.

learn by doing
did I get this

Muscle contractions are among the largest energy-consuming processes in the body, which is not surprising considering the work that muscles constantly do. Skeletal muscles move the body in obvious ways such as walking and in less noticeable ways such as facilitating respiration. The structure of muscle cells at the microscopic level allows them to convert the chemical energy found in ATP into the mechanical energy of movement. The proteins actin and myosin play large roles in producing this movement.

## Skeletal Muscle Anatomy

Recall all of the structures of the fused skeletal muscle cell. If you need to, review organelles and structures specific to the skeletal muscle cells.

Structures analogous to other cell organelles:

• Sarcolemma—the membrane of the fused skeletal fiber.
• Sarcoplasm—the cytoplasm of the fused skeletal fiber.
• Sarcoplasmic reticulum—the endoplasmic reticulum of the fused skeletal fiber.

Specialized structures in muscle cells:

• Transverse tubules (T tubules)—sarcolemma tubes filled with extracellular fluid that coordinate conduction in large muscle cells.
• Terminal cisternae—enlarged sarcoplasmic reticulum structures store calcium and surround T tubules.
• Triad—one T tubule and two terminal cisternae.
learn by doing
did I get this

## Skeletal Muscle Fiber Types

There are three main types of skeletal muscle fibers (cells): slow oxidative (SO), which primarily uses aerobic respiration; fast oxidative (FO), which is an intermediate between slow oxidative and fast glycolytic fibers; and fast glycolytic (FG), which primarily uses anaerobic glycolysis. Fibers are defined as slow or fast based on how quickly they contract. The speed of contraction is dependent on how quickly the ATPase of myosin can hydrolyse ATP to produce cross-bridge action. Fast fibers hydrolyse ATP approximately twice as quickly as slow fibers, resulting in quicker cross-bridge cycling. The primary metabolic pathway used determines whether a fiber is oxidative or glycolytic. If a fiber primarily produces ATP through aerobic pathways, it is oxidative. Glycolytic fibers primarily create ATP through anaerobic glycolysis.

Since SO fibers function for long periods without fatigue, they are used to maintain posture, producing isometric contractions useful for stabilizing bones and joints, and making small movements that happen often but do not require large amounts of energy. They do not produce high tension, so they are not used for powerful, fast movements that require high amounts of energy and rapid cross-bridge cycling.

FO fibers are sometimes called intermediate fibers because they possess characteristics that are intermediate between fast fibers and slow fibers. They produce ATP relatively quickly, more quickly than SO fibers, and thus can produce relatively high amounts of tension. They are oxidative because they produce ATP aerobically, possess high numbers of mitochondria, and do not fatigue quickly. FO fibers do not possess significant myoglobin, giving them a lighter color than the red SO fibers. FO fibers are used primarily for movements, such as walking, that require more energy than postural control but less energy than an explosive movement such as sprinting. FO fibers are useful for this type of movement because they produce more tension than SO fibers and they are more fatigue-resistant than FG fibers.

FG fibers primarily use anaerobic glycolysis as their ATP source. They have a large diameter and possess high amounts of glycogen, which is used in glycolysis to generate ATP quickly; thus, they produce high levels of tension. Because they do not primarily use aerobic metabolism, they do not possess substantial numbers of mitochondria nor large amounts of myoglobin and therefore have a white color. FG fibers are used to produce rapid, forceful contractions to make quick, powerful movements. However, these fibers fatigue quickly, permitting them to only be used for short periods.

Most muscles (organs) possess a mixture of each fiber (cell) type. The predominant fiber type in a muscle is determined by the primary function of the muscle. Large muscles used for powerful movements contain more fast fibers than slow fibers. As such, different muscles have different speeds and different abilities to maintain contraction over time. The proportion of these different kinds of muscle fibers will vary among different people and can change within a person with conditioning.

learn by doing
learn by doing
learn by doing
did I get this
did I get this
did I get this

Skeletal muscles contribute to maintaining temperature homeostasis in the body by generating heat. Muscle contraction requires energy and produces heat as a byproduct of metabolism. All types of muscle produce heat, but because of the large amount of skeletal muscle present in the body, skeletal muscle contributes most greatly to heat production. This is very noticeable during exercise, when sustained muscle movement causes body temperature to rise. In cases of extreme cold, shivering produces random skeletal muscle contractions to generate heat as part of the negative feedback mechanism of maintaining body temperature.

Example
##### Malignant Hyperthermia

Our body can use skeletal muscle contractions to maintain body temperature when we are cold, but excessive contractions can lead to the body overheating to the point that the body’s metabolic reactions are interrupted. This can occur in a condition called malignant hyperthermia, which develops in genetically susceptible individuals who are administered a specific combination of anesthetic agents during surgery. In these individuals, a drastic increase in skeletal muscle calcium leads to sustained contractions and heat generation. Because the individuals are anesthetized, they have little ability to cool themselves. If proper interventions are not administered, they will die due to a greatly increased body temperature. Because this condition is genetic, patients are asked prior to surgery if there is a family history of such problems occurring.

learn by doing
did I get this

Physical training alters the appearance of skeletal muscles and can produce changes in muscle performance. Conversely, a lack of use can result in decreased performance and muscle appearance. As you learned earlier, mature muscle cells grow from hypertrophy, not cell division. The loss of structural proteins and muscle mass occurs during atrophy. Cellular components of muscles can also undergo changes in response to changes in muscle use.

Example
##### Sarcopenia

Although atrophy due to disuse can often be reversed with exercise, muscle atrophy that comes with age is irreversible. This is why even highly trained athletes succumb to declining performance with age, although extensive training may slow the decline. This is especially noticeable in sports that require an explosion of strength and power over a very short period of time. Examples of these kinds of sports include sprinting, competitive weight lifting, gymnastics and diving. The effects of age are less noticeable in endurance sports such as marathon running or long-distance cycling. Age-related muscle atrophy is called sarcopenia. As muscles age, muscle fibers die, and they are replaced by connective tissue and adipose tissue. Because those tissues cannot contract as muscle can, muscles lose the ability to produce powerful contractions. The decline in muscle mass causes a loss of strength, including strength required for posture and mobility. This may be caused by a reduction in the proportion of FG fibers that hydrolyse ATP quickly to produce short, powerful contractions. Muscles in older people sometimes possess greater numbers of SO fibers, which are responsible for longer contractions and do not produce powerful movements. There may also be a reduction in motor units, resulting in fewer fibers being stimulated and less muscle tension being produced.

Example
##### Anabolic Steroids

Some athletes attempt to boost their performance by using various agents that may enhance muscle performance. Anabolic steroids are one of the more widely known agents used to boost muscle mass and increase power output. Anabolic steroids are a form of testosterone, a male sex hormone that stimulates muscle formation, leading to increased muscle mass. They have been used by athletes in many sports, but sprinting is one sport in which the effects of steroids are readily apparent. Because a 100-meter dash can last less than 10 seconds, incredible amounts of power need to be created by the muscles. Increasing the muscle mass increases the numbers of actin and myosin cross-bridges, increasing the power that can be produced by a muscle, which provides a competitive advantage in a sport measured in hundredths of seconds. Similarly, creatine has become a substance used by some athletes to increase power output. Because creatine phosphate provides quick bursts of ATP to muscles in the initial stages of contraction, increasing the amount available to cells is thought to produce more ATP and therefore increase explosive power output. However, both creatine and steroids are banned in sports and they can be extremely harmful to other systems of the body as well as to long-term muscle health.

Slow fibers are predominantly used in endurance exercises that require little force but involve numerous repetitions. The aerobic metabolism used by slow-twitch fibers allows them to maintain contractions over long periods. Endurance training modifies these slow fibers to make them even more efficient by producing more mitochondria to enable more aerobic metabolism and more ATP production. Endurance exercise can also increase the amount of myoglobin in a cell, as increased aerobic respiration increases the need for oxygen. Myoglobin is found in the sarcoplasm and stores oxygen. Endurance training can also trigger the formation of more extensive capillary networks around the fiber, a process called angiogenesis, to supply oxygen and remove metabolic waste. To allow these capillary networks to supply the deep portions of the muscle, muscle mass does not greatly increase, maintaining a shorter distance for the diffusion of nutrients and gases. All of these cellular changes result in the ability to sustain low levels of muscle contraction for greater periods of time without fatiguing.

Example
##### EPO

Endurance athletes also engage in drug use, but instead of trying to add muscle mass or produce power, they focus on substances that increase muscle endurance and reduce fatigue. This includes trying to boost the availability of oxygen to muscles to increase aerobic respiration by using substances such as erythropoietin, or EPO. EPO is a hormone that triggers the production of red blood cells, which carry oxygen in the blood. This oxygen can then be used by muscles for aerobic respiration. Human growth hormone is another commonly used agent, and although it can facilitate building muscle mass, its main role is to promote the healing of muscle and other tissues after strenuous exercise. Increased growth hormone allows for faster recovery after muscle damage, reducing the rest required after exercise, and allowing for more sustained high-level performance. As with creatine and steroids, these substances are harmful to the body and can negatively impact the homeostasis of other systems.

As discussed previously, there are a number of proteins that are important in regulating and carrying out the contractile process. Thus there are genetic disorders that lead to altered protein formation and dysfunction of the muscular system. Such dysfunction tends to affect many body systems, of which the respiratory system may be most important. Without the ability to appropriately contract the skeletal muscles of respiration, people cannot live very long. The skeletal muscular system is also very dependent upon a constant supply of ATP. Like many other systems, this requires the intracellular pathways to convert glucose into energy.

Example
##### Beriberi

Thiamine (vitamin B1) is a necessary cofactor in the production of ATP from glucose. Deficiencies in thiamine and other vitamins can lead to extreme muscle weakness as well as neurological problems. Thiamine deficiency leads to a disease called beriberi, which was common in people who ate white rice as their major food source. Beriberi can affect skeletal and cardiac muscles as well as the nervous system. Eating a balanced diet and the increase of vitamin-enriched foods have eliminated beriberi from developed countries, but many disorders of vitamin deficiency exist in developing areas.

Think of all of the activities you do that require function of your muscular system. These include walking, chewing, swallowing, breathing, talking, etc. Dysfunctions of this system (such as weakness or hypertonia) can prevent the body from carrying out any of these activities normally. This in turn can affect many other systems. For example, if we can’t bring in appropriate nutrients and oxygen, every other system in the body would be affected, as they are all dependent on fuel sources.

Muscles require a large amount of energy and thus require a constant supply of oxygen and nutrients. Blood vessels enter muscle at its surface, after which they are distributed through the entire muscle. Blood vessels are found in the connective tissue that surrounds muscles, allowing oxygen and nutrients to be supplied to muscle and metabolic waste to be removed. The epimysium houses the arteries and veins that allow blood to enter and exit muscle. The blood vessels then branch into the epimysium to serve each fascicle and then further branch in the endomysium to form a capillary network that contacts each muscle fiber. The flexible, extensively branched capillary networks are able to withstand muscle contractions without being damaged.

Skeletal muscles are under neural control, which means that nerves must be present for the muscle to function. The epimysium contains nerve fibers that branch through the perimysium and epimysium to connect neurons to individual muscle fibers.

did I get this

Although this unit has primarily focused on skeletal muscle, don't forget about cardiac and smooth muscle, both of which play vital roles in the cardiovascular system (and smooth muscle in other systems as well). Your heart needs to continuously contract in order to keep blood flowing to your organs, and in turn, supply them with needed oxygen and nutrients. But smooth muscle also plays a vital role. It is found in the walls of all blood vessels except for capillaries, and its function is to dilate or constrict, depending on the needs of the body and the downstream tissues. For example, if the skeletal muscles in your legs increase their metabolic rate because you start running, smooth muscle cells in the arteries feeding these muscles will relax. This dilates these arteries, allowing for a greater blood flow to the muscles of the legs. In fact, arteries to other regions (such as the gastrointestinal tract) may partially constrict in an effort to shunt more blood toward the legs. It is these smooth muscles that play a vital role in sending higher amounts of blood to where it is needed most. Skeletal muscles also play a role within the cardiovascular system. The heart acts as the pump to move blood out to the body cells, but the skeletal muscles assist with the movement of blood back to the heart. Because of valves in the veins that prevent back flow, the contraction of skeletal muscles around the major veins helps move the blood from one compartment to the next, slowly returning blood back to the heart.

learn by doing
did I get this

Muscles are extremely important in the digestive system as well. The muscles of our mouth, tongue and jaw are responsible for biting and chewing our food. Within our digestive tract, sphincters located throughout the digestive system are responsible for compartmentalizing the digestive processes within discrete organs. We are most familiar with the anal sphincter that we are able to control to excrete waste from the digestive system. Also, throughout the digestive system, smooth muscle helps generate small forces to mix food in the stomach and help maintain movements throughout the digestive process.

learn by doing
did I get this

The integumentary system is one of the main protective systems of the human body. It’s not a commonly known system. It contains your skin, hair, nails, and several glands. Did you know your skin is the largest organ in your body? It makes up approximately 7% of your body weight! The skin is also known as your integument or covering. Have you ever heard the expression that “beauty is only skin deep”? It’s an interesting statement because everything you see on another person’s appearance is dead! The layer of skin and hairs that are visible are actually dead epithelial cells!

The skin is actually formed from two layers: the superficial epidermis layer which is composed of epithelial tissue and the deeper connective tissue layer known as the dermis. The hypodermis is below the dermis and composed of loose connective tissue. When you give a subcutaneous (or sub-Q) injection you inject the drug into the hypodermis layer. Subcutaneous means below the cutaneous membrane which is another term for your skin. One medication commonly given via this method is insulin.

Let’s test your knowledge on some common facts and myths of the integumentary system.

did I get this

Let’s check out the integumentary system in action in the following case study.

You and your friend, Tori, are baking cookies. It’s the end of the semester and you both have been craving chocolate chip goodness. While the cookies are in the oven, you and Tori decide to study your anatomy and physiology. You are currently studying the integumentary system. The timer goes off and Tori jumps up, very excited, grabs a dish towel and pulls the cookie sheet out of the over. “OW!” Tori yells – as she drops the cookie sheet onto the table. “I just burned my hand on the cookie sheet”.

You reply, “Quick, rinse it under cold water, I think that is supposed to stop the burn.”

“It really hurts!” Tori exclaims while running her hand under the cool water from the faucet.

“Let me see your hand” you tell Tori.

When she shows you, you notice a couple blisters beginning to form on her fingers and palm. “I think you burned through your epidermis layer and maybe to the dermis. Don’t blisters mean you have a second degree burn?” you ask her.

“What does that mean?” Tori asks. “Should I go to that prompt care place?”

“Let’s look it up, I think if you keep it clean you will be ok. There are several layers of cells in the epidermis, aren’t there?” you ask. “Our textbook says if the skin blisters it is a sign of a second degree burn. These burns don’t typically damage the lower layer, the dermis.”

“It’s a good thing it didn’t burn through the dermis, then I would be more prone to other infections, wouldn’t I? Didn’t we read about the skin protecting us from microbes around us?” Tori asks?

learn by doing

The integumentary system is vital for our body’s homeostasis. As we saw with Tori, the skin is an important barrier for protection. If the skin is damaged from a burn, or torn, it opens up an entry point for microbes to enter our body. This is why we always wear protective gloves when handling body fluids. The gloves protect us in case there are any openings in our skin. It’s better to be extra cautious about this. Our epidermis is multi-layered to make it better suited for protection. If Tori’s burn had penetrated deeper it also would have increased fluid loss and dehydration. The skin functions as a cover to keep interstitial fluids inside rather than seeping out. Every day we lose a small amount of water through our skin and our lungs from breathing. This water loss is termed insensible perspiration and is accelerated when in dry air. Our cells in the epidermis produce a protein known as keratin that helps to decrease water loss from our skin. If skin becomes dry, it cracks and creates an opening in our defenses. When you think of maintaining homeostasis, protection is probably one of the first processes you think of and the skin is vital for this.

The integumentary system is also crucial for body temperature regulation. When we are too warm, blood vessels going to the skin open up (vasodilate) and more blood flows to the surface of the skin to release heat to cool the body. Our skin turns pink or red when this happens. If body temperature continues to rise, our sweat glands become active and we sweat to cool off (this is termed sensible perspiration). When we are cold, the blood vessels shrink (vasoconstrict) to decrease blood flow, and consequently heat loss, from our skin. Our skin might turn blue from the decrease in blood flow. We also have a layer of body hair covering our body which insulates and helps us retain heat. It’s a good idea to wear a hat when in cold weather to reduce heat loss from our head!

Another function of the skin, isn’t commonly known. The skin produces vitamin D in response to sunlight or UV radiation. Vitamin D is a very important vitamin, it’s crucial for calcium absorption from our food, and has recently been shown to have anti-cancer properties. If our vitamin D levels fall, this could impact our skeletal system by decreasing the absorption of calcium, and consequently the amount that gets to our bones.

Our skin is also tied into our nervous system. One of our main senses – touch is dependent on numerous receptors located in our skin. We can feel and process information regarding pressure, temperature, light touch, and pain through our skin. If Tori didn’t feel pain when she touched the hot cookie sheet, she wouldn’t have dropped it to reduce the damage from the heat.

Clearly, the integumentary system is more involved in our functioning than a clear skin and gorgeous hair!

learn by doing

The integumentary system is composed not only of the skin, but also nails, glands, and hair. The most numerous component of the integumentary system is the integument or skin. The skin contains the superficial epidermis, which consists of epithelial tissue, and the deeper dermis which is formed from dense irregular connective tissue. The epidermis contains nerve endings for pain, which is why Tori felt the pain of the burn. The epidermis is avascular, which means it doesn’t have blood capillaries. Nutrients get to the epidermis from the vascular dermal layer. Only those cells closest to the dermis are able to receive the nutrients and these cells have rapid mitotic rates. The cells in the epidermis migrate to the surface, and then are shed daily. They are constantly being replaced by the cells deeper. The dermis contains the blood vessels, sweat and oil glands. The dermis also has receptors for touch. Below the dermis is the hypodermis layer. This is the fatty layer that anchors the skin to your body. The hypodermis is technically not part of the integumentary system.

The skin also contains sweat and oil (sebaceous) glands. Sweat glands release sensible perspiration to cool us when we overheat. Sweat is mostly water but also contains electrolytes and a waste product known as urea. Urea is one of the main components of urine too! Sebaceous glands produce oil, otherwise known as sebum. Sebum and sweat form a chemical barrier on our skin to decrease bacterial growth on our skin.

Hair and nails are additional structures associated with the integumentary system. Body hair takes up space to compete with pathogens for room on our skin. Body hair also insulates us. Did you know that there are approximately 100,000 hairs on your head and 30,000 in a man’s beard? Fingernails and toenails provide leverage and protection when we grab and manipulate objects.

The epidermis contains the pigment melanin, which protects our cells from UV radiation. Melanin is also responsible for our hair, skin and eye color. Keratin was previously mentioned and is important for decreasing water loss from our skin. Many skin lotions contain keratin to prevent dry skin. Another important protein is collagen. Collagen provides strength to our skin. Collagen has a white appearance and often when the skin heals extra collagen is placed at the site. Sometimes this results in a white scar.

When you study the integumentary system, you will learn about the chemical and cellular components which work together to maintain the integrity of the system. As consumers, we spend a lot of money on products meant to make our skin and hair look better, younger, and healthier. As you read through this topic, think about whether those products really can make a difference or if they are just the result of well-played marketing campaigns!

learn by doing

The skin is made up of two mutually dependent layers that are distinguished based on their structure and location. These layers – the epidermis and the dermis – contain a variety of structures, including blood vessels, hair follicles, and sweat glands. Beneath the dermis lies the hypodermis (subcutis). It is composed mainly of fatty tissue.

The most superficial layer, the epidermis, is composed of stratified squamous epithelia that are keratinized at the outermost surface, melanocytes, immune cells (Langerhans that modulate immune response) and sensory receptors (Merkel cells that detect light touch). The function of the epidermis layer is "protection." The keratinocytes and immune cells help protect the skin.

The dermis lies beneath the epidermis and is composed of two layers of connective tissue: a loose layer (papillary) and a dense irregular layer (reticular). Both layers of the dermis contain connective tissue components (collagen, elastin, fibroblasts), plus blood vessels, sensory receptors and lymphatics. The dermis is a "functional" layer. The dermis is connective tissue that can stretch and retract because of the strong and elastic extracellular matrix. The dermis also contains nerves.

Beneath these two layers lies the hypodermis, composed of loose connective tissue (adipose and areolar). The hypodermis is the "connection" layer. It connects the integument (epidermis and dermis) to organs and muscles in the body. This layer contains adipose tissue and connective tissue as well as blood vessels, nerves and immune cells.

learn by doing
did I get this

The levels of organization of the skin and its accessory structures are listed below. You will be exploring these further in the coming pages.

• Molecular level – keratin, melanin and vitamin D
• Microscopic level – stem cells and skin cells
• Tissue level – epithelial and connective tissue
• Organ level – skin, consisting of the epidermis, dermis, and hypodermis, as well as hair, nails and glands
did I get this

## Keratin

Keratin is a group of fibrous proteins that give hair, nails, and skin their tough, water-resistant properties. Keratins are filaments formed from the polymerization of intermediate filament proteins. In addition to intra- and intermolecular hydrogen bonds, keratins have large amounts of the sulfur-containing amino acid cysteine, which forms disulfide bridges that confer additional strength.

Keratins are an excellent example of protein assembly. Keratins have an alpha-helix secondary structure in the central rod domain. Two keratin proteins then come together and the helices wind around themselves to form a quaternary structure of a coiled-coil dimer. These dimers then assemble into protofilaments and then filaments. The twists of twists are similar to fibers inside of ropes. However, keratins aren't twisted by machines; they self assemble based on their primary structure.

## Melanin

Melanin is a class of photopigment ("photo," meaning "light," and "pigment," meaning "colored material") with a molecular structure that allows it to absorb UV (ultraviolet) radiation from the sun. Melanin transforms the energy from the radiation into harmless heat, and melanin prevents the indirect DNA damage from the sun that is responsible for many skin cancers. Melanin also gives skin, hair and eyes their color. Melanin is produced by specialty cells called melanocytes, inside special vesicles called melanosomes. About 10 days after initial sun exposure, melanin synthesis peaks, which is why pale-skinned individuals tend to suffer sunburns of the epidermis initially.

did I get this
Example
##### Albinism

Albinism is a genetic disorder that affects (completely or partially) the coloring of skin, hair, and eyes. The defect is primarily due to the inability of melanocytes to produce melanin. Individuals with albinism tend to appear white or very pale due to the lack of melanin in their skin and hair. Melanin protects the DNA of skin cells from the harmful effects of UV rays from the sun. Individuals with albinism need more protection from the sun and must limit their outdoor activities. Treatment of this disorder usually involves addressing the symptoms.

learn by doing

The epidermal layer of human skin synthesizes the precursor to vitamin D when exposed to UV radiation. In the presence of sunlight, an isomer of vitamin D3, cholecalciferol, is synthesized from a derivative of the steroid cholesterol in the skin. The liver converts cholecalciferol to calcidiol, which is then converted to calcitriol (the active chemical form of the vitamin) in the kidneys. Vitamin D, which is really a hormone, is essential for normal absorption of calcium and phosphorous, which are required for healthy bones. In the present day, this hormone is added as a supplement to many foods including milk and orange juice, compensating for the need for sun exposure.

In addition to affecting bone health, Vitamin D is essential for general immunity against bacterial, viral and fungal infections. Recent studies are also finding a link between insufficient vitamin D and cancer.

Example
##### Rickets

Rickets is a disease of bone deterioration often caused by insufficient vitamin D, leading to insufficient calcium absorption. Children are especially prone to effects from this vitamin deficiency due to their rapid bone turnover and formation. In adults, the deficiency of vitamin D is called osteomalacia. Typically rickets is found in developing countries where malnutrition would prevent proper supply of calcium and dietary vitamin D.

learn by doing

The epidermis (or epithelial layer) is stratified squamous epithelia, composed of four to five layers (depending on body region) of epithelial cells. The top layers of the epidermis are made up of keratinocytes, which are cells containing the protein keratin. The keratinocytes on the most superficial layer of the epidermis are dead, and periodically slough away, being replaced by cells from the deeper layers. As keratinocytes move superficially from the deeper layers, they lose cytoplasm and become flattened, allowing for many layers in a relatively small space.

Basal cells are an example of tissue-specific stem cells, meaning they can turn into a variety of cell types found in that tissue. Under normal conditions, daughter basal cells most commonly replace lost keratinocytes.

The deepest layer of the epidermis and the most superficial layer of the dermis give out projections that interlock with each other (like Velcro) and strengthen the bond between the epidermis and the dermis. The projections originating in epithelial cells of the bottom layer of the epidermis are called desmosomes, and the ones originating in the dermis are called dermal papillae. Think of the projections as a formation of folds of cellular matter. The greater the fold, the stronger the connections made.

Merkel cells are sensory receptors that detect light touch. They form synaptic connections with sensory nerves that carry touch information to the brain. These cells are abundant on the surface of the hands and feet.

Melanocytes are cells in the bottom layer of epidermis that produce the pigment melanin, which gives hair and skin its color. Individuals whose melanocytes produce more melanin have darker skin color. Cellular extensions of the melanocytes reach up in between the keratinocytes.

Dendritic or Langerhans cells are tissue macrophages that contribute to the immune function of the skin. They engulf foreign organisms and signal to the immune system. Since the skin is in constant contact with the environment, it is important to have immune cells to help destroy any pathogens that might get past the cell barrier of the epidermis.

Example
##### Eczema

Eczema is an allergic reaction that manifests as dry, itchy patches of skin that resemble rashes. Normally it is useful to have immune cells in the skin, but they can also lead to dysfunction if they become overactive. In eczema, this excess activity may be accompanied by swelling of the skin, flaking, and in severe cases, bleeding. Other allergic (immune-mediated) reactions include hives. Symptoms of these conditions are usually managed with moisturizers and topically with corticosteroid or antihistamine creams that reduce the inflammatory immune response.

did I get this

Cancer in general is initiated because of DNA damage that accumulates in a particular cell over time. Exposure to UV rays from the sun can ultimately lead to mutations in the genomes of various skin cells. Accumulation of genetic mutations over a period of time, in addition to other possible causes, can trigger cells to grow out of control. The normal signals that control cell divisions (even stem cells have these controls) are lost, and cells grow to form a tumor, or mass of cells. While some tumors are benign (stay in one place), some produce cells that dislodge from the tumor and establish tumors in other areas of the body. In other words, they metastasize and form secondary tumors.

## Basal Cell Carcinoma

Basal cell carcinoma is caused by mutations that lead to lack of control over the growth of stem cells located in the stratum basale. It is the most common form of all cancers that occur in the United States. The head, neck, arms, and back are most susceptible, due to long-term sun exposure. Although UV radiation is the main culprit, exposure to other agents, such as electromagnetic radiation or carcinogenic chemicals, can also lead to this type of cancer. Injury to the skin due to open sores, tattoos, burns, etc. may be predisposing factors as well. Basal cell carcinoma usually starts as an uneven patch, bump, growth, or scar on the skin surface and responds best to treatment when caught early. Complete surgical excision of the lesion usually cures this form of cancer.

Of skin cancers, about 80 percent are basal cell carcinoma, 16 percent are squamous cell carcinoma, and four percent are melanoma.

## Squamous Cell Carcinoma

Squamous cell carcinoma is the second most common skin cancer, and affects the keratinocytes. Lesions are usually scaly and red and are most common on the scalp, ears, and hands. If not removed, they can metastasize. Surgery and radiation are used to cure squamous cell carcinoma.

## Melanoma

Melanoma affects melanocytes, the pigment-producing cells in the epidermis. It is the most fatal of all skin cancers, as it is highly metastatic and can be difficult to detect before it has spread. Melanomas usually appear as asymmetrical brown and black patches with uneven borders and a raised surface. Treatment typically involves surgical excision and immunotherapy.

did I get this

The skin contains many tissue types. The epidermis is classified as epithelial tissue composed of stratified squamous epithelia. The dermis is made of different types of connective tissues including areolar and dense irregular connective tissue, and histiocytes (tissue macrophages). The hypodermis contains areolar connective tissue, adipose tissue, and glands.

The epidermis is mainly made up of stratified (layered) squamous (flat) epithelial cells. Epithelial cells found in the different layers of the epidermis have different shapes. Stratification (layering) is important in the epithelial tissue of the integumentary system, which forms a barrier. Epithelial cells found in other systems have other surface cell shapes, including cube-like (cuboid) and column-like (columnar) in a single layer (simple) or multiple cell layers (stratified).

The epidermis contains several cell types of different origins, including keratinocytes (95 percent of the cells are keratinocytes), melanocytes, Langerhans cells and Merkel cells. The epidermis does not contain blood vessels or nerves, but Merkel cells provide signals to the sensory neurons below this layer in the dermis. Since there are no blood vessels, living cells of the epidermis are nourished by diffusion from the capillaries of the dermal papillae below.

did I get this

While the epidermis is composed of epithelial cells, the dermis is composed of connective tissue. The dermis connects the epidermis to the hypodermis and provides structure and elasticity from collagen and elastin fibers. These proteins are made by fibroblasts found in the dermis. Collagen and elastin work together: collagens provide strength; elastins, as the name implies, are elastic and allow for distension. The skin must remain strong to protect you from abrasions and other cuts. However, the skin also needs to be able to deform and, hopefully, return to its original shape.

Example
##### Wrinkles

The permanent folds in the skin caused by a lack of "retraction" are called wrinkles. Wrinkling in the skin is caused by habitual facial expressions, aging, sun damage, smoking, poor hydration, and various other factors. Wrinkling is a surprisingly complex phenomenon. Primarily, sun or other damage to the skin causes a breakdown in collagen and elastin as well as a breakdown in the replacement of these extracellular matrix proteins in the dermis.

Example
##### Stretch marks

Stretch marks usually accompany rapid weight gain during puberty and pregnancy as well as during the rapid gain of muscle associated with weight lifting. When the dermis (and possibly the hypodermis) is stretched beyond its limits of elasticity, the skin stretches to accommodate the excess pressure. In some cases, the dermis can’t adequately fill in over the stretched areas and may actually tear, causing the epidermis to become thin and making the underlying blood vessels more visible. They initially have a reddish hue, but lighten over time as the tissue repairs itself and heals. Other than for cosmetic reasons, treatment of stretch marks is not required. They occur most commonly over the hips and abdomen.

learn by doing
did I get this

Skin contains different types of melanin, including pheomelanin, which is reddish, and eumelanin, which is dark brown. The amount and types of melanin produced is under genetic control. The combinations of the different types of melanin result in the wide range of skin colors and tones seen in humans. While the number of melanocytes do not vary too much between individuals, the skin tone depends on the amount and type of melanin produced by these cells. If a person has more eumelanin producing melanocytes, that person would have darker skin color. The predominance of pheomelanin is responsible for the reddish coloration of hair in some individuals.

Exposure to the sun causes melanin to build up, because sun exposure stimulates keratinocytes to secrete a peptide hormone that in turn stimulates melanocytes into producing melanin. The melanocytes produce and then transfer the melanin to keratinocytes. This buildup of melanin results in the darkening of the skin, or a tan. Increased melanin also protects the skin’s DNA from UV ray damage to some extent, although even very dark-skinned individuals can get skin cancer. Melanin synthesis does not peak until about 10 days after initial sun exposure, which is why pale-skinned individuals tend to suffer sunburns of the epidermis initially. Individuals with darker skin can also get sunburns, but are more protected than light-pigmented individuals.

Melanosomes, the cellular organelles that contain melanin, are temporary structures and are eventually destroyed by fusion with lysosomes, which makes tanning impermanent. Too much sun exposure can eventually lead to wrinkling of the skin due to destruction of the cellular structure of the skin, and in severe cases it can cause sufficient DNA damage to result in skin cancer. An uneven distribution of melanocytes in the skin results in the appearance of freckles.

## Sunscreen and UVA and UVB Radiation

"UV" is an abbreviation for "ultraviolet." Ultraviolet radiation is a portion of the electromagnetic spectrum between visible light and x-rays. The sun emits two ranges of ultraviolet light that penetrate earth's atmosphere: UVA and UVB. UVB radiation is partially absorbed by the ozone layer, but some still reaches the surface of the Earth. UVA radiation is not filtered, and all of it reaches the surface of the Earth. One of the functions of our integumentary system is to protect us from this UV radiation. Exposure to this radiation can cause skin damage and cancer. Sunscreens are designed to protect our skin from UV radiation. Sunscreens with a sun protection factor (SPF) of 15 or more provide good protection from UVB radiation. To be protected from UVA radiation, you must have a “broad-spectrum” product.

learn by doing
did I get this

The skin, the integumentary system's organ, is composed of the epidermis (epithelial tissue) and dermis (connective tissues), with an underlying hypodermis that is technically not part of the skin organ. Several layers of keratinocytes at the surface form the epidermis. The topmost layer is dead and sheds continuously. It is progressively replaced by stem cells that divide in the basal layer (stratum basale). The dermis connects the epidermis to the hypodermis and provides strength and elasticity due to the presence of collagen and elastin fibers. The hypodermis is the name for the layer of connective tissue that connects the dermis to the underlying organs. It also harbors adipose tissue for fat storage. Let's look at the structure and function of these parts of the skin organ in detail.

The epidermis (or epithelial layer) is made up of four or five distinct layers (strata), depending on the region of the body. From deep to superficial, they are named the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum. The stratum lucidum is unique to areas like the palms of the hand (palmar surfaces) and soles of the feet (plantar surfaces), where the skin is thicker than it is in the rest of the body. The stratum basale is made up of the many cell types already discussed, including basal cells, melanocytes, Langerhans cells and Merkel cells. As you look at the more superficial layers, you see that they become mostly (or completely) composed of keratinocytes, which protect and waterproof the body. As the cells are pushed superficially (toward the surface) they make keratin. As the cells begin to fill with keratin, they become increasingly impervious to water, and it becomes more difficult for osmosis and diffusion to occur inside the cell. In addition, as cells enter each superficial layer (further away from the dermis, which contains the blood supply), the distance across which oxygen and other nutrients must diffuse increases, making it harder for the cells to get the nutrients they need. The keratinocytes in the stratum corneum (the most superficial layer) are usually inert, or dead, and periodically slough away, being replaced by cells from the deeper layers.

## Stratum Basale

The stratum basale (also called stratum germinativum) is the deepest epidermal layer and attaches the epidermis to the basal lamina, below which lie the layers of the dermis. The stratum basale is primarily made up of a single layer of basal cells. These cells are considered to be stem cells. The function of this layer is to divide to replicate the cells that are lost from the surface. The daughter cells then differentiate into keratinocytes. Merkel cells and melanocytes are also dispersed among the basal cells in the stratum basale.

Fingerprints form in the growing fetus where the basal cells of the stratum basale meet the connective tissue of the underlying dermal layer (papillary layer). The basal cells form strong cell-to-cell junctions called desmosomes not only with adjacent cells, but also with the basal lamina between themselves and the underlying connective tissue. During development, some areas of basal cells divide at a different rate, forming epidermal ridges that extend down in the dermis, and the dermal tissue proliferates to form dermal papillae. This results in the formation of deep ridges that get transmitted through the other layers of the skin to form fingerprints on the surface. Fingerprints are unique to every individual and are used for forensic analysis because the patterns do not change with the growth and aging processes. Even identical twins with the same genes will have different fingerprints because of this random process.

## Stratum Spinosum

As the name suggests, the stratum spinosum is spiny in appearance due to the polyhedral shape of the cells and desmosomes visible when tissue is prepared for microscope slides. As basal cells divide at different rates, keratinocytes get pushed up but maintain these strong cell-to-cell connections, changing cell shapes and forming a protective barrier. This stratum is composed of eight to 10 layers of keratinocytes, formed as a result of cell division in the stratum basale. Interspersed among the keratinocytes of this layer are the Langerhans cells, which help with immunity.

## Stratum Granulosum

The stratum granulosum has a grainy appearance due to further changes to the keratinocytes as they move up from the stratum spinosum. The cells (three to five layers deep) become flatter, and their cell membranes thicken. At this point, the keratinocytes generate large amounts of the proteins keratin and keratohyalin in the cytoplasm and, with other lipids and enzymes, form vesicles called lamellar granules, which may be secreted by exocytosis. The cellular secretions act to retard water loss and entry of foreign materials. These two proteins eventually make up the entire mass of the keratinocytes in the stratum granulosum (the nuclei and other cell organelles disintegrate) and mark the transition between the metabolically active strata and the dead cells of the superficial strata.

## Stratum Lucidum

The stratum lucidum appears lucid, or clear, and is not present throughout the body, but only on parts with thick skin, such as the surface of the palms and the soles of the feet. The stratum lucidum is a smooth, clear, thin layer, just superficial to the stratum granulosum. The keratinocytes in this layer are derived from the stratum granulosum, and mainly consist of keratin fibers. They are flat and densely packed.

## Stratum Corneum

The stratum corneum is the most superficial layer of the epidermis, and is the layer that is exposed to the environment. The increased keratinization (also called "cornification") of the cells in this layer gives it its name. There are usually 15 to 30 layers of dead cells in the stratum corneum. This dry, dead layer prevents the growth of microbes and keeps the rest of the underlying layers healthy. It is also resistant to penetration by water and protects the inner layers from environmental damage. Dead cells in this layer are shed periodically (approximately every two weeks) and are replaced by cells from the stratum granulosum (or stratum lucidum in the case of the palms and soles).

Example

Exfoliation is the removal of the outermost layer of dead cells. Cosmetic procedures like microdermabrasion or chemical peels help remove some of the dry upper layer of the skin and aim to keep the skin looking “fresh” and healthy. The ancient Egyptians are credited with first discovering the beauty effects of exfoliation. Too much exfoliation can cause damage to underlying, living tissue.

did I get this
did I get this

The thickness of thick skin is a function of the four upper layers of the epidermis: the stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum. The stratum corneum, consisting of keratin-packed dead cells, is substantially thicker in thick skin than in thin skin (more than 300 layers versus 15 layers of cells). The palms of your hands, soles of your feet, and your lips have thick skin. Thick skin is adapted to specialized activities, including gripping, walking and suckling, and the wear and tear that goes with those activities. Thick skin does not have hair, and has few glands.

Most of the rest of your skin is thin. The stratum lucidum isn’t even present in thin skin. The packed keratin provides most of the protective properties associated with the epidermis. Whereas the stratum corneum of thin skin may be completely shed and replaced in about a week, this replacement may take about a month in thick skin.

did I get this
Example
##### Calluses

When you wear shoes that do not fit well and are a constant source of abrasion on your toes, you tend to form calluses at the point of contact. This occurs because the basal stem cells in the stratum basale are triggered to divide more often. This increases the thickness of the skin at the point of abrasion so as to provide greater protection to the underlying tissue. Calluses can also form on your fingers if they are subject to constant mechanical stress like long periods of writing or playing stringed instruments or video games. The formation of calluses is an example of how tissues can adapt to a minor or local stress. Corns are a specialized form of calluses. They are formed due to the abrasion on the skin as a result of an elliptical-type motion.

did I get this

The skin's dermis is made up of two distinct layers of connective tissue. The papillary layer is made up of areolar connective tissue and the underlying reticular layer is composed of dense irregular connective tissue. This dermal part of the skin (organ) is vasculated (has blood vessels) and is innervated (has nerves). As described earlier, the dermis is sparsely populated with fibroblasts that produce collagen and elastin fibers in the extracellular matrix. This leads to a strong and elastic tissue structure. The matrix can also contain mast cells involved in allergic reactions.

## Papillary Layer

The fibroblasts are dispersed within the collagen and elastin fibers of the areolar tissue (loose connective tissue) of the papillary layer. This forms a loose mat, which contains an abundance of small blood vessels. The dermal papillae with blood capillaries interdigitate (become interlocked) with the epidermal ridges of the stratum basale. In addition, the papillary layer contains phagocytes — defensive cells that help fight bacteria or other infections that have breached the skin. This layer is also interspersed with lymph vessels and sensory receptors.

## Reticular Layer

The reticular layer appears “reticulated” (net-like) because it is composed of a mesh of collagen fibers and elastin fibers. Fibrocytes form the bundles of collagen that extend into the papillary layer and the hypodermis, making these layers hard to distinguish. The flexible collagen provides structure and strength, while elastin lends limited elasticity to the skin. Collagen also binds with water, keeping the skin hydrated. Water is necessary to maintain the normal elasticity and resiliency (called "turgor") of the skin. Dehydration causes a loss of turgor; if the skin of a dehydrated person is pinched it remains domed and does not immediately flatten out.

Collagen injections and Retin-A creams help restore skin turgor by introducing collagen externally in the former case or by stimulating blood flow and repair of the dermis in the latter case.

learn by doing
 By NIST database (Fingerprint_Whorl). Public Domain
did I get this

The hypodermis (also called the subcutis or subcutaneous layer) functions to connect the integument (epidermis and dermis) to the underlying muscles and organs. The hypodermis is not considered part of the skin, but has several important functions. Like the dermis, the hypodermis is made up of areolar tissue, collagen, and elastic fibers, providing it with some elasticity. Additionally, it contains adipose tissue, which functions as a mode of fat storage. The hypodermis is vascular and contains arteries, veins, and blood capillaries.

Adipose tissue present in the hypodermis accumulates fat, which serves as an energy reserve, insulates the body, and prevents heat loss. The fat distribution changes as our bodies mature and age. It is also hormone-dependent. Men tend to accumulate fat in different areas (neck, arms, lower back, and abdomen) than do women (breasts, hips, thighs, and buttocks). Physical inactivity due to a lack of exercise and sedentary jobs, combined with the consumption of high-calorie foods, has resulted in the highest rates of obesity ever seen in our country. While accumulation of fat provided an evolutionary advantage to our ancestors, who experienced unpredictable bouts of famine, it is now considered a major health threat. Improved diet and increased exercise are the best ways to control body fat accumulation, especially when it gets to levels that increase the risk of heart disease.

did I get this

Accessory structures of the skin include hair, nails, sweat glands, and sebaceous glands. Although these structures appear to be part of the dermis, they are actually derived from the epidermis. The hair shaft is made of dead, keratinized cells and gets its color from melanin pigments. Nails are also keratinized and protect the extremities of our fingers and toes from mechanical damage. Sweat glands and sebaceous glands produce sweat and sebum, respectively. Each of these fluids has a role to play in maintaining homeostasis. Sweat helps the body remove excess fluids and electrolyte wastes and also cools down the body surface when it gets overheated. Sebum acts as a natural moisturizer of the dead, flaky outer keratin layer of skin and hair. Sebum is also known for its microbicidal and microbiostatic properties.

learn by doing
did I get this

Hair is part of the integumentary system. Strands of hair originate from the base of the downward extension of living epithelial cells into the dermis that is called the hair follicle. Hair follicles are surrounded by the dermis, but the cells are part of the epidermis and are separated from the dermis by basal lamina layer. Hair forms in a manner similar to the skin: rapid division and differentiation of stem cells into keratinocytes that get pushed up and become flattened, dead, keratinized cells. The part of hair that is exposed on the skin surface is called the hair shaft, and the rest of the follicle is called the hair root. The bulge at the base of the hair root is called the hair bulb, which is made up of a layer of basal cells called the hair matrix. The hair matrix contains the cells that rapidly divide to form the hair. The hair bulb surrounds the hair papilla (made up of connective tissue, blood capillaries and nerve endings).

 With permission from Jesus Lozano and Lorena Monarrez (172X10_hair_bulb_labelled) With permission from Jesus Lozano and Lorena Monarrez (172-1x-Hair_follicle_labelled)

Just as the layers of the skin form on the inner layers and get pushed out to the surface as the dead skin on the surface sheds, basal cells in the center of the hair bulb divide to form layers of keratinocytes that form the medulla, cortex, and cuticle of the hair bulb. These layers are visible in a longitudinal section of the hair follicle. Keratin formation starts in the cells of the medulla and the keratin continues to be produced in the cortex and cuticle. Keratinization is completed as the cells are pushed to the skin surface to form the shaft of hair that is externally visible. The external hair is composed entirely of keratin.

Additionally, the hair follicle is made up of three concentric layers that make up the wall of the follicle — the internal root sheath, the external root sheath, and the glassy membrane. The cells of the internal root sheath are derived from the basal cells of the hair matrix. This layer does not surround the entire hair strand, but stops short at the base of the hair shaft. The external root sheath, which encloses the hair root, is made up of basal cells at the base of the hair root and tends to be more keratinous in the upper regions. The glassy membrane is a thick, clear connective tissue sheath covering the hair root and connecting it to the tissue of the dermis.

Hair serves a variety of functions. For example, hair on the head protects it from the sun and from heat loss; and hair in the nose and ears and around the eyes (eyelashes) defends the body by trapping dust particles that may contain allergens and microbes. Hair on the eyebrows prevents sweat and other particles from bothering the eyes. Hair also has a sensory function due to innervation of the hair papilla. Hair is extremely sensitive to changes in the environment, much more so than the skin surface. The hair root is connected to smooth muscles called arrector pili that contract in response to stimuli, making the external hair shaft “stand up.” This is visible in humans as goose bumps and even more obvious in animals, such as when a frightened cat’s fur puffs out. In many animals, the puffing out makes the animal appear larger, and could possibly enable it to scare off a predator. Another advantage of this ability to cause the hair to stand up is that it can trap air and can act as an insulator, decreasing heat loss.

Hairs grow during a phase called anagen, and they are eventually shed, only to be replaced by newer ones. When hair is naturally ready to be shed, the follicle becomes inactive during a phase called catagen. The follicle then becomes smaller, and becomes detached from the dermal papilla at the base, during the phase called telogen. The basal cells in the hair matrix then produce a new hair follicle during anagen. Hair typically grows at the rate of 0.3 mm per day and can continue growing for two to five years before being shed. About 50 hairs may be lost and replaced per day. Hair loss occurs if there is more hair shed than what is replaced, and it can happen due to hormonal or dietary changes.

Just like the skin, hair gets its color from the pigment melanin, produced by melanocytes in the hair matrix. Different hair color results from differences in the type of melanin, which is genetically determined. As a person ages, the melanin production decreases and hair tends to lose its color, becoming gray and/or white.

Example
##### Alopecia

Many individuals can experience hair thinning and/or loss with advanced age. This is called alopecia. This can lead to complete hair loss, called baldness. Most baldness is caused by a genetic sensitivity of hair follicles to the androgen hormone dihydrotestosterone (DHT). DHT causes the hair follicle to receive less blood flow, so that the hair follicle begins to atrophy and any hair that is produced is thin.

A common form of baldness is male pattern baldness, which results from a mutation on the X chromosome. It is seen more often in men because men only receive one copy of the X chromosome. Many women may be carriers of this trait, having one normal X chromosome and one X chromosome that has the male pattern baldness gene. Women usually do not exhibit the balding patterns seen in men.

learn by doing
did I get this

The nail is a specialized structure of the epidermis that occurs at the tips of our fingers and toes. The nail body is formed on the nail bed, and it is designed to protect the tips of our fingers and toes, as they are the farthest extremities and the parts of the body that experience the maximum mechanical stress. The epidermis in this part of the body has evolved a specialized structure upon which nails can form. The nail body forms at the nail root. Lateral nail folds, folds of skin that overlap the nail on its side, help anchor the nail body. The nail fold that meets the proximal end of the nail body forms the nail cuticle, also called the eponychium. The nail bed is rich in blood vessels, making it appear pink, except at the base, where there is a crescent-shaped region called the lunula. The nail body is composed of keratin-rich, densely packed dead keratinocytes. The area beneath the free edge of the nail, where debris gets lodged, is called the hyponychium.

learn by doing
did I get this

## Sweat (Sudoriferous) Glands

When the body becomes overheated, sweat is produced to cool the body's temperature and prevent overheating. There are two types of sweat glands responsible for excreting sweat — eccrine (merocrine) sweat glands and apocrine sweat glands. Eccrine glands are present throughout the skin surface, especially on the palms of the hand, the soles of the feet, and the forehead. Like hair and nails, they are derived from the epidermis. They are coiled glands that lie in the dermis, with the duct opening to a pore on the skin surface, where the sweat is released (although some may open into hair follicles, like sebaceous glands). The sweat released by eccrine sweat glands is mostly water, with some salt, antibodies, traces of metabolic waste, and a microbe-killing compound called dermcidin. The main function of eccrine sweat glands is to help regulate body temperature through evaporation.

Eccrine glands are controlled by the sympathetic division of the autonomic nervous system. The sympathetic division is known as the "fight or flight" division. When you are nervous, you might notice that your palms sweat. This is because when the sympathetic division is activated, it triggers sweating.

Apocrine glands are usually associated with hair follicles and are activated in densely hairy areas like armpits and genitals. They are larger than merocrine sweat glands and lie deeper in the dermis, sometimes even reaching the hypodermis. They release a thicker fluid due to a higher concentration of fatty acids, which may give it a whitish color. These fats are often decomposed by bacteria on the skin, resulting in an unpleasant odor, commonly called body odor. Apocrine glands do not begin to function until puberty. Apocrine sweat glands are stimulated during emotional stress and sexual excitement.

## Sebaceous Glands

Sebaceous glands are oil glands that are found all over the body. Most are associated with hair follicles. They generate and excrete a mixture of lipids, called sebum, onto the hair and skin surface, thereby naturally lubricating the dry and dead layer of keratinized cells of the stratum corneum and hair shaft. Sebum also has antibacterial properties, and prevents water loss from the skin in low-humidity environments. The secretion of sebum is stimulated by hormones, many of which do not become active until puberty. Thus, sebaceous glands are relatively inactive during childhood and become active only after puberty has occurred.

Example
##### Acne

Acne is a skin disturbance that typically occurs on areas of the skin that are rich in sebaceous glands (the face and back). It is most common during the onset of puberty due to associated hormonal changes, but can continue into adulthood. Hormones such as androgen and other sex steroid hormones stimulate the release of sebum. When sebaceous glands overproduce and get blocked with sebum, it leads to the formation of blackheads. Blackheads are the result of hyperkeratinization of the area, which causes the formation of a keratin plug and blockage of hair follicles in the area. Blackheads are prone to infection by acne-causing bacteria (i.e. Propionibacterium and Staphylococcus), which leads to redness and swelling. In severe cases, acne can lead to scarring due to the production of scar tissue during the wound healing process.

learn by doing
did I get this

In earlier sections, you learned about the amazing regenerative capacity of skin: Basal cells divide and differentiate to form keratinocytes, which move superficially to the surface and change their structure along the way. There are some cases where this regenerative property can cause problems, and some traumas where regeneration is put to the test.

Example
##### Psoriasis

Psoriasis is an autoimmune disorder where too many skin cells are produced. Skin rapidly accumulates and looks silvery-white in appearance. Plaques from plaque psoriasis frequently occur on the skin of the elbows and knees, but can affect any area, including the scalp, palms of hands and soles of feet, and genitals. The disorder is a chronic recurring condition that varies in severity from minor localized patches to complete body coverage.

## Wound Repair and Scarring

The first step to repairing damaged skin is the formation of a blood clot that scabs over with time. Many different types of cells are involved in wound repair, especially if the surface area that needs repair is extensive. Before the basal stem cells of stratum basale can re-create the epidermis, fibroblasts and mesenchymal cells mobilize and divide rapidly to repair the damaged tissue, forming a loose, highly vascular tissue called granulation tissue. This increased vascular network helps deliver the oxygen and nutrients necessary for further repair. Immune cells, like macrophages, roam the area and engulf any foreign matter, reducing the chance of infection while also clearing away any tissue debris.

Scars occur when there is repair of skin damage, but the healing process prevents regeneration of the original skin structure. Almost every cut or wound, with the exception of ones that only scratch the surface (epidermal wounds), leads to some degree of scar formation. As the tissue tries to repair itself to the original state, fibroblasts often generate a greater density of collagen fibers than were in the original tissue, which is what results in scar formation. This dense, fibrous structure (connective tissue) has few cells and does not allow for the regeneration of accessory structures (epithelial tissue) like hair follicles, sweat glands, or sebaceous glands.

Sometimes, scarring does not stop when the wound is healed. This results in the formation of a raised or hypertrophic scar called a keloid. In contrast, scars that result from acne and chickenpox have a sunken appearance and are called atrophic scars.

Scarring of skin after wound healing is a natural process and does not need to be treated further. Application of oil and lotions may reduce the formation of scar tissue by keeping the skin soft and pliable as it heals, allowing the separate edges to be pulled together. However, modern cosmetic procedures like dermabrasion, laser treatments, and filler injections have been invented as remedies for severe scarring. All of these procedures try to reorganize the structure of the epidermis and underlying collagen in the connective tissue to make it look more natural.

did I get this

Burns are wounds that result when the skin is exposed to intense heat, radiation, electrical current, or caustic chemicals. Burns cause skin cells to die, disrupting the epithelial barrier that normally prevents fluid loss. Depending on the severity of the burn, dehydration, electrolyte imbalance, and renal and circulatory failure may follow. Burn patients are treated with intravenous fluids to offset the dehydration, as well as intravenous nutrients that enable the body to repair tissues and replenish lost proteins. Another serious threat to a burn patient is the high possibility of infection. Burned skin is extremely susceptible to bacteria and other pathogens, as the loss of body covering provides a direct pathway for the entry of microorganisms.

Burns are classified by the degree of their severity. In first-degree burns, only the epidermis is damaged. Although painful, these burns typically heal on their own within a few days. A typical sunburn is a first-degree burn. Second-degree burns destroy both the epidermis and the dermis. They result in painful blistering of the skin. It is important for individuals with second-degree burns to keep the area clean and sterile in order to prevent infection. If this is done, the burns heal on their own within several weeks.

Third-degree burns are more serious and penetrate the full thickness of the skin, including the subcutaneous (hypodermis) layer. The skin may appear white, red, or black. Fourth-degree burns are the most severe, affecting the underlying muscle and bone as well. Third- and fourth-degree burns are usually not as painful because the nerve endings themselves are damaged. However, a third- or fourth-degree burn results in rapid water loss and infection due to the exposure of the underlying tissue, and requires emergency trauma care. Full-thickness burns cannot be repaired locally because the local repair machinery itself is damaged. Full-thickness burns require excision of the affected tissue (amputation in severe cases), followed by grafting of skin from an unaffected part of the body, or from skin grown in tissue culture for grafting purposes.

## Puberty

During puberty, the changes in the endocrine system produce hormones that regulate aspects of the integumentary system. Sebaceous glands, apocrine sweat glands and hair growth become active or more active.

All organ systems in the body, including the integumentary system, undergo subtle changes over time that add up as a person ages. Reductions in metabolic activity and cell division, lowered blood circulation, and decreased hormonal levels are some of the basic changes that occur in the human body as it ages.

The epidermis is made up of several layers of cells that are shed and replaced by basal stem cell division. With aging, these cells divide less reliably and aging skin becomes thinner. The dermis, which is responsible for the elasticity and resilience of the skin, also weakens since elastin fibers become cross-linked and don’t stretch. Repair of wounds occurs more slowly as a person ages. The hypodermis, which stores fats in its adipose tissue, loses its structure due to the reduction and redistribution of fat, which in turn is affected by hormonal levels. The accessory structures also have lowered activity, generating thinner hair and nails, and reduced amounts of sebum and sweat. Reduced sweating ability causes the elderly to be unable to tolerate extreme heat. Other cells in the skin, such as melanocytes and dendritic cells, also become less active, leading to a paler appearance and lowered immunity. Wrinkling of skin occurs mainly due to the breakdown of collagen and elastin, the weakening of muscles under the skin, and the inability of the skin to retain adequate moisture.

Many anti-aging products line the shelves of stores today. These products (mainly composed of tretinoin, or Retin-A) try to introduce more structure into the skin, first by rehydrating the skin with moisturizers, and then by triggering mitotic activity of the underlying cells to encourage tissue formation and regeneration. Some products contain epidermal growth factor, which induces collagen synthesis, the end-product of wound healing, to give the skin a healthier look.

did I get this

The integumentary system regulates body temperature through several different means. Recall that sweat glands — accessory structures to the skin — excrete water, salt, and other substances to cool the body when it becomes warm. This is termed "sensible perspiration." Even if the body does not appear to be noticeably sweating, approximately 500 mL of sweat are secreted a day. If the body becomes excessively warm due to high temperatures, vigorous activity, or a combination of the two, the blood vessels in the integumentary system dilate and sweat glands produce large amounts of sweat — up to three gallons a day. As the sweat evaporates from the skin surface, the body is cooled; in a way, the skin surface acts like the radiator of a car. The dilated blood vessels in the dermis that account for the redness that many people experience when exercising on a hot day also help in the dissipation of body heat by increasing the superficial blood flow.

When temperatures are cold, the adipose tissue of the hypodermis helps insulate the body. Goosebumps and the arrector pili muscles help to insulate by trapping air on the surface of the skin. Additionally, the dermal blood vessels constrict to decrease blood flow (and heat loss) at the skin.

did I get this

The fact that you can feel an ant crawling on your skin, causing you to flick it off before it bites, is due to the fact that the sensory receptors in the skin (especially the hair root plexus associated with the hair in the follicles) can sense changes in the environment. This occurs via sensory receptors that convert physical or chemical stimuli into electrical signals that are sent to the central nervous system (CNS; brain and spinal cord). The CNS then processes this sensory input and generates a voluntary response to the ant. The skin acts as a sense organ because the dermis and hypodermis contain sensory receptors that extend into the epidermis. These receptors, such as Merkel discs, are more concentrated at the fingertips and lips, which are most sensitive to touch. Examples of other sensory receptors present in the skin are tactile (Meissner's) corpuscles and lamellated (Pacinian) corpuscles that respond to pressure and vibration, respectively, and free nerve endings that are sensitive to temperature (hot or cold) and pain.

## Skin Conditions and General Health

There are a variety of conditions that can change the appearance of the skin. In vitiligo, the melanocytes in certain areas lose the ability to produce melanin, possibly due to an autoimmune reaction, leading to loss of pigmentation in patches. Liver disease or liver cancer can cause an accumulation of bile and the yellow pigment bilirubin, leading to the skin appearing yellow or jaundiced ("jaune" is French for "yellow"). Tumors of the pituitary gland can result in the secretion of large amounts of corticotropin-releasing hormone (CRH), which can stimulate excessive levels of melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH). In Addison’s disease excessive CRH stimulates production of adrenocorticotropic hormone (ACTH) and MSH. In these diseases, the skin takes on a deep bronze color.

The oxygen content of blood in the dermal vascular system is reflected in skin hue. Healthy individuals who have adequate supplies of the red-colored oxygen-bound hemoglobin usually have a pink hue to their cheeks and lips. Indeed, hemoglobin and the vasculature of the skin also contributes to skin color in people with fairer skin. A sudden drop in oxygenation of the skin can initially cause the skin to turn ashen (or white). If there is a prolonged reduction in oxygen levels, it makes the skin appear blue (cyanosis), which happens when a person has a limited oxygen supply to the body. The blue color is most obvious in areas where blood capillaries are close to the surface, like the lips and nail beds. Blue lips is a sign of hypoxia and hypothermia, which lead to drastically reduced peripheral circulation, or of any other condition that prevents adequate oxygenation of the blood, which can occur in a variety of lung diseases. At the other extreme, elevated blood levels of carbon monoxide can cause the lips and oral mucosa to appear bright cherry red because the carbon monoxide molecule binds to hemoglobin tighter than oxygen, giving the hemoglobin in the red blood cells the bright red color. Carbon monoxide poisoning is fatal, and prompt treatment with pure oxygen is indicated.

did I get this

Maintaining homeostasis within the body requires the coordination of many different systems and organs. Communication between neighboring cells, and between cells and tissues in distant parts of the body, is done through either the nervous system or the endocrine system. The nervous system utilizes electrochemical impulses to regulate muscles and glands. These signals, carried by neurons, elicit responses in target cells within milliseconds. However, the duration of those responses is very brief unless neuronal signalling continues. The endocrine system regulates biological processes through the release of chemicals called hormones. Hormones are released into body fluids—usually blood, which carries these chemicals to their target cells, where they elicit a response. The responses elicited by hormones usually take several seconds to several days to occur, and the duration of the response can last just as long without further signalling. Unlike nearly instantaneous nerve impulses, hormones of the endocrine system can regulate functions of the body on longer time scales to maintain homeostasis.

The major function of the endocrine system is to participate in homeostatic feedback loops by acting as a means of communication between integrators and effectors, and sometimes acting as the sensor as well. Since the function of the endocrine system is to maintain homeostasis, there will be many system level examples at the end of this chapter. Also, this is an excellent time to review the concept and formal structure of homeostasis if you are uncertain or out of practice.

The endocrine system is also involved with growth, development and adaptation. Within all of these changing processes, our bodies tolerate fluctuations within certain limits but still overall homeostasis needs to be maintained.

Example
##### Endocrine System Homeostasis and Integration with Other Systems

When we grow in height, our bones increase in length. However, proper homeostasis must be maintained to ensure that we always have calcified bone to support our weight. Muscles, tendons and ligaments must also grow proportionately. The endocrine system integrates these changes while still maintaining homeostasis.

learn by doing

## Common Dysfunctions of the Endocrine System

We feel the effects of changes in the endocrine system at various points in our lives. Hormone levels fluctuate during puberty, and even after we eat a meal. Common dysfunctions of the endocrine system include an inability to regulate glucose, called diabetes mellitus, and an inability to regulate calcium levels in the bones, which may lead to osteoporosis. Other common disorders of the endocrine system include over- or under-production of thyroid hormone (hyperthyroidism and hypothyroidism, respectively), which impacts energy metabolism. In this unit, you will learn about dysfunctions of the endocrine system and the downstream results of such dysfunctions.

did I get this
did I get this

The lipid-derived hormones include steroid hormones and eicosanoids. Steroid hormones, the primary class of lipid hormones in humans, are derived from cholesterol and show structural similarity to that molecule. Examples of steroid hormones include estrogen and testosterone, which are released by reproductive organs, and aldosterone and cortisol, which are released by the adrenal glands.

Steroid hormones are released as synthesized. They are insoluble in water, so to circulate through the blood they bind to transport proteins in serum. Since they are bound to carrier proteins, steroid hormones typically remain in circulation longer than other classes of hormones. Recall that the "lifetime" of a molecule from production to destruction is called the half-life. The steroid hormone cortisol has a half-life of 60 to 90 minutes, whereas epinephrine, an amino acid-derived hormone, has a half-life of approximately one minute. They are eventually degraded and excreted in urine or bile.

Biosynthetic pathways for some selected steroid hormones.

Eicosanoids are a class of signalling molecules derived from polyunsaturated fatty acids. They are typically released as paracrine signals upon stimulation and are only active for a few seconds.

did I get this

Of the amino acid-derived hormones, some circulate for only a few minutes while others may circulate for days. The amino acid tyrosine is the precursor for two groups of hormones: the thyroid hormones, produced in the thyroid gland; and the catecholamines (epinephrine and norepinephrine), produced in the adrenal medullae. The amino acid tryptophan is the precursor for the hormone melatonin, secreted by the pineal gland, and the hormone serotonin, which is quite widespread in the body. Some of these hormones have a circulating half-life of a few days (thyroid hormones) while some are rapidly degraded (catecholamines).

did I get this

Peptide hormones are short peptides and polypeptide chains. Recall that peptides are usually made up of fewer than 50 amino acids and proteins are typically longer than that. Some peptide hormones of longer lengths can have secondary structures. Protein hormones, being much longer than peptides, can have more extensive three-dimensional structures and can even be globular.

Peptide hormones are a diverse group and include molecules that are only a few amino acids, such as antidiuretic hormone and oxytocin (each with 9 amino acids), produced by the pituitary gland. This class also includes proteins, such as growth hormone (191 amino acids), and glycoproteins, such as follicle-stimulating hormone (92 amino acids with glycosylation). Peptide hormones can either be released as produced or stored and released in response to stimulus. Most are water soluble and are easily transported in blood plasma, but some also bind to transport proteins. Most have a half life of minutes.

learn by doing
did I get this

Hormone production can be regulated by positive and negative feedback pathways. In positive feedback systems, the release of a hormone leads to an action that stimulates release of more of the same hormone.

Example
##### Positive Feedback Loop in the Endocrine System

Oxytocin released by the pituitary gland prior to childbirth stimulates contraction of the uterus and increases pressure on the cervix. The increased pressure signals the pituitary to release even more oxytocin, which increases force of contractions, leading to even more cervical pressure. This amplification cycle continues until childbirth is complete.

In a hormonal negative feedback loop, when a stimulus causes the release of a hormone (Hormone A), the hormone binds to the target cell receptor, causing the necessary metabolic change toward homeostasis. In a negative loop, the effect of this metabolic change is to counter the stimulus that caused the release of Hormone A. Once the cause of the stimulus returns to normal range, the production of that hormone stops and plasma level of that hormone returns to the normal (pre-stimulus) level. In this way, the concentration of most hormones in blood is maintained within a narrow range.

Example
##### Negative Feedback Loop in the Endocrine System

The hypothalamus monitors the plasma level of thyroid hormones, among others. When the level drops, the hypothalamus stimulates the anterior pituitary to release a hormone (Thyroid Stimulating Hormone, or Thyrotropin) that stimulates the thyroid to release thyroid hormones. Increased levels of the thyroid hormones in the blood then feed back to the hypothalamus and anterior pituitary to inhibit further stimulation of the thyroid gland. Other homeostatic imbalances, such as low body temperature, can also stimulate the hypothalamus to stimulate the anterior pituitary to release thyrotropin. Thyroid hormones play an important role in metabolic heat production via ATP production.

learn by doing
learn by doing
did I get this

There are three mechanisms by which endocrine glands are stimulated to synthesize and release hormones: humoral regulation, hormonal regulation, and neural regulation.

## Humoral Stimuli

The term humoral is derived from the term humor, which refers to bodily fluids such as blood and other extracellular fluids. Humoral stimuli regulate the release of hormones in response to specific changes in extracellular fluids, such as the concentration of a particular ion or solute in the blood or even the overall solute levels in the blood.

Example

A rise in blood glucose level triggers the pancreatic release of insulin. Insulin causes blood glucose levels to drop, which signals the pancreas to decrease insulin production through a negative feedback loop. Similarly, low blood calcium stimulates the release of parathyroid hormone from the parathyroid gland which stimulates the release of calcium from bone, decreases calcium excretion in urine and promotes calcium absorption in the digestive system.

## Tropic Hormonal Stimuli

With tropic hormonal stimuli, a hormone is produced and released by an endocrine gland in response to another hormone (known as "tropic hormones"). These hormones controlling release of another hormone are called tropic (meaning "turn toward," pronounced “tro’-pick”; not same as geographical “trop-ic”).

Example

The hypothalamus produces hormones that stimulate the anterior pituitary. The anterior pituitary in turn releases hormones that regulate hormone production by other endocrine glands. For example, the anterior pituitary releases thyroid-stimulating hormone, which stimulates the thyroid gland to produce the hormones T3 and T4. As blood concentrations of T3 and T4 rise, they inhibit further hormone production by both the pituitary and the hypothalamus in a negative feedback loop.

Note...

Sometimes students get confused between tropic and trophic hormones. Tropic hormones stimulate release of other hormones from endocrine cells, such as those discussed here. Trophic (meaning “nourishment or nurse”) horomones stimulate non-endocrine cell growth and development, such as growth hormone, estrogen and testosterone.

## Neural Stimuli

The nervous system can also directly stimulate endocrine glands to release hormones through a mechanism known as neural stimuli.

Example

Neuronal signaling from the sympathetic nervous system directly stimulates the adrenal medulla to release the hormones epinephrine and norepinephrine in response to stress.

## Length Scale of Hormonal Signaling

Cells communicate with one another via chemical messengers. The communication may happen between cells close by or far away from the cells that produces the messenger (signal). For example, released hormones travel throughout the body and affect any cells with receptors for the specific hormones. Autocrine signaling (auto- means self) affects the cells that released the signaling molecule. Autocrine signaling (auto- means self) affects local cells other than the secreting cells. While traditionally a hormone is thought to have its effect at a distances from where it is secreted, the definition of hormones now include paracrine and autocrine mechanisms as well. The all-inclusive term, Endocrine signaling, includes all types of communication where chemical molecules produced from a cell affect the metabolism of another cell (paracrine or endocrine) or that of its own (autocrine).

learn by doing
did I get this

Steroid hormones are lipophilic and need transport proteins in the blood. Once released from their transport protein, the non-polar hormone is able to diffuse across the plasma membrane of cells. Recall that the lipid bilayer of the plasma membrane of cells uses amphiphilic phospholipids to compartmentalize the cytoplasm of a cell. When a steroid hormone crosses the plasma membrane of a target cell, it binds to an intracellular hormone receptor in the cytoplasm, on intracellular membrane system (ER) or, within the nucleus of the cell. The receptor/hormone complex can then bind to a specific site on DNA and act as a transcription regulator to increase or decrease the synthesis of particular mRNA molecules coded by these specific genes. This, in turn, alters mRNA production, which determines the amount of corresponding protein that is synthesized. The steroid hormone regulates specific cell processes. The rate of transcription and protein synthesis is directly proportional to the amount of hormone forming receptor/hormone complexes; so if the hormone production increases, so does the physiological effect in the body.

The thyroid hormones, T3 and T4, also use plasma transport proteins and intracellular DNA-binding receptors. There are, however, some important physiological differences with the steroid hormone mechanism. The target cells have membrane transport proteins that transport the thyroid hormones into the cell. The Thyroid hormone receptor is found bound to a transcription repressor protein on the DNA. The binding of the hormone with the receptor-repressor complex to form the receptor/hormone complex causes the repressor protein to dissociate, and a transctiption activator protein becomes associated with the receptor. This, in turn, initiates transcription.

Most peptide and amino acid hormones are polar and therefore cannot diffuse through the plasma membrane of cells. So, they bind to plasma membrane hormone receptors on the outer surface of the plasma membrane. Unlike steroid hormones, polar hormones also alter intracellular processes and can also affect the target cell’s transcription. Since they cannot enter the cell and act directly on any DNA-binding proteins, they exert their transcriptional effects through intermediate molecules called second messengers as described below. Catecholamines (amine class) and polar eicosanoids (lipid-derived class) also bind to cell-surface hormone receptors.

Binding of these hormones to a cell membrane surface receptor results in activation of a signaling pathway that triggers a cascade of intracellular activity and specific effects associated with the hormone. Most hormones that bind at the surface receptor remain outside the target cell. Some hormones are taken into the cell by endocytosis to initiate the intracellular biochemical response from within vesicles. The hormone that initiates the signaling pathway, the first messenger, activates a second messenger within the cell.

Example

Glucagon is produced when blood sugar drops. The glucagon binds to its receptor on target liver cells and stimulates two different metabolic reactions inside the cell. The liver cells will be stimulated to break down stored glycogen to glucose and to synthesize new glucose from some amino acids. As a result, glucose is released into the blood and blood sugar returns to normal.

did I get this

G-proteins are a class of trans-membrane cell surface proteins that can be activated by hormones or ions and other chemicals for cell signaling. G-proteins remain inactive unless a hormone is bound to its cell surface receptor. Inactive G-proteins are bound to GDP on its cytoplasmic side. When a hormone binds to the cell surface receptor the bound GDP is replaced by GTP.

Activated G-proteins can have different functions depending on the hormone receptor: it can open a membrane protein channel; it can release a small molecule; or it can activate a membrane-bound enzyme. There is a large variety of G-protein-induced effects. For example, G-protein-linked ion channels can stimulate movements of ions across the membranes. There are specific channels for potassium, sodium, calcium or chloride.

For G-protein activated membrane-bound enzymes, there are large numbers of activated enzymes. One of the membrane bound enzymes that the G-Protein coupled receptor (GPCR) activates upon binding to a hormone molecule is the adenylate cyclase. This enzyme catalyzes the conversion of ATP to cyclic AMP (cAMP). which, in turn, activates a class of enzymes called protein kinases. These kinases transfer a phosphate group from ATP to a substrate molecule in a process called phosphorylation. The phosphorylation of a substrate molecule changes its shape, thereby activating it. This chain of reactions, where hormone binding to the GPCR leads to the appearance of cAMP in the cytoplasm as the second messenger which, in turn, leads to the activation of protein kinase is an example of a “reaction cascade.” In this case, since a signal from the exterior of the cell is transferred to the interior via the formation of a “second messenger,” the process is called “signal transduction cascade." Other second messengers that can be involved as a result of hormone binding to a cell membrane receptor include cyclic GMP (derived from guanosine triphosphate), tyrosine kinases, inositol phospholipids, and even calcium ions. Cellular responses to hormone binding of a cell membrane receptor include altering membrane permeability, activating metabolic pathways, stimulating synthesis of proteins and enzymes, and hormone release.

The binding of a hormone at a single cell membrane receptor causes the activation of many G-proteins, which can catalyze many reactions simultaneously. Thus, the effect of a peptide hormone is amplified as the signaling cascade progresses. A small amount of hormone can trigger the formation of a large amount of cellular product. To stop hormone activity, the cascading chemical reaction is interrupted; for example cAMP is deactivated by the cytoplasmic enzyme phosphodiesterase (PDE). PDE is always present in the cell, and it breaks down cAMP spontaneously, preventing overproduction of cellular products. The specific response of a cell to a lipid-insoluble hormone depends on the type of receptors that are present on the cell membrane and the substrate molecules present in the cell cytoplasm.

did I get this

The pituitary-hypothalamus axis links the nervous system with the endocrine system. The hypothalamus is a region of the brain that is located inferior to the thalamus. It coordinates signals from internal organs and other regions of the brain and regulates a response from the endocrine system via the pituitary. The hypothalamus secretes both releasing hormones that stimulate the anterior pituitary to secrete a hormone and inhibiting hormones that inhibit the release of a hormone from the anterior pituitary.

The pituitary gland is a pea-sized gland located at the base of the brain attached to the hypothalamus via a stalk called the infundibulum. The pituitary gland is primarily regulated by nerve impulses or hormones released by neurosecretory cells of the hypothalamus. The pituitary, in turn, releases hormones that either have a direct effect on target cells or regulate hormone production by other endocrine glands. Those hormones that control the release of another hormone from an endocrine gland are called tropic hormones. The pituitary has two distinct regions: the anterior pituitary, and the posterior pituitary. The anterior pituitary secretes seven different peptide or protein hormones: growth hormone(GH), prolactin (PRL), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ATCH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and melanocyte stimulating hormone (MSH). The posterior pituitary is an extension of the brain and releases hormones produced by the hypothalamus. The posterior pituitary releases antidiuretic hormone (ADH) (also known as vasopressin) and oxytocin. The pituitary looks like one gland because the anterior and posterior pituitary do not have externally visible distinctions, but from a cell and tissue perspective, they are really two different and distinct organs.

did I get this

The anterior pituitary gland, or adenohypophysis, is surrounded by a capillary network. This capillary network is a part of the hypophyseal portal system that carries substances from the hypothalamus directly to the anterior pituitary. Remember that substances such as hormones can only leave or enter the circulatory system at capillaries, and portal systems (portal systems are also found in the digestive system) move material from one capillary bed to another without returning it to the main circulation. Anterior pituitary hormones then enter the capillaries and travel to the heart and through the systemic system in the same way other hormones do.

Several anterior pituitary hormones (TSH, ACTH) are tropic hormones, because they control the functioning of other endocrine glands. While these hormones are produced by the anterior pituitary, their production is controlled by regulatory hormones produced by the hypothalamus. Negative feedback mechanisms regulate how much of these regulatory hormones is released, and how much anterior pituitary hormone is secreted.

learn by doing
did I get this

The posterior pituitary is significantly different in structure and function from the anterior pituitary. As its name implies, the posterior pituitary is behind the anterior pituitary (toward the back). It contains mostly axons of secretory neurons and neuroglial cells; the cell bodies of these neurons are in the hypothalamus. The posterior pituitary and the infundibulum together are referred to as the neurohypophysis.

The posterior pituitary does not produce hormones, but stores hormones produced by the hypothalamus and releases them into the bloodstream. The hormones antidiuretic hormone (ADH) and oxytocin are produced by neurons in the hypothalamus and transported within these axons along the infundibulum to the posterior pituitary. They are released into the posterior pituitary capillaries in response to neural signaling from the hypothalamus. These hormones are considered to be posterior pituitary hormones, even though they are produced by the hypothalamus, because that is where they are released into the circulatory system.

did I get this

The thyroid gland possesses two lobes that are connected by the isthmus. It is located in the neck, just below the larynx with the isthmus in front of and lobes lateral to the trachea. It has a dark red color due to its extensive vasculature. When the thyroid increases in size due to dysfunction, it can be felt under the skin of the neck. The main function of the thyroid gland is the synthesis and storage of thyroid hormones that are involved in maintaining metabolic homeostasis.

The thyroid gland is made up of many spherical thyroid follicles, which are lined with simple cuboidal epithelium. These follicles contain a viscous fluid called colloid that stores the glycoprotein thyroglobulin, the precursor to the two thyroid hormones. Thyroglobulin is not normally released into circulation unless the thyroid gland is damaged due to disease or injury. Other endocrine cells, called parafollicular cells, are located between adjacent follicles and produce a different hormone, calcitonin, that is involved in blood calcium homeostasis.

did I get this

Unlike most endocrine glands, the thyroid gland stores large amounts of some of the hormones it synthesizes. Thyroglobulin is produced and secreted by follicle cells into the lumen of follicles as a colloid. There it undergoes post-translational modification to produce functioning thyroid hormones. Iodide molecules are added to the thyroglobulin precursor to produce the hormones thyroxine and triiodothyronine. Thyroxine is also known as T4 because it contains four atoms of iodine, and triiodothyronine is also known as T3 because it contains three atoms of iodine. In developed countries, the iodide required for hormone synthesis is obtained primarily from iodized salt. However, seafood and plants grown in iodine rich soil at lower elevations also provide the required iodide. Since iodine as a molecule is quite volatile, the food grown in higher elevations (lower atmospheric pressure) lacks sufficient iodine. Iodide ions are actively transported into the follicular lumen from the capillaries by follicle cells. Follicle cells are stimulated to release stored T3 and T4 from the lumen into the blood capillaries by thyroid stimulating hormone (TSH), which is produced by the anterior pituitary. Follicle cells also begin synthesizing more T3 and T4 in response to TSH stimulation.

A third hormone, calcitonin, is produced by parafollicular cells, or C cells of the thyroid. Calcitonin release is not controlled by TSH, but instead is released when calcium ion concentrations in the blood rise. Calcium ions bind to specific receptor on the C cell and stimulate release of calcitonin. Calcitonin acts primarily in children to lower blood calcium levels when levels get too high. Calcitonin causes decreased tubular reabsorption of Ca2+ in the kidneys, leading to calcium loss in urine. It inhibits bone resorption activity of osteoclasts and calcium absorption in intestine to also reduce plasma calcium levels. It is also suspected to have an indirect effect stimulating osteoblast activity and development. However, in adult humans it appears to play only a minor role in calcium homeostasis because abnormalities in calcitonin production do not appear to be associated with specific plasma calcium imbalances. Research has implicated its role during times of high calcium demands, such as pregnancy and lactation.

learn by doing
did I get this

The four parathyroid glands are each the size of a grain of rice and are usually located on the posterior surface of the thyroid gland. The exact location and number of parathyroid glands can vary from person to person. The parathyroid glands are named for their proximity to the thyroid gland (para- means next to), often seeming to be part of the same gland; however, their cells are distinct from those of the thyroid gland.

Note that this image is on a different anatomical plane than the previous image of the thyroid.

Each parathyroid gland is covered by connective tissue and contains many secretory cells called chief cells, which synthesize and secrete parathyroid hormone (PTH). Another type of cell, oxyphil cells, can be distinguished histologically in the parathyroid but they are not clearly understood. They appear to increase during renal failure, but their function is still a subject of clinical research.

PTH is synthesized as a pro-peptide that is cleaved into an active hormone, which is vital in maintaining blood calcium levels. Calcium is required for nerve impulse transmission, for muscle contractions and for many cellular processes--including signal transduction. Therefore, plasma calcium concentrations must be maintained within a narrow normal range of 9–10 mg/dL. PTH functions by increasing blood calcium concentrations when calcium ion levels fall below normal. Calcium ions bind to specific receptors on the chief cell and inhibit release of PTH; when the plasma calcium level falls, PTH secretion is stimulated. PTH stimulates reabsorption of calcium from filtrate during urine formation, increased absorption in the intestines from digested products and increased activity of osteoclasts to release calcium (and phosphate) from bone matrix into the plasma. There is some evidence that it may also indirectly inhibit osteoblast activity.

A parathyroid adenoma is a benign tumor of the parathyroid gland that can cause an overproduction of PTH leading to hyperparathyroidism. Hyperparathyroidism results in hypercalcemia, which can lead to kidney stones. Additionally, increased rate of bone resorption due to higher osteoclast activity due to this condition may also lead to osteoporosis. Usually only one of the four parathyroid glands is affected and can be surgically removed without any adverse effects. However, removal of all the parathyroid glands will cause an imbalance in blood calcium levels resulting in death.

learn by doing
did I get this

The adrenal glands help regulate the body’s response to stress, controlling blood pressure, and maintaining the body’s water, sodium, and potassium levels. The adrenal glands are associated with the pair of kidneys which are retroperitoneal and lateral to the spinal column ; one gland is located on the superior surface of each kidney (hence they are also known as suprarenal glands). The adrenal glands consist of an outer adrenal cortex (cortex means outer layer) and an inner adrenal medulla (medulla means middle). Functionally and anatomically the adrenal gland is really two glands packaged together. The cells of the cortex are endocrine and those of the medulla are neurosecretory. The cells look very different and embryologically they come from different tissues. These regions secrete different hormones: the adrenal cortex produces steroid hormones, and the adrenal medulla produces catecholamine hormones.

learn by doing
did I get this

The adrenal cortex is the outer layer of the adrenal gland and is made up of layers of epithelial cells and associated capillary networks. These layers form three distinct regions that secrete different steroid hormones: the outer zona glomerulosa produces mineralocorticoids (influence salt and water balance), the middle zona fasciculata produces glucocorticoids (impact metabolism and inflammation), and the inner zona reticularis produces androgens (regulate catabolism and sexual characteristics).

The main mineralocorticoid is aldosterone, which regulates the concentration of ions in urine, sweat, and saliva. Aldosterone release from the adrenal cortex can be triggered by a number of things including decrease in blood concentrations of sodium ions, blood volume, or blood pressure, or an increase in blood potassium levels.

The three main glucocorticoids are cortisol, corticosterone, and cortisone. The glucocorticoids stimulate the synthesis of glucose from non-glycogen sources, and they promote the release of fatty acids from adipose tissue. These hormones increase blood glucose levels to maintain levels within a normal range between meals. They are secreted in response to ACTH, and levels are regulated by negative feedback.

Androgens are a class of hormones and that affect sexual characteristics. Testosterone is associated with male sexual characteristics, while progesterone and estrogen are associated with female reproductive function; androstenedione is an intermediate molecule in the synthetic pathways of these and many of the steroid hormones.

Example

In situations where the gonads are not functioning the progesterone made in the adrenal glands does influence sexual characteristics. One of the reasons why post-menopausal women develop more male characteristics is that the progesterone their adrenal makes gets converted to testosterone.

did I get this

The adrenal medulla is the inner layer of the adrenal glands and contains chromaffin cells, which are large, irregularly shaped cells that are closely associated with blood vessels. These cells are innervated by autonomic (involuntary) nerve fibers from the central nervous system, which allows for quick hormone release.

Chromaffin cells of the adrenal medulla produce epinephrine (adrenaline) and norepinephrine (noradrenaline). Epinephrine is the primary adrenal medulla hormone accounting for 75–80 percent of its secretions. Epinephrine and norepinephrine increase heart rate, breathing rate, cardiac muscle contractions, and blood glucose levels. They also accelerate the breakdown of glucose in skeletal muscles and stored fats in adipose tissue.

Both are stored in vesicles or granules in the adrenal medulla, very similar to the way posterior pituitary cells store the neurosecretory hormones from hypothalamus for release. The release of epinephrine and norepinephrine into the blood is stimulated by neural impulses from the sympathetic nervous system. These neural impulses originate from the hypothalamus in response to stress to prepare the body for the fight-or-flight response.

## Blood Supply to the Adrenal Glands

The adrenal glands have a large blood supply. They receive arterial blood from the renal arteries, the phrenic arteries, and suprarenal arteries from the aorta. Arterial blood enters the adrenal glands at the adrenal cortex and drains into venules in the adrenal medulla. The suprarenal vein of the right adrenal gland drains into the inferior vena cava, and the suprarenal vein of the left adrenal gland drains into the left renal vein.

did I get this

The pineal gland is located between the cerebral hemispheres of the brain. It is attached to the roof of the third ventricle in the diencephalon. The pineal gland consists of secretory cells, called pinealocytes, that secrete the hormone melatonin. Melatonin is derived from serotonin (a neuropeptide) and is regulated in response to the light and dark of the environment (the diurnal cycle). Photons, packets of light, are detected by the retinas of the eyes, which initiate a nerve impulse that is detected by the pineal gland. This mechanism is similar to the process in the posterior pituitary or adrenal medulla. The pineal gland synthesizes the highest levels of melatonin during the night, when light levels are the lowest, and the increased blood concentrations of melatonin makes us sleepy. Blood concentrations of melatonin are lowest during the day, when light exposure inhibits the synthesis of the hormone.

The target cells of melatonin are located in the suprachiasmatic nucleus (SCN) of the brain. The SCN functions as a biological clock that regulates physiological processes such as the sleep-wake cycle, appetite, and body temperature. Melatonin is thought to inhibit the release of gonadotropins from the anterior pituitary, which affect the onset of puberty.

Higher melatonin levels at night make us sleepy, and a disruption in melatonin synthesis can disrupt the sleep cycle. Travel across several time zones can result in disruptions to the sleep cycle, or jet lag. This is due to the change in the dark-light cycle that the body is accustomed to, and it can take several days for melatonin synthesis to adapt to the change. Melatonin supplements are available to treat jet lag as well as other sleep disorders; however, their efficacy has not been conclusively established.

did I get this

The pancreas is an elongated organ that plays a central role in energy metabolism, storage, and utilization of glucose (carbohydrate). It is located slightly dorsal to the stomach and between the stomach and the small intestine. The tapered distal end lies in contact with the spleen, while the ducts from broader proximal end enter the duodenum at gastro-duodenal junction. The pancreas contains both exocrine cells that excrete digestive enzymes and endocrine cells that release hormones. Approximately 99 percent of pancreatic cells are exocrine cells that are arranged around ducts in clusters called acini (singular is acinus).

The endocrine cells of the pancreas form clusters called pancreatic islets or the islets of Langerhans (islets are small islands) with associated blood capillaries. The pancreatic islets contain two major cell types: alpha cells, which constitute 20 percent of the total mass of the islets and produce the hormone glucagon, and beta cells, which constitute 75 percent of the total mass of the islets and produce the hormone insulin. These hormones regulate blood glucose levels. Alpha cells release glucagon as blood glucose levels decline below the set point. When blood glucose levels rise, alpha cells stop secreting glucagon, and beta cells then release insulin. When blood glucose levels drop below the set point (which does not happen under normal conditions), beta cells stop secreting insulin.

Pancreatic cells also contain two minor populations of cells: delta cells, which constitute 4 percent of the total mass of the islets and secrete somatostatin, and F (or PP) cells, which constitute 1 percent of the total mass of the islets and secrete pancreatic polypeptide. They have specific paracrine regulator effects in the pancreas. Pancreatic polypeptide is secreted after a high protein meal or fasting and inhibits pancreatic exocrine secretion and stimulates gastric juice secretion (opposite effect of cholecystokinin, CCK, of the small intestine). It also stimulates both alpha and beta cells.

learn by doing
did I get this

The gonads, the male testes (sing. Testis) and female ovaries, function in production of gametes (sperm and ovum) and also produce steroid hormones. The testes produce androgens, testosterone being the most prominent. Testosterone stimulates the development of male secondary sex characteristics and the production of sperm cells. The testes also produce the hormone inhibin, which inhibits the release of the tropic hormone from the anterior pituitary follicle-stimulating hormone (FSH) needed for the development of sperm (spermatogenesis).

The ovaries produce the hormones estrogen and progesterone, which stimulate the development of female secondary sex characteristics, regulate the menstrual cycle, and prepare the body for childbirth. The ovaries also produce the hormone inhibin, which inhibits the release of FSH.

The placenta, which supplies the necessary nutrients to the fetus, is also an endocrine organ. It synthesizes and secretes a number of hormones that are crucial for the maintenance of pregnancy. The human chorionic gonadotropin hormone (hCG), that is the basis of urine pregnancy tests is another of the placental hormones. As the fetus develops, the placenta takes over the production of estrogen and progesterone to maintain pregnancy. The high level of estrogen facilitates the growth of the uterus and the mammary glands during gestation. Progesterone is important in suppressing maternal immune response towards the fetus and inhibiting uterine smooth muscle contraction. The placenta also produces relaxin, that affects collagen metabolism and softens the pubic symphysis to facilitate birthing. It also produces lactogen, which is structurally similar to prolactin and growth hormone (pituitary hormones), but its role, if any, in human lactation is still being investigated.

did I get this
Endocrine Gland Associated Hormones Main Effect
Pituitary (Anterior) Growth hormone Promotes growth of body tissues
Prolactin Promotes milk production
Thyroid-stimulating hormone (TSH) Stimulates thyroid hormone release
Follicle-stimulating hormone (FSH) Stimulates gamete production
Luteinizing hormone (LH) Stimulates androgen/estrogen production by gonads
Pituitary (Posterior) Antidiuretic hormone (ADH; also called vasopressin) Stimulates water reabsorption by kidneys
Oxytocin Stimulates uterine contractions during childbirth
Thyroid Thyroxine, triiodothyronine Stimulate metabolism
Calcitonin Reduces blood Ca2+ levels, primarily in children
Parathyroid Parathyroid hormone (PTH) Increases blood Ca2+ levels
Adrenal (Cortex) Aldosterone Increases blood Na+ levels, and related water conservation by kidneys, Decreases blood K+ levels
Cortisol, corticosterone, cortisone Increase blood glucose levels
Adrenal (Medulla) Epinephrine, norepinephrine Stimulate fight-or-flight response
Pineal Melatonin Regulates sleep cycles
Pituitary Glucagon Increases blood glucose levels
Insulin Decreases blood glucose levels
Testes Testosterone Stimulates development of male secondary sex characteristics and sperm production
Inhibin Inhibits secretion of FSH
Ovaries Estrogen and progesterone Stimulates development of female secondary sex characteristics, egg production and preparation of the body for childbirth
Inhibin Inhibits secretion of FSH
learn by doing
did I get this

There are several organs whose primary functions are non-endocrine but that also possess endocrine functions. These include the heart, gastrointestinal tract, kidneys, adipose tissue, skin, and thymus.

## Heart and Cardiovascular System

The heart possesses specialized cardiac muscle cells, which are endocrine cells in the walls of the atria. These cells respond to increased blood volume by releasing the hormone atrial natriuretic peptide (ANP). Natrium is the name for sodium in many languages and is the reason that Na is the chemical symbol for sodium. High blood volume causes the cells to be stretched, opening stretch-activated membrane channels, resulting in hormone release. ANP acts on the kidneys to reduce the reabsorption of Na+, causing Na+ and water to be excreted in the urine. ANP also reduces the amounts of renin released by the kidneys and aldosterone released by the adrenal cortex, further preventing the retention of water. In this way, ANP reduces the concentration of Na+ in the blood and causes a reduction in blood volume and blood pressure. Another natriuretic hormone, BNP (misnamed brain natriuretic because it was first isolated from pig brains) from the heart ventricle, enhances the effect of ANP.

Endothelial cells lining the cardiovascular system also have an endocrine function. They produce paracrine endothelin, a vasodilator and stimulator of ANP secretion, and nitric oxide (NO), a vasodilator and inhibitor of ANP secretion.

## Digestive System

The digestive system produces several hormones that aid in digestive and metabolic homeostasis. Endocrine cells are located in the mucosa of the GI tract throughout the stomach and small intestine. Hormone secretion is controlled by receptors monitoring the chemical content of the digestive lumen. Some of the hormones produced include gastrin (from stomach), secretin, and cholecystokinin CCK (from small intestine) that act on the GI tract and accessory organs such as the pancreas, gallbladder, and liver. They trigger the release of digestive juices that help to break down and digest food in the GI tract. The GI tract also produces the hormones glucose-dependent insulinotropic peptide (GIP) (from stomach) and glucagon-like peptide 1 (GLP-1) (from small intestine). These hormones are secreted in response to glucose in the intestinal lumen. GIP and GLP-1 target cells are beta cells in the pancreas, which are stimulated to release insulin and alpha cells that are inhibited from releasing glucagon. The stomach also produces ghrelin that mediates hunger, stimulating appetite and growth hormone release.

The liver, as an accessory organ of the digestive system, also has an endocrine function in production of insulin-like growth factor (IGFs) and thrombopoietin (THPO). IGFs work with growth hormone to regulate cell metabolism while THPO triggers the formation of platelets in the blood. The liver also produces prohormones (angiotensinogen and calcidiol, vitamin D) and plasma proteins that transport many of the hormones.

## Kidneys and Urinary System

The adrenal glands associated with the kidneys are major endocrine glands, and the kidneys themselves also possess endocrine functions. Renin ('renal' generally describes aspects of the kidney) is released in response to decreased blood volume or pressure and is part of the renin-angiotensin system that is responsible for the formation of angiotensin II and ultimately leads to the release of aldosterone. Both angiotensin II and aldosterone then causes the retention of Na+ and water, raising blood volume. The kidneys also release the steroid hormone calcitriol, which is the biologically active form of vitamin D that aids in the absorption of Ca2+. Erythropoietin (EPO) is a protein hormone that triggers the formation of red blood cells in the bone marrow. EPO is released in response to low oxygen levels. Because red blood cells are oxygen carriers, increased production results in greater oxygen delivery throughout the body. The banned substance EPO had been used by athletes at one point to improve performance, as greater oxygen delivery to muscle cells allows for greater endurance. Because red blood cells increase the viscosity of blood, artificially high levels can cause severe health risks.

Adipose tissue is a connective tissue found throughout the body. It produces the hormone leptin (Greek “leptos” means “thin”) in response to food intake. Leptin binds to neuropeptide Y in the CNS neurons, producing a feeling of satiety after eating, thus affecting appetite and reducing the urge for further eating. Note that it has the opposite effect of ghrelin secretion from the stomach, but when leptin levels drop, the brain detects a state of starvation and the feeling of hunger increases. These two hormones are the subject of much research related to obesity.

## Skin

Skin produces cholecalciferol, which is an inactive hormone form of vitamin D3. It is formed when cholesterol molecules in the skin, in the form of 7-dehydrocholesterol, are exposed to ultraviolet radiation. Cholecalciferol then enters the bloodstream and is modified in the liver to form calcifediol. Calcifediol is then modified in the kidneys to form calcitriol, which is the active form of vitamin D3. Vitamin D plays an important role in bone formation.

## Bone

Bones not only respond to hormones to maintain blood calcium homeostasis, but recent research shows they also have an endocrine function. Osteocytes have been found to produce two hormones (fibroblast growth factor 23 and osteocalcin) that act on kidney, pancreas and other body tissues influencing Vitamin D and glucose homeostasis.

## Thymus

The thymus is an organ that is found behind the sternum and is most prominent in infants, becoming smaller in size through adulthood, replaced by adipose tissue that continues to produce angiogenic factors. The thymus is part of the immune system, with a role in maturation and immunocompetence of T-lymphocytes. The thymus also produces a group of hormones called thymosins, because they were first discovered from the thymus, but now are understood to be produced by many different tissues in the body. They appear to have an anti-inflammatory effect and stimulate tissue repair. Thymosin is also involved in neuroplasticity, and they may have clinical implications in the treatment of cardiovascular, infectious and autoimmune diseases as well as cancer.

learn by doing
Organ Associated Hormones Main Effect
Heart Atrial Natriuretic Peptide (ANP) Reduces blood volume, pressure, and Na+ concentration
Gastrointestinal Tract Gastrin, Secretin, and Cholecystokinin Aid in the digestion of food
Kidneys Renin Stimulates production of angiotensin II
Calcitriol Aids in the absorption of Ca2+
Erythropoietin Triggers the formation of red blood cells in the bone marrow
Adipose Tissue Leptin Promotes satiety signals in the brain
Skin Cholecalciferol Modified to form vitamin D
Thymus Thymosins Aid in the development of the immune system
did I get this

Hormones have a wide range of effects and modulate many different body processes. The key processes that will be examined in this section are hormonal regulation of the excretory system, the reproductive system, metabolism, blood calcium concentrations, growth, and the stress response.

We will see how hormones help the body to maintain homeostasis, by integrating different organ systems.

Maintaining a proper water balance in the body is important to avoid dehydration or excess water. The water concentration of the body is monitored by osmoreceptors in the hypothalamus, which detect the concentration of electrolytes in the blood. The concentration of electrolytes in the blood rises when there is water loss due to excessive perspiration, inadequate water intake, or low blood volume due to blood loss. An increase in blood electrolyte levels results in a neural signal being sent from the osmoreceptors to the hypothalamus. The hypothalamus produces antidiuretic hormone (ADH), which is transported to, and released from, the posterior pituitary. It is also known as vasopressin. The target cells for ADH are the distal tubule cells in the kidneys, which are stimulated to absorb more water from urine, resulting in an increase in the water level of blood and making urine which is more concentrated.

Chronic underproduction of ADH results in diabetes insipidus. If the posterior pituitary does not release enough ADH, water cannot be retained by the kidneys and is eliminated in the urine. This causes increased thirst, but water taken in is lost again, and water must be continually consumed. If the condition is not severe, dehydration may not occur, but severe cases can lead to electrolyte imbalances due to dehydration.

Another hormone responsible for maintaining electrolyte concentrations in extracellular fluids is aldosterone, a steroid hormone that is produced by the adrenal cortex. In contrast to ADH, which promotes the reabsorption of water to maintain proper water balance, aldosterone maintains proper water balance by enhancing Na+ reabsorption from extracellular fluids. Because it affects the concentrations of minerals, Na+, aldosterone is referred to as a mineralocorticoid. Aldosterone release is stimulated by a decrease in blood sodium levels, blood volume, or blood pressure, or an increase in blood potassium levels. Aldosterone targets the renal tubules of the kidneys, where it causes the reabsorption of Na+ from urine and the secretion of K+ into the urine. It also prevents the loss of Na+ from sweat, saliva, and gastric juice. The reabsorption of Na+ also results in the osmotic reabsorption of water, which alters blood volume and blood pressure.

Aldosterone production can be stimulated by low blood pressure, which triggers a sequence of chemical releases. When blood pressure drops, cells in the juxtaglomerular apparatus of the kidney detect this and release renin. Renin circulates in the blood and reacts with a protein produced by the liver called angiotensinogen. When angiotensinogen is cleaved by renin, it produces angiotensin I, which is then converted into angiotensin II. Angiotensin II impacts water and Na+ reabsorption and causes the release of aldosterone by the adrenal cortex with a similar effect; ultimately these increase blood pressure. Angiotensin II also causes an increase in ADH and increased thirst, which both help to increase fluids and raise blood pressure.

did I get this

Regulation of the reproductive system is a process that requires the action of hormones from the pituitary gland, the adrenal cortex, and the gonads. During puberty in both males and females, the hypothalamus produces gonadotropin-releasing hormone (GnRH), which stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. These hormones regulate the gonads (testes in males and ovaries in females) and therefore are called gonadotropins. In both males and females, FSH stimulates gamete production, and LH stimulates production of hormones by the gonads. An increase in gonad hormone levels inhibits GnRH production through a negative feedback loop.

## Regulation of the Male Reproductive System

In males, FSH and LH regulates the maturation of sperm cells. FSH stimulates the support cells in the testes called Sertoli (sustentacular) cells. These cells nourish and regulate the maturation of the sperm and produce androgen binding protein (ABP). ABP keeps the level of testosterone high within the testes, relative to the plasma levels. FSH production is inhibited by the hormone inhibin, which is also released by the Sertoli cells in the testes. LH stimulates production of the sex hormones (androgens) by the interstitial or Leydig cells of the testes and therefore is also called interstitial cell-stimulating hormone (ICSH).

The most important androgen in males is testosterone. Testosterone promotes the production and maturation of sperm and determines secondary sex characteristics. The adrenal cortex of both males and females also produces small amounts of testosterone, although the role of this additional hormone production in males is not well understood.

## Regulation of the Female Reproductive System

In females, FSH stimulates development of support cells around the egg, which develop into structures called follicles. LH regulates the development and release of the egg from the follicle. Follicle cells initially produce the hormone estrogen that has effects on the hypothalamus and anterior pituitary, as well as the uterus. LH stimulates the egg to mature within the growing follicle. As estrogen levels rise, it triggers the anterior pituitary to release a surge of LH that stimulates ovulation. The follicle cells remaining in the ovary become the corpus luteum and now produce both estrogen and progesterone as well as inhibin, all of which inhibit the anterior pituitary.

Estrogen and progesterone are steroid hormones that prepare the body for pregnancy. Estrogen produces secondary sex characteristics in females, while both estrogen and progesterone together regulate the uterine menstrual cycle.

## Regulation of the Female Reproductive System and Childbirth

In addition to producing FSH and LH, the anterior pituitary also produces the hormone prolactin (PRL). In females, prolactin stimulates the production of milk by the mammary glands following childbirth. Prolactin levels are regulated by the hypothalamic hormones prolactin-releasing hormone (PRH) and prolactin-inhibiting hormone (PIH), the latter of which is now known to be dopamine. Usually prolactin production is inhibited, but PRH, estrogen and infant suckling stimulation remove the inhibition. Males can produce small amounts of prolactin and its role in other aspects of reproduction and immunity are not well understood but are being investigated in humans.

The posterior pituitary releases the hormone oxytocin, which stimulates contractions during childbirth. The uterine smooth muscles are not very sensitive to oxytocin until late in pregnancy when the number of oxytocin receptors in the uterus peaks. Stretching of tissues in the uterus and vagina stimulates oxytocin release in childbirth. Contractions increase in intensity as blood levels of oxytocin rise until the birth is complete. Oxytocin also stimulates the contraction of myoepithelial cells around the milk-producing cells of the mammary glands. As these cells contract, milk is forced from the secretory alveoli into milk ducts and is ejected from the breasts in a milk let-down reflex. Oxytocin release is stimulated by the suckling of an infant, which triggers the synthesis of oxytocin in the hypothalamus and its release into circulation at the posterior pituitary.

learn by doing
did I get this

Blood glucose levels vary widely over the course of a day as periods of food consumption alternate with periods of fasting. Insulin and glucagon are the two hormones that are primarily responsible for maintaining homeostasis of blood glucose levels. Additional regulation is mediated by the thyroid hormones.

## Regulation of Blood Glucose Levels by Insulin and Glucagon

Cells of the body require nutrients in order to function, and they obtain these nutrients through feeding. In order to manage nutrient intake, storing excess and utilizing stores when necessary, the body uses hormones to modulate energy metabolism. Insulin is produced by the beta cells of the pancreas, which are stimulated to release insulin as blood glucose levels rise, for example, after a meal is consumed. Insulin lowers blood glucose levels by enhancing glucose uptake by most body target cells, which utilize glucose for ATP production; muscle cells are a good example. It also stimulates the liver to convert glucose to glycogen, which is then stored by cells for later use. Increased glucose uptake occurs through an insulin-mediated increase in the number of glucose transporter proteins in cell membranes, which remove glucose from circulation by facilitated diffusion. As insulin binds to its target cell, it triggers the cell to incorporate transport proteins into its membrane. This allows glucose to enter the cell, where it can be used as an energy source. However, this does not always occur in all body cells, as some cells in the kidneys and brain have been shown to regularly access glucose without the use of insulin. Insulin also stimulates the conversion of glucose to fat in adipocytes and the synthesis of proteins. The actions of insulin which cause blood glucose concentrations to fall, called a hypoglycemic effect, inhibit further insulin release from beta cells through a negative feedback loop.

Decreased insulin production or reduced sensitivity of cells to insulin can lead to a condition called diabetes mellitus. This prevents glucose from being absorbed by cells, causing high levels of glucose in the blood, or hyperglycemia. High blood glucose levels make it difficult for the kidneys to reabsorb all the filtered glucose, resulting in glucose being lost in urine. High glucose levels also result in less water being reabsorbed by the kidneys because the water is retained in the urine to osmotically balance the high levels of excess glucose. This causes increased urination, which may result in dehydration. Over time, high blood glucose levels can cause nerve damage to the eyes and peripheral body tissues, as well as damage to the kidneys and cardiovascular system. On the other hand, over-secretion of insulin can lead to low blood glucose levels, or hypoglycemia. This causes insufficient glucose availability to cells, often leading to muscle weakness, and can sometimes cause unconsciousness or death if left untreated.

When blood glucose levels decline below normal levels, for example, between meals or when glucose is utilized rapidly during exercise, the hormone glucagon is released from the alpha cells of the pancreas. Glucagon raises blood glucose levels, called a hyperglycemic effect, by stimulating the breakdown of glycogen to glucose in skeletal muscle cells and liver cells in a process called glycogenolysis (glycogen-splitting). Glucose can then be utilized as energy by muscle cells and released into circulation by the liver cells. Glucagon also stimulates absorption of amino acids from the blood by the liver, which then converts them to glucose. This process of glucose synthesis is called gluconeogenesis (new glucose formation). Glucagon also stimulates adipose cells to release fatty acids into the blood. Collectively, these glucagon-mediated actions result in an increase in blood glucose levels to normal homeostatic levels. Rising blood glucose levels inhibit further glucagon release by the pancreas. In this way, insulin and glucagon work together to maintain glucose homeostasis.

## Regulation of Blood Glucose Levels by Thyroid Hormones

The basal metabolic rate, which is the amount of calories required by the body at rest, is determined by two hormones produced by the thyroid gland: thyroxine, also know as tetraiodothyronine or T4, and triiodothyronine, also know as T3. Dietary iodine is needed to synthesize these hormones. These hormones affect nearly every cell in the body except for the adult brain, uterus, testes, and spleen. They cross the plasma membrane of target cells and bind to receptors on the mitochondria, resulting in increased ATP production. In the nucleus, T3 and T4 activate genes involved in energy production and glucose oxidation. This results in increased rates of metabolism and body heat production, which is known as the hormone’s calorigenic effect.

Disorders can arise from both the underproduction and overproduction of thyroid hormones. Hypothyroidism, under activity of the thyroid hormones, can cause a low metabolic rate, leading to weight gain, sensitivity to cold, and reduced mental activity, among other symptoms. In children, hypothyroidism can cause cretinism, which causes mental retardation and growth defects. Hyperthyroidism, the over-activity of thyroid hormones, can lead to an increased metabolic rate, causing weight loss, excess heat production, sweating, and an increased heart rate. Graves’ disease is one such hyperthyroid condition. In the absence of iodine, thyroid hormones are not produced, colloid storage increases, and thyroid enlargement (goiter) occurs.

did I get this

Regulation of blood calcium concentration is important for proper muscle contractions and release of neurotransmitters. Calcium also affects voltage-gated plasma membrane ion channels, affecting nerve impulses and other cell physiology. If plasma calcium levels are too high, membrane permeability to sodium decreases and membranes become less responsive. If plasma calcium levels are too low, membrane permeability to sodium increases and convulsions or muscle spasms can result.

Blood calcium levels are regulated by parathyroid hormone (PTH), which is produced by the parathyroid glands. PTH is released in response to low blood Ca2+ levels. PTH increases Ca2+ levels by targeting the skeleton, the kidneys, and the intestine. In the skeleton, PTH stimulates osteoclasts, causing bone to be broken down and releasing Ca2+ from bone into the blood. PTH also inhibits osteoblasts, reducing Ca2+ deposition in bone. In the kidneys and intestines, PTH stimulates the reabsorption of Ca2+. While PTH acts directly on the kidneys to increase Ca2+ reabsorption, its effects on the intestine are indirect. PTH triggers the formation of calcitriol, an active form of vitamin D, which acts on the intestines to increase absorption of dietary calcium. PTH release is inhibited by rising blood calcium levels.

Example

Hyperparathyroidism results from an overproduction of parathyroid hormone. This results in excessive calcium being removed from bones and being introduced into blood circulation. This causes structural weakness of the bones, which can lead to deformation and breakage, and nervous system impairment due to high blood calcium levels. Hypoparathyroidism, the underproduction of PTH, results in extremely low levels of blood calcium, which causes impaired muscle function and may result in tetany—severe sustained muscle contraction.

The hormone calcitonin is produced by the parafollicular or C cells of the thyroid and has the opposite effect on blood calcium levels as PTH. Calcitonin decreases blood calcium levels by inhibiting osteoclasts, stimulating osteoblasts, and stimulating calcium excretion by the kidneys. This results in calcium being added to the bones to promote structural integrity. Calcitonin appears to play a major plasma calcium homeostasis role only in children, and in pregnant women to reduce maternal bone loss. Its role in adults is not well understood and it may be more important in regulating bone remodeling than blood plasma homeostasis.

learn by doing
did I get this

Hormonal regulation is required for the growth and replication of most cells in the body. Growth hormone (GH) produced by the anterior pituitary accelerates the rate of protein synthesis, particularly in skeletal muscle and bones. Growth hormone has direct and indirect mechanisms of action. One direct action is the stimulation of fat breakdown (lipolysis) and release into the blood by adipocytes. This results in a switch by most tissues from utilizing glucose as an energy source to utilizing fatty acids. This process is called a glucose-sparing effect. Another direct action occurs in the liver, where GH stimulates glycogen breakdown, and subsequent release of glucose into the blood. Blood glucose levels increase as most tissues are metabolizing fatty acids instead of glucose. The GH-mediated increase in blood glucose levels is called a diabetogenic effect because it is similar to the high blood glucose levels seen in diabetes mellitus.

The indirect mechanism of GH action is mediated by somatomedins or insulin-like growth factors (IGFs), which are a family of growth-promoting proteins produced by the liver. IGFs stimulate the uptake of amino acids from the blood, allowing the formation of new proteins, particularly in skeletal muscle cells, cartilage cells, and other target cells. GH levels are regulated by two hormones produced by the hypothalamus. GH release is stimulated by growth hormone-releasing hormone (GHRH) and is inhibited by growth hormone-inhibiting hormone (GHIH), also called somatostatin. Both of these are produced by the hypothalamus and delivered to the anterior pituitary by the hypophyseal portal vein.

Over-secretion of growth hormone can lead to gigantism in children, causing excessive growth. In adults, excessive GH can lead to acromegaly, a condition in which bones still capable of growth in the face, hands, and feet enlarge. Under-production of GH in adults does not appear to cause any abnormalities, but in children it can result in pituitary dwarfism, in which growth is proportionally reduced.

learn by doing
did I get this

When a threat or danger is perceived, the body responds by releasing hormones that will ready it for the fight-or-flight response. The effects of this response are familiar to anyone who has been in a stressful situation: increased heart rate, dry mouth, butterflies in your stomach and sweating. This is what we call a short-term stress. When one is under stress for more than several hours (or chronically), it translates into long term stress.

The sympathetic nervous system regulates the stress response via the hypothalamus. Stressful stimuli cause the hypothalamus to signal the adrenal medulla via nerve impulses, which mediates short-term stress responses, and to the adrenal cortex, via the hormone adrenocorticotropic hormone (ACTH), which mediates long-term stress response.

## Short-Term Stress Response

Upon stimulation, the adrenal medulla releases the hormones epinephrine (also known as adrenaline) and norepinephrine (also known as noradrenaline), collectively referred to as the catecholamines. The release of these hormones into the blood provides the body with a burst of energy that is needed to respond to a stressful situation. Epinephrine and norepinephrine increase blood glucose levels by stimulating the liver and skeletal muscles to break down glycogen and by stimulating glucose release by liver cells. These hormones also increase oxygen availability to cells by increasing the heart rate and dilating the bronchioles. In addition, they increase the blood supply to essential organs such as the heart, brain, and skeletal muscles by stimulating specific blood vessels to relax or by constricting other vessels to divert blood away from nonessential organs such as the skin, digestive system, and kidneys.

## Long-Term Stress Response

In a long-term stress response, the hypothalamus triggers the release of ACTH from the anterior pituitary. The adrenal cortex is stimulated by ACTH to release steroid hormones called corticosteroids. The two main corticosteroids are glucocorticoids, such as cortisol, and mineralocorticoids, such as aldosterone. The glucocorticoids primarily affect glucose metabolism by stimulating glucose synthesis. They also stimulate the redistribution of fat stored in adipose tissue for use in meeting long-term energy requirements. Glucocorticoids also have anti-inflammatory properties through inhibition of the immune system. For example, cortisone is used as an anti-inflammatory medication; however, it cannot be used long term as it increases susceptibility to disease due to its immune-suppressing effects as well as changes to blood pressure and constant heart stimulation.

Mineralocorticoids function to regulate ion and water balance of the body. The hormone aldosterone stimulates the reabsorption of water and sodium ions in the kidney, which results in increased blood pressure and volume.

Hypersecretion of glucocorticoids, unrelated to a normal stress response, can be caused by a condition known as Cushing’s disease. This can cause the accumulation of adipose tissue in the face and neck and excessive glucose in the blood. Hyposecretion of the corticosteroids, independent of the normal stress response, is often the result of Addison’s disease, which may result in low blood sugar levels and low electrolyte levels.

learn by doing
did I get this

## Tumors

Endocrine glands tightly regulate hormone synthesis and release to maintain homeostasis in the body. Although they are rare, tumors in endocrine glands do occur, disrupting normal hormone synthesis. These cancers, called neuroendocrine tumors or NETs, affect cells of the endocrine and nervous system that control hormone synthesis.

Tumors of endocrine glands can produce symptoms that are similar to those caused by hypersecretion of hormones in endocrine disorders. For example, tumors of the adrenal glands that result in the excess production of steroid hormones produce symptoms of Cushing’s disease, which includes the accumulation of adipose tissue in the face and neck and excessive glucose in the blood.

Tumors of the pancreas that affect beta cells are called insulinomas, and those that affect alpha cells are called glucagonomas. Beta cell tumors result in the production of excess amounts of the hormone insulin, which results in hypoglycemia. Alpha cell tumors result in the production of excess amounts of the hormone glucagon, which results in hyperglycemia and symptoms similar to those seen in diabetes.

Tumors of the pituitary gland fall into two groups: secreting and non-secreting tumors. Secreting tumors cause the secretion of excess amounts of pituitary hormones. Symptoms of secreting pituitary tumors are related to the function of the hormone that is affected. For example, growth hormone-producing tumors can lead to gigantism and acromegaly.

Medullary thyroid cancer (MTC) is a cancer of the parafollicular cells of the thyroid gland. The parafollicular cells produce the hormone calcitonin, which plays a role in calcium regulation and bone formation. Unlike in other cancers, the increased levels of calcitonin produced by MTC in adults are not harmful. Increased blood calcitonin levels are used to diagnose MTC.

Many secretory NETs can be tentatively diagnosed by measuring blood hormone levels to identify hormones that are present in excess. Treatment of these tumors can include surgery to remove the tumor or affected endocrine gland and chemotherapy.

## Osteoporosis

Osteoporosis is a disease of the skeletal system characterized by a decrease in bone density and deterioration of bone tissue. The mechanism of disease onset is an imbalance between bone formation and bone resorption, with bone resorption occurring at a greater rate than bone formation. Hormone levels play a vital role in maintaining a balance in bone turnover. Osteoporosis affects primarily the elderly and is three times more common in women than in men. This may be related to lower peak bone mass in women and to hormonal changes that occur during menopause. Low estrogen levels increase the rate of bone turnover, which alters the balance between bone formation and bone resorption. The decrease in estrogen that occurs during menopause appears to be the primary cause of osteoporosis in women over 50 years of age.

The elderly also have decreased levels of the hormone calcitriol, which is the active form of vitamin D3. Vitamin D helps maintain calcium balance in the skeleton by stimulating calcium absorption in the intestines and by maintaining calcium and phosphate levels for bone formation. Vitamin D also helps to maintain homeostatic levels of parathyroid hormone (PTH). Decreased vitamin D levels are associated with increased PTH levels, which result in increased bone turnover and bone loss.

Decreased dietary intake of calcium in the elderly is also associated with osteoporosis. In addition to the decreased availability of calcium for bone formation, low blood calcium levels stimulate the parathyroid glands to synthesize more PTH. PTH stimulates the release of calcium from bones to maintain blood calcium levels, resulting in increased bone loss.

Osteoporosis can be prevented by maintaining a lifestyle that includes exercise and proper nutrition. It can be treated using the hormone calcitonin, which is normally produced by the parafollicular cells of the thyroid gland. Calcitonin functions to lower blood calcium levels and promotes bone formation. Calcium and vitamin D supplements have also been shown to reduce the incidence of osteoporosis.

learn by doing

The digestive system is basically a tube within our body, from mouth to anus. It includes the stomach and intestines, as well as accessory organs such as the liver, gall bladder and pancreas. The space within any tubular body structure, such as blood vessels or this digestive tract, is known as a lumen. During embryological development, embryonic cells (endoderm) forming the primitive yolk sac, turn outside-in (invaginates) forming the anal opening to the outside. This endoderm layer becomes the epithelial tissue lining of the future gastrointestinal (GI) tract and many associated organs. Later in the development process, the mouth opening breaks through the outer layer of embryonic cells (ectoderm) from the opposite side, meeting the endoderm. This ectoderm lines the mouth and forms the salivary glands. As a result, anything inside the space or lumen of the GI tract can technically be described as still being “external” to the body tissues. So, the caustic process of digestion is occurring in an “external” tube, without destroying the “internal” body tissues themselves. Then the products of digestion are absorbed from this “external environment” into the body cells and tissue fluids.

As early as the 2nd century, early anatomists understood the basic structure and important function of the digestive system. Many of the terms we still use for anatomy were developed then and during the medieval period, when they described the importance of the stomach and intestines for proper nutrition and digestion to maintain health. They also recognized the association of the liver and gall bladder to produce and store bile, although they didn’t correctly understand its physiology. It was identified as one of the four body fluids (blood, phlegm, yellow bile and black bile) that Hippocrates proposed were the physiological foundation for different human emotions and behaviors; thus they were called “humors”. The imbalance of these four humors was thought to be the cause of physical and mental illnesses. This and many of the early physiological theories have since been discarded. However, their idea that the stomach was an animate organ with ability to think or feel doesn’t seem totally ridiculous as you learn about how modern science is discovering the physiological importance of a specific part of the nervous system that resides entirely in our gut. By the renaissance period, physiologists were focusing their research on the chemical basis of digestion occurring inside the GI tract.

learn by doing
 did I get this

Several of the core ideas in A&P are clearly demonstrated as you investigate the digestive system in this module:

1. Living organisms are causal mechanisms whose functions are to be understood by the applications of the laws of physics and chemistry.

Both mechanical and chemical digestion are necessary to convert the food we eat into a form that can be absorbed.

2. The cell is the basic unit of life and cell plasma membranes control transport and signaling necessary for life.

Specialized cells are able to secrete substances into the digestive system space (lumen), to protect the body from this mixture because some of these substances would otherwise digest the body, and then to absorb specific substances from the mixture into the body.

3. Life requires information flow within and between cells and between the environment and the organism.

Receptors monitor the composition of the mixture as it moves through the digestive system lumen, stimulating secretion of hormones and nerve impulses that coordinate the release of substances and control the movement from one segment to another by circular muscles called sphincters.

4. Living organisms must obtain matter and energy from the external world. This matter and energy must be transformed and transferred in varied ways to build the organism and to perform work.

Food in the diet must be broken down into its basic units for absorption and then these are used to fuel ATP production, build and repair cells and tissues, and participate in other metabolic activities of the body.

5. Homeostasis (and “stability” in a more general sense) maintains the internal environment in a more or less constant state compatible with life.

In addition to nutrients, the absorption of vitamins, electrolytes and water are critical to maintaining body homeostasis, with disorders and diseases occurring when malabsorption occurs.

6. Understanding the behavior of the organism requires understanding the relationship between structure and function (at each and every level of organization).

This is best illustrated by the concept of increased surface area for efficient absorption in the digestive system.

7. Living organisms carry out functions at many different levels of organization simultaneously.

Cell level function is supported by all the tissue structures that make up the different segments and organs of the digestive system.

8. All life depends upon the proper interactions and supporting functions among interrelated organ systems.

In addition to obtaining necessary metabolic substances needed by all other body systems, the digestive system has several mechanisms to protect other systems against pathogens that can enter with things we ingest.

did I get this

Here is a preview of each of the modules to come:

• Structures and Functions, will explore how the major organs of the digestive system are able to accomplish the major system level functions:
• movement through the length of the digestive system
• complementary mechanisms for digestion in different segments
• structural components enhancing efficient absorption

Pay attention to not only what structures are similar and what are unique in the different sections, but how this contributes to the overall function of the system as a whole.

• Levels of Organization, will examine this structure and function in more detail, progressing through the major levels of organization in the human organism from the chemical and cellular levels to the tissues, organs and organ systems:
• nutritive and digestive molecules
• cells of the stomach, small and large intestine, liver, and pancreas
• tissue layers and organs that make up the GI tract, from mouth to anus
• accessory organs that contribute secretions to the GI tract

Pay attention to the function of cells for both secretion and absorption of specific substances in the different parts of the digestive tract and accessory organs. What these specific cells produce and how they move materials across cell membranes is critical to understanding the function of the system as a whole.

• Homeostasis, will delve into how this system contributes to the body’s natural tendency to maintain a stable internal environment:
• how hormones and nerves control and coordinate the digestive system
• what happens when digestive system malfunctions

Pay attention to how not only is the rate of movement from one section to another controlled, but what is released into the lumen is controlled based on monitoring of content of food eaten. Don’t get the endocrine secretion of hormones into the blood for control and regulation confused with the exocrine secretion of substances into the lumen for the digestion and absorption processes – both are happening.

• Integration of Systems, will investigate which systems are subsets of larger systems, and how they function together in harmony and conflict:
• how digestive system interacts with the other body systems
• how other systems affect the digestive system functions

Pay attention to the relationship between proper movement and secretion for digestion and the subsequent absorption and transport of materials for metabolism. This links the digestive tract and accessory digestive organs to the other systems.

did I get this

The digestive system moves water, nutrients and electrolytes from the external environment to the internal environment. Within the digestive system, the gastrointestinal tract is a continuous hollow tube from the mouth to the anus and is technically contiguous with the external environment. This internal space is called a lumen. All digestive system organs play vital roles in breaking down food moving through the gastrointestinal tract into its chemical building blocks, absorbing these building blocks into the blood, and eliminating residual indigestible materials.

Different parts of the digestive system will secrete substances into the digestive tract lumen. These secretions come from both the cells that make up the epithelial lining of the digestive tract and from exocrine accessory organs that have ducts emptying into the tube. These substances will assist with the movement of food from one part of the tract to the next (such as mucus) and with the digestion of the food while it is in the tube (such as enzymes).

In order to absorb digested substances, that material has to be first moved from the lumen, into the apical or tube-side of the epithelial cells lining the digestive tract, then out of the other basal side of those cells, into the body’s interstitial fluid, and into blood or lymph capillaries for transport through the body. This process can happen passively or require ATP cellular energy. You may want to review membrane transport in the cell module. Various chemicals secreted into the lumen can enhance the absorption of some material, such as vitamins and lipids. Anatomical structures that increase the area of the absorptive surface exposed to the digested substances in the tube will also enhance absorption.

learn by doing

Many different digestive dysfunctions have very similar symptoms. Understanding the biochemical and cellular functions of the digestive system can help in understanding some of the various causes.Celiac disease is a digestive system disorder that is also known as gluten intolerance. Gluten is made up of amino acids and is found in wheat. When the enzyme transglutiminase reacts with gluten in the digestive system, it can cause an autoimmune response that destroys the lining of the small intestine. This causes improper absorption and associated symptoms.

There will be another kind of secretion involved in regulating this whole process, including how long food stays in one section of the digestive tract for the most efficient digestion or absorption. These are endocrine secretions from cells that are part of the digestive organs themselves. These hormones are secreted into the blood, not the digestive lumen, and transported by blood to target cells of the digestive system organs. In this way, it helps regulate and coordinate the functions among the different organs. The autonomic nervous system also plays a role in regulating and coordinating the digestive system.

learn by doing

Some people with Panic Disorder have been found to have an inherited metabolic defect that prevents them from producing a digestive system hormone called cholecystokinin (CCK). CCK controls the release of digestive secretions from the liver/gall bladder and pancreas into the small intestine. CCK also acts as a central nervous system neuropeptide, affecting neuron communication in parts of the brain that regulate anxiety and stress. People with this particular genetic condition may experience Gastro-Esophageal Reflux Disease (GERD) or Irritable Bowel Syndrome (IBS), sometimes for years before they ever have a panic attack experience.

We usually don't think about the digestive system until something goes wrong with it – when we get indigestion, nausea, or diarrhea. We seldom appreciate that the digestive system is a complex string of organs that make up the body's engine, turning fuel from the food we eat into energy that keeps us going. Each organ of the digestive system performs specific functions but all these organs work together to digest the foods we eat and absorb the nutrients into our bodies. Feel free to review the overall Digestive system in the course Introduction.

learn by doing

Lactose intolerance is a digestive system disorder related to the biochemical processes. In this genetic disorder, the person doesn’t produce enough lactase to digest lactose in their diet, so lactose isn’t absorbed in the small intestine. When it moves on to the large intestine, lactose upsets the water homeostasis and bacteria can metabolize it, creating the various symptoms.

The digestive system is generally divided into two main categories: organs of the alimentary canal (aliment = “nourish”) and accessory digestive organs. The alimentary canal, also called the gastrointestinal (GI) tract or gut, is a continuous muscular tube that runs from the mouth to the anus. The internal space of this tube is called the lumen. The GI tract is involved with the digestion of food –its breakdown into smaller fragments – and the absorption of digested food fragments from the lument through the alimentary canal wall and into the bloodstream. The accessory digestive organs contribute to secretions to the GI tract, but the food doesn't pass through these organs.

Different digestive system organs are responsible for different digestive processes and functions. These functions include: extracting nutrients from food and removing waste. The processes by which these occur are called ingestion, motility of food through the GI tract lumen, mehcanical and chemical digestion of the food, absorption and breakdown of products, defecation to remove residues.

Organ Major Functions Other Functions
Mouth Ingests food; Mechanical chewing of food; Salivary amylase begins chemical breakdown of starch; Swallows food and propels it into pharynx Salivary mucus helps dissolve food; Release of flavors stimulates tastebuds allowing us to appreciate its taste; Saliva moistens food, and tongue helps create a bolus that can be swallowed; Saliva cleans and lubricates the teeth and oral cavity
Pharynx Propels bolus from oral cavity to esophagus Mucus lubricates food passageways
Esophagus Peristaltic waves propel food bolus to stomach Mucus lubricates food passageways
Stomach Peristaltic waves combine food with gastric juice and move it into the duodenum; Pepsin begins protein digestion; Absorbs some fat-soluble substances (e.g., alcohol, aspirin) Hydrochloric acid neutralizes ingested pathogens and stimulates protein-digesting enzymes; Mucus lubricates and protects the stomach; Intrinsic factor allows vitamin B12 to be absorbed in intestines
Small intestine Mixes contents with digestive juices for digestion and absorption; Brush-border enzymes digest food; Absorbs breakdown products of carbohydrates, protein, fat, and nucleic acid digestion, along with vitamins, water, and electrolytes Alkaline mucus helps neutralize acidic chyme from the stomach
Large intestine Enteric bacteria digest some food residue and vitamins; Absorbs most residual water, electrolytes, and vitamins produced by enteric bacteria; Propels feces toward rectum; Defecation reflex eliminates feces Residues are concentrated and temporarily stored prior to defecation; Mucus smoothes passage of feces through colon
Accessory organs Liver: produces bile; Gall bladder: stores and concentrates bile; Pancreas: produces enzymes that digests food Gall bladder releases bile, which emulsifies fat and stimulates the digestion of fat and the absorption of fatty acids, monoglycerides, cholesterol, phospholipids, and fat-soluble vitamins; Bicarbonate-rich pancreatic juice helps neutralize acidic chyme (from the stomach) and provide optimal environment for enzymatic activity
learn by doing
did I get this

Both voluntary skeletal muscles and involuntary smooth muscles are involved in propelling food material through the digestive system. Skeletal muscles of the tongue are involved in the voluntary first phase of swallowing, but then it becomes an involuntary reflex with skeletal muscles of the pharynx. You will learn more about this swallowing process called deglution in the next module.

The smooth muscle of the GI tract is arranged in two layers: longitudinal along the length of the tube and circular around the diameter of the tube. Coordinated contraction and relaxation of these two layers creates a wave-like propulsion of the food called peristalsis. Muscles in the esophagus mechanically transport the food via peristalsis from the mouth to the stomach. An extra smooth muscle layer in the stomach adds a churning movement within the stomach. Peristalsis continues to propel food through the small and large intestines.

Controlling the rate of food moving from one organ of the digestive tract to the next are specialized circularly arranged skeletal and smooth muscles called sphincters. Sphincters are typically contracted and relax only to allow food to move from one organ to the next. The majority of sphincters along the length of the GI tract are involuntary smooth muscle structures. The esophageal sphincter helps separate the esophagus from the stomach to maintain linear movement and protect the esophagus from acidic chemicals of the stomach. The pyloric sphincter separates the stomach from the small intestine; again there is a physical separation for compartmentalization and to maintain directionalized movement.

Material then snakes its way through the small intestine and the iloeocecal sphincter controls movement into the large intestine or colon. The anal sphincter muscle is skeletal muscle controlled consciously to relax during defecation. There is also a hepatopancreatic sphincter that controls the release of accessory secretions from the liver and pancreas into the beginning of the small intestine.

learn by doing
did I get this

Digestion is accomplished both mechanically and chemically. Mechanical digestion physically breaks food into smaller pieces, increasing surface area for more efficient chemical digestion. Chemical digestion breaks large food macromolecules down into their chemical building blocks, which can then be absorbed through the intestinal wall and into the general circulation.

Food is ingested in the mouth where it begins mechanical digestion from the grinding of the teeth and chemical digestion from enzymes in the saliva. Chemical digestion starts in the saliva and follows into the stomach. In the stomach material is broken down into smaller components by chemically strong acids, enzymes and mechanical churning. However, the small intestine is the site of most chemical digestion, and almost all absorption. Enzymes, bile, bicarbonate and other materials are mixed in from the pancreas and liver to promote chemical digestion and allow enhanced adsorption. Enzymes are responsible for the majority of this chemical digestion. The breakdown of fat also requires emulsification by bile, secreted by the liver and stored in the gall bladder.

did I get this

The mechanical and chemical digestive processes that begin in the mouth and continue through the small intestine have one endpoint: to convert food into substances that can be absorbed from the lumen by epithelial cells in the lining of the GI tract and then enter blood or lymphatic vessels. Absorbable substances are the monosaccharides, glucose, galactose, and fructose from carbohydrates; single amino acids, dipeptides, and tripeptides from proteins; and monoglycerides, glycerol, and fatty acids from lipids such as triglycerides.

Most nutrients are absorbed into digestive epithelial cells by active transport mechanisms. Nutrients not absorbed through active transport include lipids, lipid-soluble vitamins, and most water-soluble vitamins. With the help of bile salts, the breakdown products of lipids are transported into intestinal cells in structures called micelles. These absorbed fats then aggregate into chylomicrons for transport.

These substances absorbed into the epithelial cells of the digestive tract are then absorbed into either the circulatory or lymphatic capillaries for transport where needed by body cells for metabolism. Absorption from the GI lumen is enhanced by increasing the surface area. Most absorption occurs in the small intestine, the longest organ of the GI tract. Several anatomical structures at the organ, tissue, and cell level also improve nutrient, water and electrolyte absorption.

## Plicae circulares

On the organ scale, the inside lining of the small intestine lumen is not smooth. Plicae circulares, are permanent ridges or folds forming successive rings along the length of the small intestine. These folds increase the surface area of the lining exposed to contents in the lumen for a given length of small intestine, which allows increased absorption.

## Villi

At the microscopic tissue level, there are finger-like extensions of the epithelial and connective tissue called villi. The villi increase the surface area of the epithelial tissue exposed to contents moving through the lumen. This allows more superficial epithelial cells to absorb within a square millimeter of the lining than if this same millimeter surface were flat. Within each villi, deep to the epithelial basement membrane, the connective tissue supports the villi structure as it extends into the lumen. Capillary networks that pick up and transport absorbed substances through the body extend from the deeper connective tissue into each villus (singular of villi). These include blood capillaries and a central specialized lymph capillary, called a lacteal, for lipid absorption.

## Microvilli

At the cellular level, the apical surface of each epithelial cell has cell membrane extensions into the lumen called microvilli. These cells are collectively known as brush border cells because their combined microvilli along the surface of each villus looks like the surface of a brush under the microscope. Because of the microvilli, each epithelial cell has a longer cell membrane exposed to the lumen contents than it would if its apical surface were smooth, improving cellular absorption. Embedded in the cell’s folded plasma membrane are different cell membrane proteins: transporters and enzymes. The transporters absorb by active transport, but the brush border enzymes are catalysts that complete the digestion of only partially digested proteins and carbohydrates at the cell surface, so they can pass through the adjacent transporters.

## Surface Area

Explanation of increased surface of the small instestine due to the characteristics of its structures.
did I get this

In order to get the various materials needed for energy production and anabolic metabolism in all body cells, our body has to exchange nutrients, water and electrolytes from the environment. However, the substance taken into the space of the GI tract is not always in the form that can be absorbed, so it must first be broken down. Various secreted chemicals are critical to accomplishing this digestion. These ingested macromolecules are digested in different regions of the GI tract, requiring that the mixture of material be moved through the digestive system in a controlled way. Once it has been digested to a basic chemical structure, the material can be absorbed into the blood or lymph. At that point, the other body systems integrate to distribute these absorbed nutrients, fluids and electrolytes through the body as needed. Any material remaining in the GI tract as waste will then be removed from the body by defecation.

To understand these system-level functions, you will be further exploring structures and processes occurring at all levels of organization. Some examples of major digestive structures assigned to their structural level of organization of the digestive system include:

1. Chemical level - sodium, potassium, chloride, bicarbonate, and phosphate ions and hydrochloric acid
2. Macromolecular level - enzymes of digestion, bile, and the nutritive molecules such as carbohydrates, protein, lipids and nucleic acids
3. Cellular level – mucosa cells, secretory cells, and immune cells
4. Tissue level – epithelial, connective, and smooth muscle tissues
5. Organ level - gastrointestinal tract and accessory organs
6. Organ System level - integration of organs for nutrient and waste movement, digestion and absorption
did I get this

The digestive system breaks down ingested material into absorbable components (nutrients) that the rest of the body can use to maintain adequate function. We require a diverse set of nutrients to support energy production, carry out metabolism and maintain structure.

Chemical digestion generally, breaks down large food molecules into their respective chemical building blocks, called monomers, that can be absorbed. The enzymes responsible for chemical digestion are released by both intrinsic glands found in the gastrointestinal tract and the accessory glands which secrete molecules into the gastrointestinal tract.

Hydrolysis refers to the breakdown of a chemical where water breaks a covalent bond. Hydrolysis can happen spontaneously, but the breakdown of food into macromolecules and monomers occurs by enzymatic hydrolysis - where the hydrolysis reaction catalyzed by an enzyme. Hydro- is part of the name because a water molecule is added to each molecular bond that is broken, or -lysed. More specifically, hydrolysis is a method of degradation which splits a molecule of water to help break chemical bonds in a larger molecule. Usually an H+ is attached to one of the components and an OH- group to the other. Hydrolysis reactions are important for many other physiologic processes in the body in addition to the breakdown of food molecules.

Hydrolysis of a Sucrose molecule into Glucose and Fructose.

For a review of nutritive molecules, including chemical structure and bonds, revisit the Chemical Bonding and Molecules page and the rest of the Levels of Organization unit.

did I get this

The nutritive organic compounds in our food includes carbohydrates, proteins and lipids. These molecules are digested, then absorbed, and reassembled into macromolecules or used as fuel for metabolism in the body. The process of breaking down these macromolecules involves splitting into smaller molecules using water molecule, thus the name hydrolysis (“hydro” = water; “lysis” = splitting). The reverse reaction, called dehydration synthesis, can build macromolecules from the absorbed building blocks. Enzymes can speed up the rate of these reactions.

## Carbohydrates

Our daily food intake usually includes from 200 to 600 grams of carbohydrates. Carbohydrates are primarily used for quick energy, but some are also used to create important signaling and structural molecules. The monomers of carbohydrates, monosaccharides (simple sugars), are absorbed easily and can therefore be a source of quick energy for the body when we consume them in this form. Glucose, galactose, and frutose are the three common monosaccharides in our diet.

Hydrolysis: carbohydrate digestion

Disaccharides are two monosaccharides bound together and include sucrose (table sugar), lactose, and maltose. Polysaccharides are long chains of monomers and include polymerized glucose in different forms including glycogen, which is the stored form of glucose in our bodies, and starch, a polysaccharide of glucose molecules that comes from plant sources.

In many places around the world, starch accounts for the largest portion of digestible carbohydrates in the diet, with the addition of some glycogen, disaccharides and monosaccharides. There are other polysaccharides in our diet, like cellulose, but our bodies do not produce enzymes that can break them down, so they are indigestible. While indigestible polysaccharides do not give us any nutrients, they do provide bulk (fiber) that helps propel food through the digestive system.

Example
##### Lactose Intolerance

Individuals with lactose intolerance are unable to metabolize lactose, a sugar found in milk. The problem is usually caused by a lack of the enzyme lactase, which is required to break down lactose in the lining of the small intestine. Without breakdown in the small intestine, lactose flows into the large intestine where bacteria metabolize lactose in a process called fermentation. In fermentation, gasses are produced that cause abdominal bloating. Sugars and fermentation products also cause large amounts of water to enter the large intestine, leading to loose stool. Most infants are born the enzyme lactase, and as adults lose the ability to produce this enzyme.

did I get this

## Proteins

We get protein when we eat meat, seafood, eggs, beans, nuts and soy products. USDA recommends 5 to 6 ounces of protein in diet per day, although children need less. This dietary protein is usually in the form of polypeptides and must be digested into its amino acid building blocks for absorption. There are numerous enzymes that break large proteins into smaller peptides and then into amino acids. Amino acids are then absorbed from the digestive system into the circulatory system where they are delivered throughout the body. Once amino acids have entered cells throughout the body, they are bonded together to make proteins needed for cell function. As a last resort, proteins and amino acids can also be used as energy; they are metabolically converted to glucose before they are used as energy sources.

Hydrolysis: protein digestion
did I get this

## Lipids and Fats

Dietary lipids include fats and oils. While not considered a USDA food group, oils contain some essential nutrients and are recommended as part of a healthy diet, although only in small amounts. Solid fats have more saturated and trans-fatty acids and are considered empty calories when included in a diet because they add calories but not needed nutrients. Most dietary lipids are in the form of triglycerides, with one glycerol molecule and three fatty acids bound together. Lipids are processed by enzymes secreted from the pancreas (with some enzymes from the stomach and saliva) and are then solubilized for absorption by salts secreted in bile (from the liver). These steps prepare them for absorption in the small intestine. Like proteins, ingested lipids are broken down into smaller parts for absorption and then are either metabolized to make energy or are use to make cellular structures including cell membranes. Lipid absorption is also required for absorption of some fat-soluble vitamins.

Hydrolysis: lipid digestion
did I get this

## Nucleic Acids

When we eat any plant or animal foods, we are able to digest the DNA or RNA nucleic acid that was in their cells. The fundamental unit of nucleic acids is the nucleotide, with a phosphate group, a pentose sugar, and one of 5 nucleic bases. The pancreas produces and releases into the small intestine two enzymes to break down either DNA (deoxyribonuclease) or RNA (ribonuclease) into individual nucleotides. Brush border enzymes of the cells lining the small intestine further digest the nucleotide into its molecular components for absorption.

did I get this
learn by doing

Some salivary glands are always secreting saliva. Intrinsic salivary glands of the mouth secrete small amounts of saliva, usually just enough to moisten the mucous membranes and clean the mouth and teeth. The accessory salivary glands are exocrine organs under autonomic nervous system control with ducts leading into the mouth. Secretion increases when there is food in the mouth, as well as through a reflex when food is smelled, seen or thought about (you have probably heard about Pavlov’s experiment with the salivating dog and bell). Saliva is needed to moisten and lubricate the food and begin its chemical breakdown.

Saliva is mainly water, which dissolves chemicals in the food. Only dissolved chemicals can activate the different kinds of taste receptor cells on the tongue, palate and other parts of the mouth and pharynx. Mixed in with the water, saliva also contains mucus, various electrolytes typically found in blood plasma, as well as some digestive molecules, metabolic waste products and immune molecules. Each of these contributes to the various functions of saliva.

Bicarbonate and phosphate ions help maintain the pH of saliva as neutral or slightly basic (average 7.4 pH). This not only helps protect the teeth from acidic substances eaten and plaque bacteria that grow best in an acidic environment, but also maintains the optimal pH for the enzyme amylase. Salivary amylase starts breaking complex carbohydrates eaten, like starch, into sugars. This enzymatic activity will stop once the mixture of food and saliva, called a bolus, is swallowed and reaches the acidic environment of the stomach. Salivary lipase is another enzyme in saliva that breaks down dietary lipids, but it is activated when it reaches the acidic gastric juice with its optimal pH being much more acidic than the salivary pH.

In addition to the water of saliva, mucus in the saliva is composed of glycoproteins and helps moisten the food, so it can be manipulated into a mass for swallowing. It also helps lubricate the movement of food through the pharynx and esophagus by peristalsis. Lysozyme antimicrobial enzymes and antibodies (Immunoglobulin A) in the saliva help combat pathogens that might enter the body with food or drink. Like the sweat glands, salivary glands play a role in some metabolic waste excretion, so urea and ammonia are also found in saliva.

learn by doing
did I get this

## Enzymes and Acids of the Stomach

Gastric glands produce hydrochloric acid (HCl), enzymes, and intrinsic factor. HCl is responsible for the high acidity (pH 1.5 to 3.5) of the stomach contents. The acidity directly kills a lot of the bacteria we ingest with food and helps denaturedisruption of protein structure, usually making it more amenable to enzymatic digestion. proteins and substances found in plants. In the presence of gastric juice’s low pH, the inactive enzyme, pepsinogen, is modified to become the active protein enzyme, pepsin. Protein enzymes of the digestive system are produced and secreted in an inactive form, to be activated only in the lumen, thus preventing digestion of the cells themselves. The glycoprotein intrinsic factor is necessary for the absorption of vitamin B12 later in the small intestine.

It is amazing that cells of the body can produce acids that normally would destroy the cell itself. Strong acids are also produced in cells in the immune system (to break down foreign organisms) and the skeletal system (to break down mineralized bone). High levels of acidity in the wrong places can be very destructive to living cells. Our body has several mechanisms to control pH.

In the stomach cell, the enzyme carbonic anhydrase converts one molecule of carbon dioxide and one molecule of water indirectly into a bicarbonate ion (HCO3-) and a hydrogen ion (H+). In the stomach ion exchange is used to move H+ ions out the cells and into the lumen of the stomach.

did I get this

The bicarbonate ion (HCO3-) is then exchanged for a chloride ion (Cl-) on the basal side (away from the lumen) of the cell. Potassium (K+) and chloride (Cl-) ions diffuse into the secretory region of the cell called the canaliculi. Then the potassium is exchanged in this region for hydrogen ions via a H+/K+ ATPase. The hydrogen ions, which are millions of times more concentrated in this region of the cell than any other, are then pumped from the canaliculi into the lumen of the stomach. The following video illustrates this process.

## Production of Hydrochloric Acid in the Stomach

Explanation of how the stomach produces hydrochloric acid without the lumen's cells being harmed in the process.

## Mucosal Barrier

Once the hydrochloric acid is produced in the stomach lumen, this creates a low (acidic) pH that could potentially destroy the cells in the mucosal layer of the stomach. However, there are several structural and functional components that are part of an effective mucosal barrier that protects the stomach cells and prevents the stomach from digesting itself. The thick mucus layer produced by gastric mucus cells has lots of bicarbonate ions that will buffer the effect of the acid in the lumen. This stable, pH neutral mucus layer also provides a barrier to the now activated pepsin enzymes in the lumen as well. The surface gastric epithelial cells under the mucus layer have tight cell-to-cell junctions that would prevent transcellular reabsorption of hydrochloric acid from the lumen. Like epithelial tissue elsewhere in the body, these gastric surface cells are replaced continually by gastric stem cells that are stimulated to divide more rapidly if there is tissue damage from the gastric juice. Prostaglandins are chemical messages involved in cell inflammation response to injury. Prostaglandins produced in the stomach stimulate production of gastric mucus and bicarbonate and promote tissue healing. When the mucosal barrier breaks down and tissue destruction reaches into the deeper connective and muscular layers of the stomach, this is called a peptic or gastric ulcer.

Example
##### Ulcers: When the Mucosal Barrier Breaks Down

Aspirin and other non-steroid inflammatory drugs (NSAIDs) are known to increase the risk of gastric ulcers. NSAIDs break down the mucosal layer and reduce secretion of bicarbonate ion, but even when they are enteric coated to protect the cells from contact, they increase the risk of gastric ulcers.

learn by doing

The acidity of gastric juice destroys many, but not all bacteria. There is one bacterium, Helicobacter pylori, adapted to live in the stomach mucus layer. Most people have this bacterium in their stomach with no symptoms, but in some people the bacterium is linked to increased incidence of gastric ulcers. There is still uncertainty about why only some people are affected this way. The bacterium uses the enzyme urease to convert urea to ammonia that helps neutralize acid in the mucus layer locally. If the mucus becomes too acidic for the bacterium, it can also induce an inflammatory response that lowers the gastric juice acidity. This immune response and associate release of free radicals may stimulate the formation of the ulcers in affected individuals. Once the causal link between ulcers and H. pylori was discovered, a new treatment for ulcers was implemented and the number of gastric ulcers in developed countries fell sharply.

learn by doing

There is evidence to suggest that the H. pylori should be considered to be colonizing the stomach, like other GI tract microbiota, rather than infecting the stomach because it does have some protective effects. As the incidence of gastric ulcers fell in developed countries due to the use of antibiotics, the incidence of esophageal reflux and cancer increased. Research has shown that the presence of H. pylori is inversely related to the incidence of not only GERD and esophageal cancer, but also childhood diarrhea, IBS, asthma and even tuberculosis. So there are interesting interactions between this bacterium and its human host that need further study.

learn by doing
did I get this

## Pancreatic Juice In Digestion

The pancreas produces about 1.2 to 1.5 quarts (1.1 – 1.4 liters) of pancreatic juice each day. This clear, colorless liquid is mostly water, along with some salts, sodium bicarbonate, and several digestive enzymes. Sodium bicarbonate is responsible for the slight alkalinity of pancreatic juice (pH 7.1 to 8.2). The sodium bicarbonate buffers the acidic gastric juice which has arrived in the small intestine from the stomach, inactivates pepsin from the stomach, and creates an optimal pH for the activity of the digestive enzymes in the small intestine.

Just as the stomach produces pepsin in its inactive form (as pepsinogen), the pancreas creates and produces its protein-digesting enzymes as zymogens. These zymogens (trypsinogen, procarboxypeptidase, and chymotrypsinogen) are activated in the duodenum. If produced in their active forms, they would digest the pancreas itself. The intestinal enzyme enteropeptidase convertstrypsinogen to the active trypsin. Trypsin alsoconverts pancreatic enzymes procarboxypeptidase and chymotrypsinogen to their active forms, carboxypeptidase and chymotrypsin. Some pancreatic enzymes, including amylase, lipase, and nuclease, are secreted in their active form, but their optimal activity requires interactions with ions or bile in the intestinal lumen.

did I get this

## Bile

Bile is another accessory organ contribution to the GI tract lumen. Bile is made by the hepatocytes of the liver, but stored in, concentrated, and released from the gall bladder. Unlike pancreatic juice that is produced and released as needed, bile is produced in small quantities by the liver continuously. The gall bladder stores it for release into the small intestine as needed.

Like saliva, bile is a mixture of mainly water with many substances, including electrolytes, bile pigments, bile salts and lipids (including the phospholipid lecithin and cholesterol). The bile pigments include bilirubin and biliverden, which are waste by-products from the destruction of the hemoglobin in aged or damaged red blood cells destroyed in the liver. These wastes are then eliminated from the body with the feces and contribute to its color. In addition, cells lining the bile duct secrete bicarbonate ions into the bile. However, it is the lecithin and bile salts produced from cholesterol that have a digestive function related to dietary lipids.

Recall that phospholipids in the cell membrane have a hydrophilic and hydrophobic portion. Bile salts are also amphiphilic. When they are released into the small intestine as part of the bile, the hydrophobic/lipophilic portion of the molecule is attracted to fat globules in the lumen, while the hydrophilic/lipophobic portion is attracted to the water in the digestive juice mixture. This chemical attraction and mechanical mixing breaks large fat globules into smaller droplets suspended in the fluid. The bile salts prevent the droplets from rejoining and thus increase the surface area of the lipid exposed to lipase enzymes; but the bile salts don’t actually digest the lipid into fatty acids and monoglycerides. This process is called emulsification.

Example
##### Emulsification

Think of what happens when you mix oil and vinegar for a salad dressing. You can mechanically shake it up to produce smaller fat droplets suspended in the vinegar, but if left to sit, the two layers separate again. Lecithin from egg yolks is the emulsifier added to mayonnaise, which is a mixture of oil in vinegar or lemon juice that has been emulsified.

Once the lipids have been digested, the bile salts are still attracted to the lipid and form small micelles. These micells come in contact with the small intestine cell membranes, releasing and facilitating absorption of its fatty acids, monoglycerides and lipid-soluble vitamins. The bile salts are later reabsorbed themselves in the large intestine and recycled through the hepatic portal vein back to the hepatocytes, in what is called the enterohepatic circulation. Soluble fiber in the diet, such as psyllium, interferes with the reabsorption of these bile salts. As a result, the hepatocytes metabolize new bile salts using cholesterol from the blood, helping to lower LDL cholesterol.

There are also other mechanisms by which both soluble and insoluble fiber affect the body’s cholesterol metabolism and balance. The liver also excretes excess cholesterol in the bile. When the bile becomes supersaturated with such excess cholesterol, one of the three kinds of bile stones may form and obstruct the bile ducts. Not surprisingly, this type of gallstone is often associated with obesity. The absence of bile salts in bile results in a condition called steattorhea, where fats remain mainly undigested in the feces and can lead to diarrhea and fat malabsorption. This condition can result from liver damage or be a side-effect after the gallbladder is removed (cholecystectomy).

did I get this

## Intestinal Juice

The intestinal glands at the base of villi produce intestinal juice, a mixture of water and mucus. Each day, about one to two quarts (1-2 liters) are secreted. The mucus in intestinal juice is produced by both the duodenal glands and the goblet cells of the mucosa. The difference is that the mucus produced by the duodenal glands is alkaline, while goblet cell mucus is typically neutral. Progressing along the jejunum and into the ileum, goblet cells become more abundant. Secretion of intestinal juice is primarily stimulated by distension of the small intestine or the irritating effects of hypertonic or acidic chyme on the intestinal mucosa. The mucus also protects the surface cells from abrasion as the food moves through the lumen. Although the intestinal juice mucus secreted doesn’t have a direct digestive function, it does play an important role as a substrate for digestion. Extending into the mucus, but embedded in the cell membrane of intestinal villi cells, are various enzymes. These cell membrane surface enzymes are very important for the final digestion of organic substances before absorption.

## Carbohydrates in Digestion

The mouth is where the chemical digestion of starch and possibly glycogen begins. Salivary amylase acts to break down the polysaccharide starch into the disaccharide maltose, the trisaccharide maltotriose, and short chains of glucose called α-dextrins.

Pancreatic amylase in the small intestine continues the chemical digestion of starch and other digestible carbohydrates that have not been broken down into maltose, maltotriose, and α-dextrins by salivary amylase. After starch has been broken down into smaller fragments by salivary or pancreatic amylase, the brush-border enzyme α-dextrinase starts working on the resulting α-dextrins, breaking off one glucose unit at a time. The disaccharides sucrose, lactose, and maltose are not digested until they enter the small intestine. Here, three brush-border enzymes hydrolyze them into monosaccharides. Sucrase splits sucrose into one molecule of fructose and one molecule of glucose; lactase breaks down lactose into one molecule of glucose and one molecule of galactose; and maltase breaks down maltose and maltotriose into two and three glucose molecules, respectively. The digestive system can then absorb monosaccharides.

## Proteins

The digestion of protein starts in the stomach, where pepsin breaks down proteins into peptides. In the small intestine, trypsin and chymotrypsin hydrolyze polypeptides into smaller peptides, and elastase fragments whole proteins into peptides. The small peptides are then broken down into monomers. Carboxypeptidase cleaves a single amino acid from the carboxy terminus of a small peptide, whereas aminopeptidase cleave an amino acid from the amino terminus. Dipeptidase splits dipeptides in the middle, liberating two amino acids.

## Lipids

Triglycerides and their breakdown products do not dissolve in water. Before they can be digested in the watery environment of the small intestine, large lipid globules must be separated into smaller lipid globules, a process called emulsification, which is aided by the presence of bile salts. Recall that bile salts facilitate emulsification of large lipid globules.intosmall lipid globules of about 1 µm in diameter.[link to bile salts] This emulsification greatly increases the surface area to volume ratio of fat globules, which allows pancreatic lipase to access more lipid molecules.

The three lipases involved in the digestion of triglycerides and phospholipidsare lingual lipase (in the saliva), gastric lipase, and pancreatic lipase. Pancreatic lipase in the small intestine does most of the lipid digestion. Pancreatic lipase breaks down triglycerides into fatty acids and monoglycerides. The fatty acids include both short-chain (less than 10 to 12 carbons) and long-chain fatty acids.

## Nucleic Acids

Nucleic acids, including DNA and RNA, are in the cells of all once-living things which we may ingest. There are two nucleases in pancreatic juice – deoxyribonuclease, which digests DNA, and ribonuclease, which digests RNA. The nucleotides that are the products of this digestion are further broken down by intestinal brush-border enzymes (nucleosidases and phosphatases) into pentosesugars, phosphates, and nitrogenous bases, which can be absorbed through the GI tract wall.

learn by doing

## The Digestive Enzymes

Enzyme Source Food Product
Saliva
Lingual Lipase Lingual glands Triglycerides (fats and oils), other lipids Fatty acids and diglycerides
Salivary Amylase Salivary glands Polysaccharides (starches) α-Dextrins, disaccharide (maltose), trisaccharide (maltotriose)
Gastric juice
Gastric lipase Stomach chief cells Triglycerides (fats and oils) Fatty acids and monoglycerides
Pepsin* Stomach chief cells Proteins Peptides
Brush-border
α-Dextrinase Small intestine α-Dextrins Glucose
Enteropeptidase Small intestine Trypsinogen Trypsin
Lactase Small intestine Lactose Glucose and galactose
Maltase Small intestine Maltose Glucose
Nucleosidases and phosphatases Small intestine Nucleotides Phosphates, nitrogenous bases, and pentoses
Peptidases Small intestine Aminopeptidase: amino acid at amino end of peptides Dipeptidase: dipeptides Aminopeptidase: amino acids and peptides Dipeptidase: amino acids
Sucrase Small intestine Sucrose Glucose and fructose
Pancreatic juice
Carboxy-peptidase* Pancreatic acinar cells Amino acid at carboxyl end of peptides Amino acids and peptides
Chymotrypsin* Pancreatic acinar cells Proteins Peptides
Elastase* Pancreatic acinar cells Proteins Peptides
Nucleases Pancreatic acinar cells Ribonuclease: ribonucleic acidDeoxyribonuclease: deoxyribonucleic acid Nucleotides
Pancreatic amylase Pancreatic acinar cells Polysaccharides (starches) α-Dextrins, disaccharide (maltose), trisaccharide (maltotriose)
Pancreatic lipase Pancreatic acinar cells Triglycerides that have been emulsified by bile salts Fatty acids and monoglycerides
Trypsin* Pancreatic acinar cells Proteins Peptides

*These enzymes have been activated by other substances.

learn by doing

A single layer of epithelial cells forms the inner most later of the stomach, called the mucosa. The mucosa is marked by depressions called gastric pits (these are lined with epithelial cells). The gastric gland is at the bottom of the pit, which contain multiple cell types: mucous cells, stem cells, parietal cells, chief cells, and G cells (enteroendocrine cells).

## Exocrine Function

Digestion in the stomach requires a combination of acid and pepsin. In the glands of the stomach, chief cells secrete pepsinogen, which is converted to pepsin, as well as gastric lipase, which is used for digestion of fats. Parietal cells secrete hydrochloric acid (HCl) as well as intrinsic factor.The gastric mucous cells associated with the surface and neck of the gastric pit secrete a thick mucus that is more alkaline than the mucus produced by goblet cells found elsewhere in epithelial tissue. This helps provide a protective mucosal barrier from the acid and protein enzymes in the gastric juice.

## Endocrine Function

Regulation within the digestive system is tightly controlled by enteroendocrine cells. Collectively, these cells are found in the organs of the digestive system (entero- inside) and release hormones and paracrine signals which regulate production of digestive chemicals and also influence the nervous system for global regulation of digestion. Within the stomach, the enteroendocrine cells are called G-cells.

G-cells secrete the signaling molecules including gastrin. Gastrin signals parietal cells (HCl producing) and chief cells (enzyme producing) to regulate production and alters stomach motility by altering the sphincter function on either side of the stomach. G cells also secrete other paracrines – serotonin, histamine, somatostatin, and other hormones which regulate digestion.

learn by doing

## Overview of Stomach Cells

Structure Action Outcome
Gastric epithelial cells Structure of the stomach lumen Maintains structure of the mucosa
Chief cells Secrete pepsinogenSecrete gastric lipase Pepsin (activated form) breaks proteins down into peptidesBreaks down triglycerides into fatty acids and monoglycerides
G cells Secrete gastrin Activates secretion of HCl by parietal cells and pepsinogen by chief cells; contracts lower esophageal sphincter, enhances stomach motility, and relaxes pyloric sphincter
Parietal cells Secrete HClSecrete intrinsic factor Kills microbes; denatures proteins, transforms pepsinogen into pepsinEnables vitamin B12 absorption, which is necessary for red blood cell formation
learn by doing
did I get this

## Small Intestine Exocrine Function

The small intestine is primarily composed of simple columnar epithelial cells with microvilli facing the lumen for absorption of digested material. Intestinal crypts (also called the crypts of Lieberkühn) are analogous to gastric glands of the stomach and are formed by invaginations of the epithelium. Within the crypts are paneth cells, which secrete multiple defensive proteins including lysozyme definsins and phospholipase to protect the small intestine from pathogens which have survived the stomach compartment. There are also Goblet cells, which secrete mucous for protection from the acids of the stomach and enzymes from accessory organs.

## Small Intestine Endocrine Function

The small intestine also has enteroendocrine cells which secrete hormones for regulation of absorption of nutrients. S cells produce secretin to buffer intestinal pH. I cells (also called CCK cells) secrete cholecystokinin, which stimulates the release of digestive enzymes from the pancreas and gall bladder in to the intestine. K cells secrete gastric inhibitory peptide (GIP; also called glucose-dependent insulinotropic peptide), which influences insulin levels

 100CX magnification of the small intestine epithelial cells showing some of the densely packed microvilli. By Louisa Howard and Katherine Connollly(Human jejunum microvilli). Public Domain. The lining of the small intestine. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).
learn by doing
Cell Type Location in the Mucosa Function
Columnar epithelium with microvilli Lining Digestion and absorption of nutrients in chyme
Goblet Intestinal crypts Secretion of mucous
Paneth Intestinal crypts Secretion of the bactericidal enzyme lysozyme and other defensive proteins; phagocytosis
Enteroendocrine
S cells Intestinal glands Secretion of the hormone secretin
I (or CCK) cells Intestinal glands Secretion of the hormone cholecystokinin
K cells Intestinal glands Secretion of the hormone gastric inhibitory peptide (GIP)
did I get this

## Large Intestine Exocrine Function

Most of the mucosa of the large intestine is composed of simple columnar epithelial cells. An exception is the distal anal canal, which is composed of nonkeratinized stratified squamous epithelial cells. The stratified epithelium is more durable to the abrasion that occurs when feces moves. The large intestine also has crypts, which contain both epithelial cells and goblet cells. Since most digestion and absorption occurs before the large intestine, the only significant secretion is mucus, which lubricates the passage of digestive residue.

## Exocrine Function

Hepatocytes are the liver's main functional cells (hepato – liver, cytes – cells). They play a role in a wide variety of secretory, metabolic, and endocrine functions. Hepatocytes account for around 80 percent of the liver's volume. Plates of hepatocytes called hepatic laminae (singular lamina) radiate out from the center of hepatic lobules. Hepatocytes continually secrete bile, but production and release accelerate when bile acid levels in the hepatic portal blood (blood coming from the small intestine) increase. This means more bile is secreted as digestion and absorption are proceeding in the small intestine.

## Immune Function

The liver also contains star-shaped Kupffer cells that are found in the blood filled spaces (sinusoids) between laminae. These phagocytic cells remove dead or damaged red and white blood cells, as well as bacteria and other foreign material that potentially enter through the GI tract and travel to the liver in the hepatic portal vein.

did I get this

The pancreas is responsible for both endocrine (hormone secretion) and exocrine (enzyme secretion) function. Cells are organized into clusters throughout the pancreas.

## Exocrine Function

The majority of the cells in the pancreas have an exocrine function are acini cells. These epithelial cells were named this because they form clusters around a small central space or lumen that connects to small ducts, looking much like a cluster of grapes (acinus is Latin for berry or grape). Each acinus cell (singular) has a wider basal side, toward the basement membrane, and a narrow apical side toward the lumen, forming a ring or pie-shaped cells. They secrete the various enzymes and bicarbonate ions that make up pancreatic juice into this central duct.

## Endocrine Function

The majority of the cells in the pancreas have an exocrine function are acini cells. These epithelial cells were named this because they form clusters around a small central space or lumen that connects to small ducts, looking much like a cluster of grapes (acinus is Latin for berry or grape). Each acinus cell (singular) has a wider basal side, toward the basement membrane, and a narrow apical side toward the lumen, forming a ring or pie-shaped cells. They secrete the various enzymes and bicarbonate ions that make up pancreatic juice into this central duct.

You have already had some introduction to blood glucose homeostasis. We will discuss the hormonal regulation of blood glucose further in the endocrine unit. The pancreatic cells responsible for endocrine production are listed below.

Cell type Percent of islet cells Endocrine material Downstream effect
Alpha cells 15-20% Glucagon Increases blood glucose of glycogen
Beta cells 65-80% Insulin and amylin Lowers blood glucose
Delta cells 3-10% Somatostatin Restricts absorption
PP cells 3-5% Pancreatic polypeptide Regulates pancreatic function
learn by doing
did I get this

Throughout the gastrointestinal (GI) tract, walls are comprised of the same four fundamental tissue layers. From the lumen of the GI tract, these layers are the mucosa, submucosa, muscularis, and serosa.

 The lining of the small intestine. Image courtesy of Dr. Allan Wiechmann, University of Oklahoma Health Sciences Center Tissue layers of the GI tract. This work by Cenveo is licensed under a Creative Commons Attribution 3.0 United States (http://creativecommons.org/licenses/by/3.0/us/).

## The Mucosa

The mucosa is a mucous membrane that makes up the inner lining of the GI tract. It has three layers: (1) the epithelium, made of closely packed cells without a blood supply or nerves in direct contact with the foodstuffs that enter the GI tract; (2) the lamina propria, a layer of connective tissue that supports the epithelial cells; and (3) a thin smooth muscle layer called the muscularis mucosae. In the mouth, pharynx, esophagus, and distal portion of the anal canal, the epithelium is primarily nonkeratinized stratified squamous epithelium. In the stomach and intestines, it is simple columnar epithelium, whose cells participate in secretion and absorption. Every five to seven days, the harsh chemical and mechanical environment of the GI tract causes epithelial cells to be sloughed off and replaced by new ones. Epithelial cells are interspersed with exocrine cells that secrete mucus and digestive fluid into the lumen (interior space) of the alimentary canal and with enteroendocrine cells that secrete hormones and paracrines. In addition to connective tissue, the lamina propria of the mucosa contains numerous blood and lymphatic vessels, which transport nutrients absorbed into the GI tract to the liver. The lamina propria also contains most of the immune cells that make up the mucosa-associated lymphatic tissue (MALT).

The muscularis mucosae layer is not responsible for movement of material through the GI tract, but it controls the exposed surface area. Small alterations in the many small folds in the mucous membrane of the stomach and small intestine increases the surface area available for digestion and absorption. Of these folds, the rugae in the stomach are temporary structures while the plicae circulares of the small intestine are permanent. When this muscle layer contracts, rugae and plicae circulars are pushed together exposing less SA to the lumen. When it relaxes more of the mucosal surface is revealed and in contact with the digestive products in the lumen.

## The Submucosa

The submucosa binds the mucosa to the muscularis externa. It is composed of areolar connective tissue and includes blood and lymphatic vessels (which transport absorbed food molecules) and the submucosal plexus (which is part of nervous system control).

## The Muscularis

In the mouth, pharynx, and superior and middle esophagus, the muscularis externa contains skeletal muscle that we use for voluntary swallowing. The external anal sphincter is also made of skeletal muscle, giving us voluntary control of defecation. In the rest of the GI tract, the muscularis externa is smooth muscle, which contracts involuntarily to break down food, mix it with digestive juices, and move it along the GI tract. Complementary muscles in longitudinal (along the length of the tract) and circular layers creates peristalsis – the wave-like muscular movements to move good from the esophagus to the anus.

## The Serosa

The serosa is the superficial layer of the intestine that covers the parts of the GI tract that is exposed to the abdominal cavity. This serous membrane is made up of areolar connective tissue and simple squamous epithelium (mesothelium). The esophagus has a single layer of tough connective tissue called the adventitia; it does not have a serosa.

learn by doing
did I get this

The peritoneum, is the largest serous membrane in the body and lines the abdominal cavity. The tissue has several components including the the mesothelium and an underlying supporting areolar connective tissue layer. The connective tissue in turn has two layers: the parietal peritoneum, which lines the abdominal wall, and the visceral peritoneum, which covers some organs and serves as their serosae. The peritoneal cavity is the small space between the parietal and visceral peritoneum that contains the lubricating serous fluid.

The peritoneum includes large folds that bind organs to each other and to the abdominal walls. This keeps the organs in the proper place and suspends them when we are upright. Within these folds are blood vessels, lymphatic vessels, and nerves that innervate the abdominal organs.

## The Five Major Peritoneal Folds

Fold Description Comment
Greater omentum Drapes over the transverse colon and small intestine High adipose tissue content vastly expands with weight gain, creating the characteristic "beer belly"
Falciform ligament Attaches the liver to the anterior abdominal wall and diaphragm The liver is the only digestive organ attached to the anterior abdominal wall
Lesser omentum Suspends the stomach and duodenum from the liver Provides a pathway for the blood supply of liver; contains the common bile duct
Mesentery Attaches the jejunum and ileum of the small intestine to the posterior abdominal wall Includes blood and lymphatic vessels, and lymph nodes
Mesocolon Attaches the transverse colon and sigmoid colon of the large intestine to the posterior abdominal wall Along with mesentery, it holds intestines loosely in place, enabling movement with muscle contractions
Example
##### Homeostatic Imbalances of the Peritoneum: Peritonitis

Inflammation of the peritoneum is called peritonitis. It can be caused by an injury that penetrates into the abdomen or from an ulcer that perforates the stomach wall, allowing gastric fluids into the peritoneal cavity. The most common cause of peritonitis is a ruptured appendix. The appendix is a terminal part of the cecum (a peritoneal pouch at the beginning of the large intestine), and the function (if any) is still debated. When the appendix bursts open, bacteria-laden feces spurt into the peritoneum. Usually, the peritoneal layers will bind together around the site of inflammation, keeping the infection from spreading, while macrophages move in to dispose of infected tissue. Peritonitis that spreads out into the peritoneal cavity can be life-threatening. The condition is treated by surgically removing the infected tissue and administering high doses of antibiotics. Generally, peritonitis is a concern with any kind of puncture wound to the abdomen.

did I get this

The cheeks, tongue, hard palate, and soft palate frame the mouth, also called the oral cavity or buccal cavity. The mouth is involved in both mechanical and chemical digestion. Mechanical digestion consists of mastication (chewing), in which the tongue manipulates food, the teeth grind it, and saliva mixes with it. Mastication turns food into an easy-to-swallow bolus and breaks the food into smaller pieces so that there is more contact area for digestive enzymes.

The cheeks make up the oral cavity's lateral walls. The outer covering of the cheeks is the skin, and the inner covering is the mucous membrane. This membrane is made up of nonkeratinized stratified squamous epithelium; the multiple layers are resistant to abrasion. Between the skin and mucous membranes are connective tissue, fat tissue and buccinator muscles.

The lips, also called labia ("fleshy borders"), encircle the opening of the mouth. Their outer covering is skin, and their inner lining is mucous membrane. Between these two layers is the orbicularis oris muscle. The labial frenulum is a midline fold of mucous membrane that attaches the inner surface of each lip to the gum. When we chew food, the buccinator muscles in the cheeks and the orbicularis oris muscle in the lips contract, which keeps food between the lower and upper teeth. These muscles also play a role in speech.

The area between the lips (or cheeks) and teeth is called the oral vestibule. The oral cavity is the area than runs between the gums and teeth and the entrance to the throat (oropharynx), also called the fauces ("passages"). If you puff out your cheeks, you can increase the size of the oral vestibule but not the oral cavity.

The septum that separates the oral cavity and nasal cavity is called the palate. Anatomically, a septum (plural, septa) is a wall within a single organ or cavity that separates the space into distinct sides. For example, the nasal septum divides the nostrils. This is separating two distinct cavities.

The palate, which forms the roof of the mouth, is what allows us to breathe while chewing food. The anterior part of the roof of the mouth is called the hard palate. It is created by the maxillae and palatine bones and is covered by mucous membrane. The hard palate makes up the bony wall between the oral and nasal cavities. The posterior part of the roof of the mouth, the soft palate, is also lined with mucous membrane. This arch-shaped muscular structure forms a dividing wall between the oropharynx and nasopharynx.

The uvula (Latin for ‘little grape’) is a cone-shaped muscular process that hangs from the end of the soft palate. It plays a role in speech and articulation of words. It also plays a small role in preventing foods and liquids from entering the nasal cavity. Two muscular folds on each side of the base of the uvula extend down the lateral sides of the soft palate. The anterior fold is called the palatoglossal arch, which terminates next to the base of the tongue. The posterior fold, the palatopharyngeal arch, lies at the interface with the pharynx. Between these two arches on the lateral wall are the palatine tonsils. The lingual tonsils are located at the base of the tongue.

There are also many small, intrinsic salivary glands within the mucous membrane of the mouth and tongue. Their secretion is independent of the presence of food. These glands either open directly into the oral cavity or indirectly through short ducts. Small amounts of saliva are secreted by the labial glands in the lips, the buccal glands in the cheeks, the palatal glands in the palate, and the lingual glands in the tongue.

did I get this
did I get this

The tongue is composed of skeletal muscle covered with a surface of nonkeratinized stratified squamous epithelium and a mucous membrane covering. The tongue and its associated muscles make up the floor of the oral cavity. A median septum extends the entire length of the tongue, dividing it into symmetrical halves. Inferiorly, the tongue is attached to the mandible, styloid process of the temporal bone, and hyoid bone.

Each half of the tongue has the same number and type of intrinsic and extrinsic muscles. As you learned in your studies of the muscular system, extrinsic muscles of the tongue are the hyoglossus, genioglossus, styloglossus and palatoglossus muscles. These muscles originate outside the tongue and insert into connective tissues within the tongue. They move the tongue from side to side and in and out, performing three important digestive functions: (1) moving food for optimal chewing, (2) shaping food into a bolus (rounded mass), (3) pushing food toward the back of the mouth to be swallowed and (4) elevates the posterior part of the tongue to assist in swallowing. Conscious control of the tongue also aids in speaking and other non-digestive processes.

The intrinsic muscles are the longitudinalis superior, longitudinalis inferior, transversus linguae, and verticalis linguae muscles (lingua and lingual refers to the tongue). These muscles both originate in and insert into connective tissues within the tongue. They change the size and shape of the tongue to facilitate swallowing and speech. A fold of mucous membrane in the middle inferior region (underside) of the tongue, the lingual frenulum, attaches to the floor of the mouth and limits the tongue's posterior movement. People with a condition called ankyloglossia have a too short or too rigid lingual frenulum, which impairs their speech. As a result, they are sometimes referred to as "tongue-tied."

The top and sides of the tongue are studded with papillae ("nipple-shaped") extensions of lamina propria layer of mucosa, which are enshrouded in stratified squamous epithelium. Most of these papillae contain taste buds; those without taste buds have touch receptors to give a sense of food’s texture. The latter increase the amount of friction between the tongue and food, which helps the tongue move food around in the mouth. Lingual glands, are found on the anterior, inferior surface of the tongue, in the lamina propria of the tongue secrete mucus and a watery serous fluid that contains the enzyme lingual lipase, which begins the digestion of triglycerides.

did I get this

The teeth, or dentes, are secured in sockets of the alveolar processes of the maxillae and mandible. Gingivae (gums; singular gingiva) cover the alveolar processes. Lining the sockets is the periodontal ligament, a dense fibrous connective tissue that secures the teeth in place. The teeth are covered by enamel, which is the hardest substance in the body. Enamel helps prevent teeth from being worn down when we chew, and it helps keep out acids that could easily dissolve the interior of a tooth.

Humans have two sets of teeth (dentitions). The 20 deciduous teeth, or baby teeth, first appear at about 6 months of age. Between ages 6 and 12 years, these teeth are replaced by the 32 permanent teeth. Closest to the midline are the two incisors, chisel-shaped teeth we use for cutting into food. The cuspids (canines) are next to the incisors. A cuspid’s pointed edge (cusp) tears and shreds food. Posteriorly, the next teeth are the two premolars (bicuspids) followed by up to three molars. Premolars and molars have broader, flatter surfaces, which we use to crush and grind food.

did I get this
Structure Action Outcome
Lips and cheeks Confine food between teeth Foods are chewed evenly during mastication
Salivary glands Secrete saliva Moistens and lubricates the lining of mouth and pharynxMoistens, softens, and dissolves food so we can tasteCleans mouth and teethSalivary amylase breaks down starch
Tongue - Extrinsic muscles Tongue moves sideways, in and out, and elevates posteriorly Maneuvers food for chewingShapes food into bolusManeuvers food for deglutition (swallowing)
Tongue - Intrinsic muscles Tongue changes shape Maneuvers food for deglutition (swallowing)
Tongue - Taste buds Sense taste and presence of food in mouth Nerve impulses from taste buds are conducted to salivatory nuclei in brain stem and then to salivary glands, stimulating saliva secretion
Lingual glands Secrete lingual lipase Breaks down triglycerides into fatty acids and diglycerides
Teeth Cut, tear, and crush food Breaks down solid food into smaller particles for deglutition (swallowing)

The pharynx (throat) is a funnel-shaped tube that runs from the choanae (internal nostrils) to the esophagus posteriorly and to the larynx anteriorly. The pharynx has three subdivisions: the nasopharynx, the oropharynx, and the laryngopharynx. The nasopharynx acts as a passageway for air during ventilation, while the other two subdivisions participate in both ventilation and digestion. Superiorly, the oropharynx is connected with the nasopharynx, inferiorly with the larynx and laryngopharynx, and anteriorly with the mouth.

Histologically, the wall of the pharynx is similar to that of the oral cavity. The mucosa includes a epithelium with mucous-producing glands. The nasopharynx is lined with pseudostratified columnar epithelium; the oropharynx and laryngopharynx are lined with stratified squamous. There are two skeletal muscle layers in the external muscle layer of the pharyngeal wall. Cells in the inner layer extend longitudinally. In the outer layer, the superior, middle, and inferior pharyngeal constrictor muscles are stacked, one inside the other, like flowerpots. Contraction of these muscles propels food toward the esophagus.

When swallowed food enters the oropharynx and laryngopharynx, it provokes contractions of the pharyngeal constrictor muscles that help push food into the esophagus. Usually during swallowing, the soft palate moves back to close off the nasopharynx, while the trachea ("windpipe") moves up under the epiglottis to cover the glottis (the opening to the larynx or voice box); this effectively blocks off air passages. But we all know what it feels like to have food "go down the wrong tube," which means it either goes into the nasal cavities or the trachea. When food enters the trachea, our reaction is to cough, which usually forces the food up and out of the trachea and back into the pharynx.

The esophagus is a collapsible tube located posterior to the trachea. This muscular tube is about 10 inches long. The esophagus runs a mainly straight route through the mediastinum of the thorax. To enter the abdomen, the esophagus penetrates the diaphragm through an opening called the esophageal hiatus. At the cardiac orifice, the esophagus joins with the stomach. Surrounding this orifice is the lower esophageal sphincter (also called the gastroesophageal or cardiac sphincter). Remember that sphincters are circular muscles that surround tubes and serve as valves, closing the tube when the sphincters contract and opening it when they relax. The lower esophageal sphincter relaxes to let food pass into the stomach, then contracts to prevent stomach contents from backing up into the esophagus. Surrounding this sphincter is the muscular diaphragm, which helps close off the sphincter when no food is being swallowed. When the lower esophageal sphincter does not completely close, some of the stomach contents can reflux (i.e., back up into the esophagus), causing heartburn or gastroesophageal reflux disease (GERD).

The esophageal mucosa is made up of nonkeratinized stratified squamous epithelium, lamina propria, and a muscularis mucosa. The mucosa near the stomach also includes mucous glands. The stratified squamous epithelium protects against abrasion and erosion from food particles. In the superior third of the esophagus, the muscularis is skeletal muscle, in the middle third it is both skeletal and smooth muscle, and in the inferior third it is smooth muscle. A slight prominence at either end of the esophagus creates two sphincters: the upper esophageal sphincter, made of skeletal muscle, and the lower esophageal sphincter, made of smooth muscle. As we have already learned, the superficial layer of the esophagus is called the adventitia, not the serosa. In contrast to the stomach and intestines, the areolar connective tissue of the adventitia is not covered by mesothelium.

did I get this

The esophagus secretes mucus that lubricates food, and it propels food into the stomach. Chemical digestion that began in the mouth continues in the esophagus, but there aren’t any new digestive enzymes secreted. The upper esophageal sphincter controls the movement of food from the pharynx into the esophagus. The lower esophageal sphincter controls the movement of food from the esophagus into the stomach. Rhythmic waves of peristalsis begin in the esophagus and then continue in the rest of the digestive tract organs. The feeling of having a lump in your throat when you are nervous is caused by peristalsis that occurs when there is no food in the esophagus.

Action Outcome
Upper esophageal sphincter relaxation Allows bolus to move from the laryngopharynx to the esophagus
Peristalsis Propels bolus down the esophagus
Lower esophageal sphincter relaxation Allows bolus from the esophagus to enter the stomach
Mucus secretion Lubricates the esophagus, allowing easy passage of bolus
did I get this

Deglutition is another word for swallowing – the movement of food from the mouth and into the stomach. The entire process takes about four to eight seconds for solid or semisolid food and about one second for very soft food and liquids. Deglutition involves the mouth, pharynx, and esophagus. It is facilitated by the secretion of mucus and saliva. There are three stages in deglutition: the voluntary phase, the pharyngeal phase, and the esophageal phase.

The voluntary phase of deglutition is also called the oral phase or buccal phase. In this phase, swallowing is set in motion when the tongue moves upward and backward against the palate, pushing the bolus to the back of the oral cavity and into the oropharynx. At this point, the two involuntary phases of swallowing begin.

In the pharyngeal phase, stimulation of receptors in the oropharynx sends impulses to the deglutition center (a collection of neurons that controls swallowing) in the medulla oblongata. Impulses are then sent back to the uvula and soft palate, provoking them to move upward to close off the nasopharynx. Sequential contractions of the pharyngeal constrictor muscles move the bolus through the oropharynx and laryngopharynx. Relaxation of the upper esophageal sphincter then allows food to enter the esophagus.

The entry of food into the esophagus marks the beginning of the esophageal phase of deglutition. Peristalsis propels the bolus through the esophagus and toward the stomach. The circular muscle layer of the muscularis immediately superior to the bolus contracts, pinching the esophageal wall, forcing the bolus forward. At the same time, the longitudinal muscle layer of the muscularis inferior to the bolus also contracts, shortening this inferior area and pushing out its walls to receive the bolus. Waves of contractions keep moving the food toward the stomach. When the bolus nears the stomach, relaxation of the lower esophageal sphincter allows the bolus to pass into the stomach. During the esophageal phase, esophageal glands secrete mucus that lubricates the bolus and minimizes friction. Peristalsis is completely involuntary even though there is skeletal muscle in the first 2/3 of the esophagus.

The stomach is an expansion of the GI tract that lies below the esophagus. It is a very mobile structure between its relatively fixed upper and lower ends. The stomach is found between the esophagus to the first part of the small intestine (the duodenum). The stomach's position and size are always changing. It is about as big as a large sausage when empty, and stretches to hold 1 liter of food when full; the stomach has a final capacity of 2-3 liters. One of the digestive functions of the stomach is to serve as a temporary "holding chamber". This is an important step in digestion, because we can eat a meal far more quickly than it can be digested and absorbed in the small intestine. So the stomach pushes only a small amount of food into the small intestine at a time.

The stomach plays several important roles in chemical digestion, including the continued digestion of starch and the initial digestion of proteins and triglycerides. The stomach is also where the semisolid bolus is converted to a liquid (chyme) and where some ingested substances are absorbed.

## Stomach Anatomy

There are four main regions in the stomach: the cardiac, fundus, body, and pylorus. The cardiac (cardia region) is a small area surrounding the cardiac orifice through which food from the esophagus enters the stomach. Lying beneath the diaphragm, superior and to the left of the cardiac, is the dome-shaped fundus, which functions as a temporary storage center for food. Inferior to the fundus is the body, the large central part of the stomach. The funnel-shaped pylorus connects the stomach to the duodenum. The pyloric antrum is the wider, more superior portion of the pylorus that connects to the body of the stomach. The pyloric antrum narrows into a region called the pyloric canal, which leads into the duodenum. The pylorus communicates with the duodenum via the smooth muscle pyloric sphincter. This sphincter controls stomach emptying. In the absence of food, the stomach deflates inward and its mucosa and submucosa fall into large folds called rugae.

The convex lateral surface of the stomach is called the greater curvature; the concave medial border is the lesser curvature. Two fatty mesenteries (peritoneal folds) called omenta hold the stomach in place. The lesser omentum extends from the liver to the lesser curvature. The greater omentum runs from the greater curvature to the posterior abdominal wall.

learn by doing

The wall of the stomach is made of the same four tissue layers as most of the rest of the GI tract, but with adaptations to the mucosa and muscularis externa for the unique functions of this organ. In addition to the typical circular and longitudinal smooth muscle layers, the muscularis externa has an inner oblique smooth muscle layer that runs diagonally around the organ. As a result, in addition to moving food through the GI tract, the stomach can more vigorously churn and mix food, mechanically breaking it down into smaller particles.

Millions of deep gastric pits in the epithelium lead into gastric glands, which secrete gastric juice. The walls of the gastric pits are made up primarily of epithelial cells. The gastric glands are made up of different types of cells. Glands of the cardia and pylorus are composed primarily of mucus-secreting cells. Cells that make up the pyloric antrum secrete mucus and a number of hormones, including gastrin. The much larger glands of the fundus and body of the stomach, the site of most chemical digestion, produce most of the gastric secretions. These glands are made up of a variety of secretory cells, including mucous neck, parietal, chief, and enteroendocrine cells (G-cells).

did I get this
Structure Action Outcome
Muscularis Externa Mixing wavesPeristalsis Forms chyme by liquefying food and mixing it with gastric juicePropels chyme through pyloric sphincter
Pyloric sphincter Controls passage of chyme from the stomach to the duodenum Delivers chyme to the intestine at a rate optimal for digestion and absorption; prevents chyme from flowing back to stomach from duodenum
Chief cells Secrete pepsinogenSecrete gastric lipase Pepsin (activated form) breaks proteins down into peptidesBreaks down triglycerides into fatty acids and monoglycerides
G cells Secrete gastrin Activates secretion of HCl by parietal cells and pepsinogen by chief cells; contracts lower esophageal sphincter, enhances stomach motility, and relaxes pyloric sphincter
Parietal cells Secrete HClSecrete intrinsic factor Kills food microbes; denatures proteins, transforms pepsinogen into pepsinEnables vitamin B12 absorption for red blood cell formation
Surface mucous cells and mucous neck cells Secrete mucusAbsorption Protects stomach wall from digestive processesAllows limited amount of water, ions, short-chain fatty acids, and certain drugs to enter bloodstream

The secretion of gastric juice is controlled by nerves, hormones, and the presence of products of digestion. Stimuli from smell, sight and taste as well as food in the oral cavity, stomach, and small intestine activate or inhibit gastric juice production. This is why the three phases of gastric secretion are called the cephalic, gastric, and intestinal phases. However, once gastric secretion begins, all three phases can occur simultaneously.

The cephalic (reflex) phase of gastric secretion, which lasts just a few minutes, takes place before food enters the stomach. The smell, taste, sight, or thought of food triggers this phase. For example, impulses from receptors in taste buds or the nose are relayed to the brain, which returns signals that increase gastric secretion to prepare the stomach for digestion. This enhanced secretion is a conditioned reflex, meaning it occurs only if we like or want a particular food. Depression and loss of appetite can suppress the cephalic reflex.

The gastric phase of secretion lasts three to four hours and is set in motion by local neural and hormonal mechanisms triggered by the entry of food into the stomach. For example, stomach distension activates stretch receptors that stimulate parasympathetic neurons to release acetylcholine, which then provokes increased secretion of gastric juice. Partially digested proteins, caffeine, and rising pH stimulate the release of gastrin from enteroendocrine G cells, which in turn provokes parietal cells to increase their production of HCl and increase motility through the stomach by altering sphincter function. The presence of proteins in the stomach raises pH, which stimulates the increased gastrin and HCl release needed to create an acidic environment for protein digestion.

did I get this
Example
##### GERD

If this control of gastric juice secretion is not working properly and too much hydrochloric acid is produced, conditions such as Gastroesophageal Reflux Disease (GERD) can occur. The acidic pH irritates the lining of the esophagus near the cardiac or lower esophageal sphincter and can lead to esophageal cancer. Antacids provide only temporary relief. Some drugs known as histamine-2 antagonists (H2-blockers) or proton-pump inhibitors (PPIs) may be needed to control the amount of stomach acid produced. However, the two drugs act on different parts of the parietal cell metabolism.

Review the process of hydrochloric acid secretion by parietal cell to analyze the physiology behind these two drugs.

did I get this

The stomach participates in virtually all digestive activities with the exception of ingestion and defecation. In addition to mechanical and chemical digestion, the stomach absorbs some fat-soluble substances, including alcohol and aspirin.

## Mechanical Digestion

A few minutes after food enters the stomach, mixing waves begin at intervals of about 15 to 25 seconds. Mixing waves are a gentle type of peristalsis that soften and moisten food. They also combine food with gastric juice and create chyme. Initial gentle mixing waves are followed by more intense waves that break down food into smaller pieces and further mix with digestive juice, starting at the body of the stomach and increasing in force as they reach the pylorus.

The pylorus, which holds around 30 mL (1 ounce) of chyme, acts as a filter, permitting only liquids and small food particles to pass through the mostly, but not fully, closed pyloric sphincter. When food enters the pylorus, periodic mixing waves force about 3 mL of chyme through the pyloric sphincter and into the duodenum, a process called gastric emptying. The rest of the chyme is pushed back into the body of the stomach, where it continues mixing. This process is repeated when the next mixing waves force more chyme into the duodenum. These forward and backward movements accomplish most of the mixing in the stomach.

Gastric emptying is regulated by both the stomach and the duodenum. The presence of chyme in the duodenum activates receptors that inhibit gastric emptying. This prevents additional chyme from being released by the stomach before the duodenum is ready to process it.

## Chemical Digestion

Some foods sit in the fundus of the stomach for an hour or so before they are mixed with gastric juice. During this time, the digestive activity of salivary amylase continues. Mixing waves soon take over however, combining chyme with acidic gastric juice, which inactivates salivary amylase and activates lingual and gastric lipase. Lingual lipase then starts breaking down triglycerides into fatty acids and diglycerides.

The digestion of protein begins in the stomach, primarily by pepsin. During infancy, gastric glands also produce rennin, an enzyme that helps digest milk protein. Lingual lipase secreted by the salivary glands may also participate in triglyceride digestion in the stomach. Parietal cells secrete hydrogen ions and chloride ions into the stomach lumen, effectively forming HCl, which denatures dietary proteins.

The contents of the stomach are completely emptied into the duodenum within two to four hours after you eat a meal. Carbohydrate-rich foods are the quickest to leave the stomach. High-protein foods exit a little more slowly. Fatty meals with high triglyceride content remain in the stomach the longest. Enzymes in the small intestine digest fats slowly. So when the duodenum is processing fatty chyme, food can stay in the stomach for six hours or longer.

did I get this

The small intestine is a convoluted tube that begins just distal to the pyloric sphincter of the stomach and then loops through the central and inferior region of the abdomen before ending at the ileocecal valve, where it merges with the large intestine. The small intestine is the primary digestive organ in the body. Not only is it the part of the GI tract where digestion is completed, it is also where the majority of absorption occurs.

Although the small intestine is the longest part of the GI tract, its diameter is about half that of the large intestine, averaging a little over one inch (2.5 cm). When we are alive, the small intestine is more than 3 meters (10 feet) long – the size of a one-story building. Its length provides expansive surface area necessary for digestion and absorption. However, circular folds, villi, and microvilli add even more surface area. With loss of muscle tone after death, the folds of the small intestine relax, extending it to about 20 feet in length.

## Small Intestine Anatomy

The duodenum precedes the jejunum and ileum and is the shortest part of the small intestine; it is less than 1 foot of the 10 foot intestine (30 cm of the 3 m). The duodenum receives the stomach contents, pancreatic juice and bile. Chemical digestion continues in the duodenum. The jejunum is the next portion (3.5 - 5.5 ft or 110-170 cm) of the small intestine and is responsible for the absorption of a majority of nutrients. In the last section of the small intestine, the ileum, vitamin B12 and bile salts are absorbed as well as materials not absorbed by the jejunum.

learn by doing

The term mucosa or mucous membrane always refers to the combination of the epithelium plus the lamina propria. The lamina propria layer of the small intestinal mucosa is composed of areolar connective tissue and quite a bit of mucosa-associated lymphoid tissue. Most solitary lymphatic nodules are located in the distal portion of the ileum. The blood supply which runs through the lamina propria and drains the villus is part of the the hepatic portal systems and not general systemic circulaions

In the ileum, the lamina propria also has aggregated lymphatic follicles (groups of lymphatic nodules) called Peyer's patches. There are more Peyer's patches toward the end of the small intestine, possibly because of the high amounts of bacteria in that area must be prevented from entering the bloodstream. The submucosa of the duodenum is the only site of the complex mucus-secreting duodenal (Brunner's) glands, which produce a bicarbonate-rich alkaline mucus that helps buffer the acidic chyme coming in from the stomach.

Like in the rest of the GI tract, the muscularis externa layer is made of two layers of smooth muscle – an outer, thinner layer of longitudinal fibers and an inner, thicker layer of circular fibers. The serosa completely enshrouds the small intestine, with the exception of a large region of the duodenum.

learn by doing
did I get this

Each day, the alimentary canal processes up to 10 liters of food, liquids, and GI secretions; of which, only about one liter enters the large intestine. Almost all ingested food and drink, 80 percent of electrolytes, and most of the water are absorbed in the small intestine. The entire small intestine is involved in absorption, but most absorption occurs before chyme reaches the ileum. Absorption in the ileum primarily involves the recycling of bile salts. The absorptive capacity of the alimentary canal is amazing. By the time chyme passes from the ileum into the large intestine, it is essentially indigestible food residue (mainly plant fibers like cellulose) some water, and millions of bacteria.

The absorption of most nutrients through the mucosa of the intestinal villi occurs via active transport mechanisms that are driven directly or indirectly by metabolic energy. These nutrients enter the capillary blood in the villus and travel to the liver via the hepatic portal vein. An exception is certain lipids, which undergo passive absorption via diffusion and then enter the modified lymph duct in the villus (called a lacteal), to be transported to the blood in lymphatic fluid. Substances cannot be absorbed between the epithelial cells of the intestinal mucosa, because these cells connect with tight junctions. This is why substances can only enter blood capillaries by passing through the epithelial cells and into the interstitial fluid.

## Carbohydrate Absorption

All carbohydrates are absorbed in the form of monosaccharides. The small intestine is highly efficient at this, absorbing monosaccharides at an estimated rate of 120 grams per hour. All normally digested dietary carbohydrates are absorbed. However, indigestible fibers including cellulose, glucose polymers made by plants which is not broken down in humans, are eliminated in feces. The monosaccharides glucose and galactose – the products of the breakdown of starch and disaccharides – are transported into the epithelial cells by common protein carriers via secondary active transport, which requires ATP). They leave these cells via facilitated diffusion and enter the capillaries through intercellular clefts. The monosaccharide fructose (which is in fruit) is absorbed and transported by facilitated diffusion alone. Monosaccharides combine with the transport proteins, which lie very near the disaccharide splitting enzymes on the microvilli, immediately after disaccharides are broken down.

## Protein Absorption

Active transport mechanisms, primarily in the duodenum and jejunum, absorb most proteins as their breakdown products, amino acids. Almost all (95 to 98 percent) protein is digested and absorbed in the small intestine. The type of carrier that transports an amino acid varies. Most carriers are linked to the active transport of sodium. Short chains of two amino acids (dipeptides) or three amino acids (tripeptides) are also transported actively. But after they enter the absorptive epithelial cells, they are broken down to their amino acids before leaving the cell and entering the capillary blood via diffusion.

## Lipid Absorption

Despite being hydrophobic, the small size of short-chain fatty acids enables them to be absorbed in intestinal chyme, enter absorptive cells via simple diffusion, and then take the same path as monosaccharides and amino acids into the blood capillary of a villus. The large and hydrophobic long-chain fatty acids and monoglycerides are not so easily suspended in the watery intestinal chyme. However, bile salts and the phospholipid lecithin (also found in bile) help make them more soluble by surrounding them and creating tiny spheres called micelles. Micelles are macromolecular structures made up of aggregates of fatty elements and bile salts that create a polar (hydrophilic) end that faces the water and a nonpolar (hydrophobic) core. The core also includes cholesterol molecules and fat-soluble vitamins. Micelles can easily squeeze between microvilli and get very near the luminal cell surface. At this point, lipid substances exit the micelle and are absorbed via simple diffusion. Without their "vehicles" (i.e., the micelles), lipids would sit on the surface of chyme, like oil on water, and would never come in contact with the absorptive surfaces of the epithelial cells. About 95 percent of lipids are absorbed in the small intestine. Bile salts not only speed up lipid digestion, they are also essential to the absorption of the end products of lipid digestion.

The free fatty acids and monoglycerides that enter the epithelial cells are reincorporated into triglycerides, which are then mixed with phospholipids and cholesterol and surrounded with a protein coat, creating chylomicrons. Chylomicrons are milky-white droplets of water-soluble lipoprotein that are processed by the Golgi apparatus for release from the cell. Chylomicrons are too big to pass through the basement membranes of blood capillaries. Instead, they enter the much larger pores of lacteals. This means that most fats are first transported in the lymphatic vessels and do not enter the venous blood until they reach the thoracic duct in the neck region. In the bloodstream, the enzyme lipoprotein lipase breaks down the triglycerides of the chylomicrons into free fatty acids and glycerol. These two breakdown products can then pass through capillary walls to become energy used by our cells or to be stored in adipose tissue as fats. Liver cells combine the remaining chylomicron material with proteins, forming "new" lipoproteins that transport cholesterol in the blood.

## Nucleic Acid Absorption

The products of nucleic acid digestion – pentose sugars, nitrogenous bases, and phosphate ions –are transported across the epithelium by special carriers in the villus epithelium via active transport.

learn by doing
Food/Breakdown Products Absorption Mechanism Entry to Bloodstream Destination
Carbohydrates
Glucose Co-transport with sodium ions Capillary blood in villi Liver via hepatic portal vein
Galactose Co-transport with sodium ions Capillary blood in villi Liver via hepatic portal vein
Fructose Facilitated diffusion Capillary blood in villi Liver via hepatic portal vein
Protein
Amino acids Co-transport with sodium ions Capillary blood in villi Liver via hepatic portal vein
Lipids
Long-chainfatty acids Diffusion into intestinal cells, where they are combined with proteins to create chylomicrons Lacteals of villi Systemic circulation via lymph in thoracic duct
Monoglycerides Diffusion into intestinal cells, where they are combined with proteins to create chylomicrons Lacteals of villi Systemic circulation via lymph in thoracic duct
Short-chainfatty acids Simple diffusion Capillary blood in villi Liver via hepatic portal vein
Glycerol Simple diffusion Capillary blood in villi Liver via hepatic portal vein
Nucleic acids Active transport via membrane carriers Capillary blood in villi Liver via hepatic portal vein
did I get this

## Electrolyte Absorption

The electrolytes absorbed by the small intestine are from both GI secretions and ingested foods and liquids. Recall that electrolytes are compounds that separate into ions in water. Most ions are absorbed throughout the entire small intestine. Exceptions are iron and calcium, which are primarily absorbed in the duodenum.

In the small intestine, sodium ion absorption is linked via co-transport mechanisms to the absorption of glucose and amino acids. A sodium-potassium pump moves sodium ions from the basolateral side of small intestine epithelial cells into the bloodstream they enter. Chloride ions are also absorbed via active transport. Changing osmotic gradients passively move potassium ions across the intestinal mucosa via facilitated diffusion (or via leaky tight junctions).

In general, all nutrients that enter the intestine are absorbed, whether we need them or not. Iron and calcium are exceptions; they are absorbed in amounts that fulfill the needs of our body. The iron ion needed for the production of hemoglobin is absorbed into mucosal cells via active transport. Once inside mucosal cells, ionic iron binds to the protein ferritin, creating iron-ferritin complexes that act as intracellular storage facilities for iron. When the body has enough iron, most of the stored iron is lost when worn-out epithelial cells slough off. When the body needs iron because, for example, it is lost during acute or chronic bleeding, there is increased uptake of iron from the intestine and accelerated release of iron into the blood. Because women experience significant iron loss during menstruation, they have around four times as many iron transport proteins in their intestinal epithelial cells as men.

Blood levels of ionic calcium (Ca2+) determine the absorption of calcium. The active form of vitamin D, under the control of parathyroid hormone, provides local regulation of this process in the intestines. When blood levels of ionic calcium drop, parathyroid hormone (PTH) secreted by the parathyroid glands stimulates the release of calcium ions from bone matrix and increases the reabsorption of calcium by the kidneys. PTH also provokes the activation of vitamin D by the kidneys, which triggers greater calcium ion absorption in the small intestine.

## Vitamin Absorption

Vitamins in our food are absorbed in the small intestine. Some of the vitamin K and B vitamins created by enteric bacteria are absorbed in the large intestine. Fat-soluble vitamins (A, D, E, and K) are absorbed along with dietary lipids in micelles via simple diffusion. In fact, you need some fat in your diet in order to be able to absorb fat-soluble vitamins. Some of the B vitamins are not actually found in our food but are made by gut bacteria. Most water-soluble vitamins are absorbed by simple diffusion , including most B vitamins and vitamin C. An exception is vitamin B12, which is a very large molecule. Intrinsic factor secreted in the stomach binds to vitamin B12, creating a combination that can bind to mucosal receptors in the terminal ileum, launching its active uptake by endocytosis.

## Water Absorption

Each day, about nine liters (9.8 quarts) of fluid enter the small intestine; about 2.3 liters are ingested, and the rest is from GI secretions. About 95 percent of water is absorbed in the small intestine. The absorption of water in the alimentary canal occurs via osmosis. Around 300 to 400 mL of water is absorbed per hour. Water can move easily in both directions across the intestinal mucosa. The active transport of solutes into mucosal cells establishes a concentration gradient that results in water moving into the cells via the process of osmosis. As water enters the cells, it concentrates the solutes left in the lumen, enhancing the absorption of those molecules absorbed by passive diffusion. This means that the absorption of water is essentially linked to the absorption of solutes, which, in turn, determines the absorptive rate of those salts and sugars that are absorbed via diffusion. The water that moves into the mucosal cells is followed by these substances along their concentration gradients.

learn by doing

The large intestine is the terminal part of the gastrointestinal tract. The primary digestive function of this organ is to finish absorption, produce some vitamins, form feces, resorb water and eliminate feces from the body.

The large intestine runs from the cecum, where it attches to the ileum, to the anus. It borders the small intestine on three sides. Despite its being around half as long as the small intestine – 4.9 feet versus 10 feet (1.5 – 3 meters) – it is called the large intestine because it is more than twice the diameter of the small intestine, 2.5 inches versus one inch (6 cm versus 2.5 cm). The large intestine is tethered to the posterior abdominal wall by the mesocolon, a double layer of peritoneal membrane.

The large intestine is subdivided into four main regions: the cecum, the colon, the rectum, and the anus. The ileocecal valve, located at the opening between the ileum in the small intestine and the large intestine, controls the flow of chyme from the small to the large intestine.

## Large Intestine Anatomical Structures

Like the small intestine, the mucosa of the large intestine has intestinal glands that contain both absorptive and goblet cells. However, there are several notable differences between the walls of the large and small intestines. For example, other than the anal canal, the mucosa of the colon is simple columnar epithelium. In addition, the wall of the large intestine has no circular folds, no villi, and essentially no enzyme-secreting cells. This is because most nutrients are already absorbed before chyme enters the large intestine. The large intestinal wall does have thicker mucosa and deeper – and more abundant – glands that contain a vast number of goblet cells. These goblet cells secrete mucus that eases the movement of feces and protects the intestine from the effects of the acids and gases produced by enteric bacteria.

The stratified squamous epithelial mucosa of the anal canal joins with the skin around the anus. This mucosa varies considerably from that of the rest of the colon to accommodate the increased abrasion in this region. The anal canal's mucous membrane is organized in longitudinal folds called anal columns that house a grid of veins. Depressions between the anal columns, called anal sinuses, secrete mucus when they are crowded by feces. This facilitates defecation. The pectinate line is a horizontal, jagged band that runs alongside the inferior margins of the anal sinuses. The mucosa superior to this line is fairly insensitive to pain, while the area inferior to this line is very pain-sensitive. The difference in pain response is due to the fact that the superior region is innervated by visceral sensory fibers, and the inferior region is innervated by somatic sensory fibers. There are two superficial venous plexuses in the anal canal – one with the anus and the other with the anal columns. Inflammation and distension of these (hemorrhoidal) veins causes hemorrhoids, an itchy condition caused by the swelling of these vessels.

Three features are unique to the large intestine: teniae coli, haustra, and epiploic appendages. The teniae coli are three bands of smooth muscle that make up the longitudinal muscle layer of the muscularis externa of the large intestine, except at its terminal end in the rectum. Tonic contractions of the teniae coli bunch up the colon into a succession of pouches called haustra, which are responsible for the wrinkled appearance of the colon. Attached to the teniae coli are small, fat-filled sacs of visceral peritoneum called epiploic appendages (omental appendices). These fatty pouches of peritoneum found in the serosa from the transverse colon through the sigmoid colon.

Although the rectum and anal canal have no teniae coli or haustra, they do have well-developed layers of muscularis externa muscle that create the strong contractions needed for defecation.

did I get this

## Large Intestine Gross Anatomy

The first part of the large intestine is the cecum, a small sac-like region that is suspended inferior to the ileocecal valve. This cecum is about 2.4 inches long. The appendix or vermiform appendix (vermiform = “worm-shaped”, and appendix = “appendage”) is a winding, coiled tube that attaches to the cecum. This 2-7 cm (~3 inch) long appendix contains lymphoid tissue and plays an important role in immunity. Nevertheless, its twisted anatomy provides a haven for the accumulation and multiplication of enteric bacteria. The mesoappendix, the mesentery of the appendix, tethers it to the inferior part of the mesentery of the ileum.

The end of the cecum joins with the colon, a long tube with several distinct areas. The ascending colon runs up the right side of the abdomen. At the inferior surface of the liver, it takes a right-angle turn, forming the right colic (hepatic) flexure and becoming the transverse colon. The transverse colon runs across to the left side of the abdomen. It then bends sharply at a point immediately anterior to the spleen, forming the left colic (splenic) flexure. As the descending colon, it runs down the left side of the posterior abdominal wall. After entering the pelvis inferiorly, it becomes the s-shaped sigmoid colon, which extends medially to the midline. Most of the colon is between the peritoneal membrane and the body wall, except for the intraperitoneal transverse and sigmoid colons, which are tethered to the posterior abdominal wall by mesocolons.

The sigmoid colon joins the rectum in the pelvis, near the third sacral vertebra. The rectum is the final 8 inches (20 cm) of the alimentary canal. It extends anterior to the sacrum and coccyx. Even though rectum is Latin for "straight," this structure has three lateral bends that create a trio of internal transverse folds called the rectal valves. These valves allow passing of gas (flatus) while preventing the simultaneous passage of feces.

The last part of the large intestine is the anal canal, which is located in the perineum, completely outside the abdominopelvic cavity. This 1 inch (3 cm) long structure opens to the exterior of the body at the anus. The anal canal includes two sphincters. The involuntary internal anal sphincter is made of smooth muscle; the voluntary external anal sphincter is skeletal muscle. Except when defecating, these two sphincters are usually closed.

did I get this

There are many species of bacteria that populate the large intestines. They digest food products for which we do not have enzymes (such as plant materials) and we absorb some of the nutrient products. They can also produce some vitamins like vitamin K and B vitamins. A byproduct of bacterial fermentation (digestion) is gas (flatus).

Although the bacteria provide additional nutrients from the food we ingest, they can also infect us. Because of the large and diverse bacterial population that resides in the large intestine, the large intestine also contains plentiful lymphatic tissue to protect us from potentially harmful effects of resident bacteria.

did I get this

Most bacteria that migrate to the cecum from the small intestine have already been killed by lysozyme and other antibacterial molecules, HCl, and protein-digesting enzymes. Those that are still living, along with bacteria that come into the alimentary canal through the anus, are referred to as the large intestine's (enteric) bacterial flora. The more than 700 species of bacterial flora in the colon participate in chemical digestion and absorption. The large intestine is also home to a number of viruses and protozoans, at least 20 of which are known pathogens.

Most enteric bacteria are nonpathogenic commensals (also called symbiotic, wityh benefit to both organisms) that cause no harm as long as they stay in the gut lumen. A refined system prevents these bacteria from crossing the mucosal barrier. First, certain bacterial components activate the release of chemicals by the mucosa's epithelial cells, which recruit immune cells, especially dendritic cells, into the mucosa. Dendritic cells open the tight junctions between epithelial cells and extend probes into the lumen to evaluate the microbial antigens. The dendritic cells then travel to neighboring lymphoid follicles in the mucosa and hand over the antigens to T cells. This triggers an IgA antibody-mediated response in the lumen that blocks the commensals from infiltrating the mucosa and setting off a far greater, widespread systematic reaction.

did I get this

The major digestive role of the large intestine involves propulsion--pushing fecal matter toward the anus and then out of the body. Chyme, which stays in the large intestine for 12 to 24 hours, contains few nutrients. Enteric bacteria are responsible for a small amount of digestion. The bacterial flora create vitamins required for normal metabolism, such as certain B vitamins and vitamin K. Most of the remaining water and some electrolytes (especially sodium and chloride) are recycled.

Structure Action Outcome
Lumen Bacterial degradation of chyme components Breaks down undigested proteins, carbohydrates, and amino acids into substances that can be absorbed and detoxified by the liver or eliminated in feces; synthesizes vitamin K and some B vitamins
Mucosa Mucus secretionAbsorption Lubricates colon; protects mucosaAbsorbs water, solidifies feces, and helps maintain water balance in body; absorbed solutes include ions and certain vitamins
Muscularis externa Haustral churningPeristalsisDefecation reflex Muscle contractions move contents between haustrumsContractions of circular and longitudinal muscles propel contents along length of colon; Propels contents into sigmoid colon and rectumContractions in sigmoid colon and rectum eliminate feces
Example
##### Ileostomy

It may surprise you that the large intestine can be completely removed without significantly affecting digestive functioning. For example, if colon cancer necessitates the removal of the large intestine, an ileostomy can be performed, in which the terminal ileum is moved out to the abdominal wall. A sac is then attached to the abdominal wall to collect eliminated food residues.

did I get this

## Mechanical Digestion

Mechanical digestion in the large intestine begins when chyme moves from the ileum into the cecum, an activity regulated by the ileocecal valve. This sphincter is usually partially closed, allowing slow movement of chyme into the large intestine. Right after we eat, peristalsis in the ileum is escalated by the gastroileal reflex, which forces whatever chyme is in the ileum into the cecum. The activity of the hormone gastrin also relaxes the ileocecal valve. When the cecum is distended with chyme, contractions of the ileocecal sphincter strengthen. Once chyme enters the cecum, colon movements begin. As food residues pass the ileocecal valve, they fill the cecum and gather in the ascending colon.

The presence of food residue in the colon stimulates slow-moving haustral contractions (haustral churning). These sluggish segmentations, primarily in the transverse and descending colons, occur about every 30 minutes and last about one minute. When a haustra is distended with chyme, its muscle contracts, pushing the residue into the next haustra. The movements also mix the food residue, which helps the large intestine absorb water.

The large intestine also has peristaltic movements, but they are slower than in more proximal portions of the alimentary canal, at a rate of from three to 12 contractions per minute. The third type of movement in the large intestine is called mass movements (mass peristalsis). These drawn-out, slow-moving, but strong peristaltic waves start around the middle of the transverse colon and quickly force the contents of the colon into the rectum. Mass movements usually occur three or four times per day, either while we eat or immediately afterward. Distension in the stomach and the breakdown products of digestion in the small intestine provoke the gastrocolic or duogenocolic reflex, which increases motility, including mass movements, in the colon. Fiber in the diet both softens the stool and increases the power of colonic contractions, optimizing the activities of the colon.

## Chemical Digestion

The glands of the large intestine secrete only mucus; they do not secrete digestive enzymes. So chemical digestion in the large intestine occurs only through the activity of the bacteria in the lumen of the colon. Bacteria ferment residual carbohydrates in the chyme and discharge the hydrogen sulfide, carbon dioxide, and methane gases that help create flatus (gas) in the colon(flatulence refers to excessive flatus). Some of these gases, including dimethyl sulfide, have foul odors. Each day, about 500 mL of flatus is produced in the colon. Much more is produced when we eat some fiber-rich foods such as beans.

did I get this

After chyme has been in the large intestine for three to 10 hours, water absorption changes it into the solid or semisolid substance called feces ("stool"). Feces is composed of undigested food residues (dietary fiber), unabsorbed digested substances, millions of bacteria, sloughed-off epithelial cells from the GI mucosa, inorganic salts, mucus, fat and just enough water to let it pass smoothly out of the body. Of every 500 mL (17 ounces) of food residue that enters the cecum each day, about 150 mL (5 ounces) becomes feces.

Although the small intestine absorbs around 90 percent of the water that enters the GI tract, the water absorbed in the large intestine is important in maintaining the body's water balance. For every 0.5 to 1.0 liter (16 to 32 ounces) of water that goes into the large intestine, only around 100 to 200 mL (3 to 7 ounces) escapes being absorbed by osmosis.

The process of defecation begins when mass movements force feces from the sigmoid colon into the rectum, stretching the rectal wall and provoking the defecation reflex, which eliminates feces from the rectum. This parasympathetic reflex is mediated by the spinal cord. It contracts the sigmoid colon and rectum, relaxes the internal anal sphincter, and initially contracts the external anal sphincter. The presence of feces in the anal canal sends a signal to the brain, which gives us the choice of voluntarily opening the external anal sphincter (defecating) or keeping it temporarily closed. When we decide to delay defecation, it takes a few seconds for the reflex contractions to stop and the rectal walls to relax. The next mass movement will trigger another defecation reflex and another until we defecate.

Feces is eliminated during defecation through contraction of the rectal muscles. We help this process by a voluntary procedure called the Valsalva maneuver, in which we increase intra-abdominal pressure by contracting our diaphragm and abdominal wall muscles and closing our glottis. Along with learned control of the external anal sphincter, these actions must be learned, which is why infants and young children wear diapers.

Diet, health, exercise and stress determine the frequency of bowel movements. The number of bowel movements varies greatly between individuals, ranging from two or three per day to three or four per week.

did I get this

Lying outside the oral mucosa are the three pairs of major salivary glands, which secrete the majority of saliva into ducts that open into the mouth. The parotid glands lie between the skin and the masseter muscle near the ears. They secrete saliva into the mouth through the parotid duct, which is located near the second upper molar tooth. The submandibular glands, which are in the floor of the mouth, secrete saliva into the mouth through the submandibular ducts near the lower central incisor. The sublingual glands, which lie below the tongue, use the lesser sublingual ducts to secrete saliva into the oral cavity.

Different salivary glands secrete unique formulations of saliva according to their cellular makeup. For example, the parotid glands secrete a watery solution that contains salivary amylase. The submandibular glands have cells similar to those of the parotid glands, along with some mucous-secreting cells. So saliva secreted by the submandibular glands also contains amylase but in a liquid thickened with mucus. The sublingual glands contain mostly mucous cells, and they secrete the thickest saliva with the least amount of salivary amylase.

Example
##### Homeostatic Imbalances of the Parotid Glands: Mumps

Infections of the nasal passages and pharynx can attack any salivary glands. The parotid glands are the usual site of infection with the virus that causes mumps (Paramyxovirus). Mumps manifest with enlargement and inflammation of the parotid glands, causing the characteristic swelling between the ears and the jaw. Symptoms include fever and throat pain, which can be severe when swallowing acidic substances such as orange juice.

In about one third of men who are past puberty, mumps also causes testicular inflammation, typically affecting only one testis and thus rarely resulting in sterility. The incidence of mumps has dropped considerably since 1967, when a vaccine was introduced.

The autonomic nervous system regulates salivation (the secretion of saliva). An average of 1 to 1.6 quarts (0.9-1.5 liters) of saliva is secreted each day. In the absence of food, parasympathetic stimulation keeps saliva flowing continuously to moisten mucous membranes and lubricate tongue and lip movements when we talk; swallowed saliva moistens the esophagus. Most saliva is reabsorbed, preventing fluid loss. During times of stress, sympathetic stimulation takes over, reducing serous salivation and causing dry mouth. When you are dehydrated, salivation stops to conserve water, causing the mouth dryness that helps stimulate feelings of thirst. Having a drink restores body water homeostasis and moistens the mouth.

Salivation from the major salivary glands is stimulated by both the taste and sensation of food. Food contains chemicals that stimulate taste bud receptors on the tongue, which send impulses to the superior and inferior salivatory nuclei in the brain stem. These two nuclei then send back parasympathetic impulses through fibers in the facial and glossopharyngeal nerves to stimulate salivation. Even after we swallow food, salivation is increased to cleanse the mouth and to dilute and neutralize any irritating chemical remnants -- such as that hot sauce in your burrito. Salivation can also be stimulated by simply thinking about, seeing, or smelling food.

did I get this

Chemical digestion in the small intestine relies on the activities of three accessory digestive organs: the pancreas, liver and gall bladder. The pancreas produces pancreatic juice, which contains digestive enzymes and bicarbonate, and delivers it to the duodenum.

The digestive role of the liver is to produce bile and export it to the duodenum. The gall bladder primarily stores and releases bile.

The soft, tadpole-shaped pancreas is a gland that is about 5-6 inches (13-15 cm) long and 1 inch (2.5 cm) thick. It lies posterior to the greater curvature of the stomach. The pancreas regions are described as the head, body, and tail. The head is next to the duodenum. The body lies behind the stomach. The tail is in contact with the spleen.

## Pancreas Ducts

The pancreas is important in digestion, because it produces pancreatic juice, a combination of fluid and digestive enzymes. Exocrine cells release this juice into small ducts that eventually unite to create two larger ducts that deliver pancreatic juice to the small intestine. The larger of these two ducts is the centrally located main pancreatic duct (duct of Wirsung). In most individuals, this duct fuses with the common bile duct from the liver and gall bladder before entering the duodenum via the hepatopancreatic ampulla (ampulla of Vater), a dilated common duct. This ampulla opens on the major duodenal papilla, an elevation of the duodenal mucosa, which is situated approximately 4 inches (10 cm) inferior to the pyloric sphincter of the stomach. The smooth muscle hepatopancreatic sphincter controls the flow of pancreatic juice and bile into the small intestine. The second large pancreatic duct, the accessory duct (duct of Santorini) runs from the pancreas directly into the duodenum, approximately 1 inch (2.5 cm) above the hepatopancreatic ampulla.

did I get this

## Pancreatic Islets

In the pancreas, small clusters of glandular epithelial (secretory) cells surround the ducts. The exocrine structures of the pancreas contains 99 percent of the clusters that are called acini (singular - acinus). Cells of the acini secrete pancreatic juice. The endocrine part of the pancreas is made up of the remaining 1 percent of clusters, which are called pancreatic islets (islets of Langerhans). These cells produce the hormones pancreatic polypeptide, insulin, glucagon, and somatostatin. Insulin and glucagon are important in carbohydrate metabolism.

did I get this

## Panreatic Acini and Exocrine Digestive Function

Regulation of pancreatic secretion is the job of both hormones and the parasympathetic nervous system. The hormone secretin, whose secretion is stimulated by the presence of HCl in the intestine, provokes cells of the pancreatic duct to release bicarbonate-rich pancreatic juice. The presence of fats (and some proteins) in the intestine stimulates the secretion of the hormone cholecystokinin (CCK), which then stimulates the release enzyme-rich pancreatic juice and enhances the activity of secretin. As a result, much more bicarbonate-rich juice is released in the presence of both hormones. Parasympathetic regulation occurs mainly during the cephalic and gastric phases of gastric secretion, when vagal stimulation prompts the secretion of pancreatic juice.

did I get this
did I get this

The liver is the largest gland in the body, as well as one of the most important organs. It plays a number of major roles in metabolism and regulation. In an adult, the reddish-brown liver weighs about 3 pounds (1.4 kg) This wedge-shaped organ lies inferior to the diaphragm in the right upper quadrant of the abdominal cavity. The liver is almost completely surrounded by the rib cage, which offers it some protection.

## The Liver’s Anatomical Structures

The liver has different levels of structure and function, and different models have been used to describe the organizational and functional relationships between hepatocytes, bile canaliculi, and hepatic sinusoids. The hepatic lobule was considered the functional unit of the liver in years past. In this model, each hexagonal (six-sided) hepatic lobule has a central vein. Radiating from this vein are rows of hepatocytes and hepatic sinusoids.