# Structural Biochemistry/Cell Signaling Pathways/Muscular System

THE MUSCULAR SYSTEM

## Fundamental Components of muscles

Muscle cells consist of myofibrils which are in turn made up of repeating subunits called sarcomeres. Sarcomeres each contain two Z-bands which make up the walls of the sarcomere to which the actin molecules are connected. In between each pair of actin, bands is a myosin molecule. When the sarcomere contracts, myosin, and actin pull the two z bands closer together shortening the overall length of the sarcomere. The distance that the sarcomere is capable of contracting is called the I band and is the space in between the z-band walls of the sarcomere, and the start of the myosin molecules.
When muscles are stressed i.e. exercise, the number of sarcomeres and myofibrils in each myocyte are increased, instead of the myocyte numbers themselves. This leads to a stronger contractile strength for each individual myocyte without increasing the overall cell population.

## Muscle Types

There are three main muscle types: cardiac, smooth, and skeletal.
Cardiac: Only found in the heart and works involuntarily throughout the human body. These muscles are controlled by the medulla oblongata, which is located at the lower section of the human brain. The heart cells come in long strips with a single nucleus in each cell. They are located at the walls of the heart. Their main function is to propel blood into circulation. Contraction of the cardiac tissue is caused by an impulse sent from the medulla oblongata to the SA nerve located at the right atrium of the heart.
Smooth: Work involuntarily. Our internal organ muscles are mostly made up of smooth muscles, such as the stomach-hyper link, throat-hyper link, and small intestine-hyper link. Maintains homeostasis in our body. only the heart is not a smooth muscle. Smooth muscles are spherical in shape and contain one nucleus.
Skeletal: Also known as striated muscle tissue. The structure involves a parallel network of fibers of actin and myosin and the formation of actin myosin crossbridges. The movement of skeletal muscle is described by sliding filament theory in which actin filament slide against myosin heads during the process of contraction. Energy is induced from the ATP released by myosin heads when they slide against the actin filaments, changing its conformation from "cocked" to its "resting" state. This process is also known as powerstroke. When calcium level is high in the sarcoplasmic reticulum and ATP is available, contraction of muscles continues. Work voluntarily for our body. They are the muscles that move the bones and show external movement. Skeletal muscles contain multiple nuclei, which account for their large size. Skeletal muscle cells also contain multiple nuclei in order to synthesize actin and myosin efficiently. They measure up to several feet in length.

## Muscle-Bone interaction

Skeletal muscles do not work alone. When muscle is attached to the skeleton, the connection will determine the force, speed, and range of movement, which is produced by contraction of a muscle and modified by attaching the muscle to a lever. A lever is a rigid bar, such as the bone, that moves on a fixed point called fulcrum. Each bone is a lever, and each joint is a fulcrum. The fulcrum helps to support the lever. Levers can change the direction of applied force when body in exercise, the distance and speed of movement affected by the force, and the effective strength of the applied force. Therefore, the movement of the muscle is based upon the type of joint. Joint helps skeleton muscles to expand or contract the muscles.
1. Bone 2. Perimysium 3. Blood vessel 4. Muscle fiber 5. Fascicle 6. Endomysium 7. Epimysium 8. Tendon
http://training.seer.cancer.gov/module_anatomy/images/illu_muscle_structure.jpg

## Myosin-actin interactions underlying muscle fiber contraction

(1) The myosin head is bound to ATP and is in its lower-energy configuration (2) The Myosin head hydrolyzes ATP to ADP and inorganic phosphate and is in its high-energy configuration (3) The myosin head binds to actin, forming a cross-bridge (4) Releasing ADP and an inorganic phosphate, myosin returns to its lower-energy configuration, sliding the thin filament (5) Binding of a new molecule of ATP release the myosin head from actin, and a new cycle begins

## Function of Myosin and the Powerstroke

Important structural domains of myosin include the motor region, the lever, and the tail. Heavy chain subunits form the major structural units of the motor region, lever and tail, with light subunits working to stabilize the major components of the myosin functional unit. Each of the over 35 myosin subclasses has minor structural variations on this theme, but in most cases, the light chains simply serve to stabilize the structure.
As its name suggests, the motor function confers the mobility to the myosin motor domain and is involved in forcibly moving the lever domain. Regions that bind actin are divided by a cleft, that when closed, initiates a strong bond with actin elements. During an active powerstroke, the myosin changes from an up conformation to a down conformation. A central region dubbed the transducer region strained under certain conditions and a relaxation of this strain contributes to the generation of the powerstroke.
The sequence of the powerstroke involves several steps. First, the myosin head binds to the actin filaments, then the conformational shift from up to down is accomplished, then a phosphate group is released, triggering a return to the up conformation. ATP can be hydrolyzed only in the up conformation, a step that leads to lever priming and firing. The conformational shift of the lever that forms the basis of the powerstroke is thought to be the rate-determining step, a process that does not occur when there has been no bind to actin.

## Skeletal Muscle Contraction

(1) Aceylcholine are released at synaptic terminal diffuses across synaptic cleft and binds to receptor proteins (2) Action potential is propagated along plasma membrane and down T tubules (3) Action potential trigger calcium ions to be released from the sarcoplasmic reticulum (4) Calcium ions bind to troponin complex in thin filament (5) Proteins bound along the actin strands shift position (6) Myosin binding site exposed (7) Myosin cross-bridges alternately attach to actin and detach, pulling thin filament toward center of sarcomere; ATP powers sliding of filaments (8) Cytoslic calcium ion is removed by active transport into sarcoplasmic reticulum after action potential ends (9) tropomyosin blockage of myosin-binding sites is restored (10) contraction ends, and muscle fiber relaxes

## How Muscles work

Bones interact with muscles through tendons. Movement happens when muscles contract and pull the attached bones to bend joints. Vertebrates have three kinds of muscles:
Skeletal muscles are also called striated muscles. They are associated with the skeletal system and are primarily involved in voluntary movement. A vertebrate has conscious control over these muscles. Each skeletal muscle cell contains many nuclei. They make up the bulk of muscle in the body and constitute about 40% of total body weight. They are responsible for positioning and moving the skeleton. Skeletal muscles are usually attached to bones by tendons made of collagen. The origin of a muscle is the end of the muscle that is attached closest to the trunk or to the more stationary bone. The insertion of the muscle is the more distal or more mobile attachment.
When the bones attached to a muscle are connected by a flexible joint, contraction of the muscle moves the skeleton. If the centers of the connected bones are brought closer together when the muscle contracts, the muscle is called a flexor, and the movement is called flexion. If the bones move away from each other when the muscle contracts, the muscle is called an extensor, and the movement is called extension. Most joints in the body have both flexor and extensor muscles, because a contracting muscle can pull a bone in one direction but cannot push it back. Flexor-extensor pairs are called antagonistic muscle groups because they exert opposite effects.
Muscles function together as a unit. A skeletal muscle is a collection of muscle cells, or muscle fibers, just as a nerve is a collection of neurons. Each skeletal muscle fiber is a long, cylindrical cell with up to several hundred nuclei on the surface of the fiber. Skeletal muscle fibers are the largest cels in the body, created by the fusion of many individual embryonic muscle cells.
The fibers in a given muscle are arranged with their long axes in parallel, and each skeletal muscle fiber is sheeted in connective tissue. Groups of adjacent fibers are bundled together into units called fascicles. Collagen, elastic fibers, nerves, and blood vessels are found between the fascicles. The entire muscle is enclosed in a connective tissue sheath that is continuous with the connective tissue around the muscle fibers and fascicles and with the tendon holding the muscle to underlying bones.
Smooth muscle is found in the walls of the internal organs. These organs include the stomach, intestines, and urinary bladder. It is an involuntary muscle. Although skeletal muscle has the most muscle mass in the body, cardiac and smooth muscle are more important in the maintenance of homeostasis. Smooth muscle is found predominantly in the walls of hollow organs and tubes, where its constriction changes the shape of the organ. Often smooth muscle generates force to move material through the lumen of the organ. For example, sequential waves of smooth muscle contraction in the intestinal tract move ingested material from the esophagus to the colon.
Smooth muscle is noticeably different from striated muscle in the way it develops tension. In a smooth muscle twitch, contraction and relaxation occur much more slowly than in either skeletal or cardiac muscle. At the same time, smooth muscle uses less energy to generate a given amount of force, and it can maintain its force for long periods. By one estimate, for example, a smooth muscle cell can generate maximum tension with only 25~30 % of its crossbridges active.
In addition, smooth muscle has low oxygen consumption rates yet can sustain contractions for extended periods without fatiguing. This property allows organs such as the bladder to maintain tension despite a continued load. It also allows some smooth muscles to be tonically contracted and maintain tension most of the time. The esophageal and urinary bladder sphincters are examples of tonically contracted muscles whose function is to close off the opening to a hollow organ. These sphincters relax when it is necessary to allow material to enter or leave the organ.
Until recently, smooth muscle had not been studied as extensively as skeletal muscle for many reasons: 1. Smooth muscle has more variety. 2. Smooth muscle anatomy makes functional studies difficult. 3. Smooth muscle contraction is controlled by hormones and paracrines in addition to neurotransmitters. 4. Smooth muscle has variable electrical properties. 5. Multiple pathways influence contraction and relaxation of smooth muscle.
Smooth Muscle vs. Skeletal Muscle Smooth muscles are small, spindle-shaped cells with a single nucleus, in contrast to the large multinucleated fibers of skeletal muscles. In neurally controlled smooth muscle, neurotransmitter is released from autonomic neuron varicosities close to the surface of the muscle fibers. Smooth muscle lacks specialized receptor regions such as the motor end plates found in skeletal muscle synapses. Instead, the neurotransmitter simply diffuses across the cell surface until it finds a receptor.
Most smooth muscle is single-unit smooth muscle (unitary smooth muscle), so called because the individual muscle cells contract as a single unit. Single-unit smooth muscle is also called visceral smooth muscle because it forms the walls of internal organs (viscera), such as blood vessels and the intestinal tract. All the fibers of single-unit smooth muscle are electrically connected to one another, so an action potential in one cell will spread rapidly through gap junctions to make the entire sheet of tissue contract. Because all fibers contract every time, no reserve units are left to be recruited to increase contraction force. Instead, the amount of calcium that enters the cell determines the force of contraction.
Multi-unit smooth muscle consists of cells that are not linked electrically. Consequently, each individual muscle cell must be closely associated with an axon terminal or varicosity and stimulated independently. This arrangement allows fine control of contractions in these muscles through selective activation of individual muscle cells. As in skeletal muscle, increasing the force of contraction requires recruitment of additional fibers.
Multi-unit smooth muscle is found in the iris and ciliary body of the eye, in part of the male reproductive tract, and in the uterus except just prior to labor and delivery. Interestingly, the multi-unit smooth muscle of the uterus changes and becomes single-unit during the final stages of pregnancy. Genes for synthesis of gap junction connexin proteins turn on, apparently under the influence of pregnancy hormones. The addition of gap junctions to the uterine muscle cells synchronizes electrical signals, allowing the uterine muscle to contract more effectively while expelling the baby.
Cardiac muscle makes up the heart. These muscles are also involuntary and can contract without stimulation from the nervous system. Cardiac muscle shares features with both smooth and skeletal muscle. Like skeletal muscle fibers, cardiac muscle fibers are striated and have a sarcomere structure. However, cardiac muscle fibers are shorter than skeletal muscle fibers, may be branched, and have a single nucleus (unlike multinucleate skeletal muscle fibers). As in single-unit smooth muscle, cardiac muscle fibers are electrically linked to one another. The gap junctions are contained in specialized cell junctions known as intercalated disks. Some cardiac muscle, like some smooth muscle, exhibits pacemaker potentials. In addition, cardiac muscle is under sympathetic and parasympathetic control as well as hormonal control.
Muscles can be thought of as participators in the nervous system. Nerves will send messages to muscles through voluntary impulse or involuntary instinct. Muscles take these messages and convert them into movement by either contracting or relaxing.
Biology (Eighth Edition) by Campbell & Reece

## Neuromuscular junction of skeletal muscles

Skeletal muscles have neuromuscular junctions, which is a synapse of an axon terminal of a motorneuron. The NMJ is responsible for the movement of action potentials across the neurons to initiate a physical reaction from the muscles. The process begins with the release of acetylcholine from synaptic vesicles of an alpha motor neuron into the synaptic cleft. Vesicles containing acetylcholine fuse to the cell membrane, and by exocytosis, releases the chemical. Acetylcholine then diffuses throughout the synaptic cleft, and binds to acetylcholine receptors that are located on the motor end plate. These are nicotinic receptors, and are ligand-gated ion channels which means they respond when a ligand binds to it. The binding of the acetylcholine signals the opening of the channels, and sodium ions flow in while potassium ions flow out. This results in a neuron depolarization, which spreads across the muscle fiber's t-tubules. The depolarization causes activates voltage gated calcium channels (dihydropyridine receptors) in the T tubule membrane. Dihydropyridine receptors interact with calcium-release channels (ryanodine receptors) in the sarcoplasmic reticulum. This causes a release of calcium ions from the sarcoplasmic reticulum, which is the holding cell for calcium. The release of calcium results in a muscle contraction when calcium binds to troponin of skeletal muscle. Enzymes called acetylcholinesterase degrade acetylcholine by hydrolysis and the neurotransmitter is diffused away. This causes the ligand gated receptors to close.

## Regulation of Skeletal Muscle Contraction

When signaled to, a synaptic terminal nearby the muscle fiber releases Acetylcholine (ACh) into the synaptic cleft. This neurotransmitter binds to receptor proteins on the muscle fiber’s plasma membrane, creating an action potential. This action potential is sent along the membrane and down through T tubule found on and within the membrane. The action potential triggers the sarcoplasmic reticulum (SR) to release Ca2+ into the cytosol of the muscle. This occurs when the plasma membrane depolarizes and an action potential sweeps along the membrane, the depolarization moves into the T-tubules and activates integral membrane proteins that are confined to T-tubule membranes in skeletal muscle fibers. The activated proteins are called dihydropyridine receptors (DHP receptors), which mechanically interact with particular proteins in the membranes of the sarcoplasmic reticulum. These proteins in the membranes of the ER are called ryanodine receptors.
These ryanodine receptors are Ca2+ channels that when activated by DHP receptors, open and allow Ca2+ to diffuse out of the SR and into the cytoplasm, where it can bind to troponin. Within the myofibril, the calcium ions bind to the troponin complex, causing the tropomyosin, which is covering the myosin binding sites, to shift, and thus exposing the myosin binding sites of the thin filament. With the aid of ATP, the myosin is able to form cross-bridges by binding to the actin. The attachment and detachment from the actin cause the sliding of the filaments, and thus the contraction of the muscle. When the motor input stops, and it is time for the muscle to relax, the filaments slide back to their original positions, with the tropomyosin blocking the myosin binding sites. The calcium ions are pumped back into the SR by transport proteins. The calcium ions accumulate in the SR until it is needed to respond to the next action potential.
Once the Ca2+ is able to bind to the troponin on the muscle fibers, the "sliding filament" theory takes place. This theory describes the mechanism of muscle contraction. In this theory, the myofilaments slide past one another when myosins bind to actins and "row" along the thin filaments (actin). When a myosin is bound to actin, the hinge between the head and the straight rod of the myosin molecule bends, which in turn releases ADP and Pi. As a result of this bending, the myosin molecule pulls itself along the actin, but actins are bound to Z-lines, so when an actin moves along myosins, they pull the Z-lines toward one another, shortening the sacromere, leading to contraction of the entire muscle as a whole. When the muscle is to relax, ATP attaches to the myosin head again, which breaks the thin filament to thick filament bonds. ATP binding is therefore the basis for relaxation of muscles.
The bound ATP is hydrolyzed to ADP and Pi, returning the hinge between the head and the rod of the myosin back to its original conformation, continuing the cycle of muscle contraction and relaxation. At any one time, many myosin heads are attached to each actin filament. The amount of tension that is exerted during a contraction is proportional to the number of connections between actin and myosin heads.
The unitary response of a muscle fiber to stimulation is called a twitch (a brief contraction). A twitch occurs in response to a depolarization of the muscle membrane, either in response to electrical stimulation or as the result of and excitatory post-synaptic potential it the neuromuscular junction. These twitches sum to produce long, strong contractions at their tetanus points. As the frequency of a stimulation increases, the frequency of twitches increases up to a maximum. Each summed twitch increases the magnitude of contraction because the elastic properties of the muscle are not sufficient to allow the muscle to return to resting length in the time between twitches. The maximum contraction in which there is no time for relaxation between stimuli is called tetanus. Therefore, the strength of a whole muscle contraction depends on the number of fibers in a muscle, because more fibers will bring a stronger contraction, the number of neurons that are active, and the frequency of contractions.
Summary of Muscle Contraction Mechanism
When an action potential reaches the neurotransmitter junction, Acetylcholine gets released into the synaptic cleft. This results in the opening of nicotinic acetylcholine receptors and entrance of sodium ions. An action potential is generated in the T-tubule, then calcium is released from sarcoplasmic reticulum. This marks the step where contraction occurs.
Highlights
Calcium is removed by calcium pumps that pump the ion back into the sarcoplasmic reticulum. This is when relaxation occurs. T-tubule contains voltage gated protein channels that open in response to depolarization.
Sarcoplasmic reticulum has several calcium channels which open when there is stimulation by T-tubules. In addition, it contains many calcium pumps that maintain a high concentration of calcium inside the cell so that ions are able to flow out during the process of contraction. The flow of calcium activates troponin, which stimulates a power stroke and results in sarcomere contraction.
There are two types of contractions:
A- Isotonic contraction which occurs when the muscle contraction is equal to the load on muscle. For example, when you lift an object and hold it in place. B- Isometric contraction which occurs when the load on muscle exceeds the force of contraction. For instance, when you try to lift a very heavy object (the muscle contracts at a maximum rate)

## Oxidative and Glycolytic Fibers

Oxidative fibers rely mostly on aerobic respiration. It is made this way to make sure a steady energy supply. It has many mitochondria, a rich blood supply, and a large amount of hemoglobin. Glycolytic fibers uses glycolysis as their primary source of ATP. It has a larger diameter and less myoglobin than oxidative fibers and it fatigue much more readily.

## Fast Twitch and Slow Twitch Fibers

Fast-twitch fibers are used for brief, rapid, powerful contractions. Fast-twitch fibers are made up of white muscles, which depend on anaerobic glycolysis for energy. Although glycolysis is very quick, it is also inefficient at producing ATP. Glycolysis produces lactic acid as a byproduct, which leads to fatigue. The use of glycogen cycle is the reason why fast-twitch muscles tire out quickly. Slow-twitch fibers are used to maintain posture. A slow fiber has less sarcoplasmic reticulum and pumps calcium more slowly than a fast fiber. Since calcium remains in the cytosol longer, a muscle twitch in a slow fiber lasts about five times as long as one in a fast fiber. Slow-twitch fibers are usually found in the red muscles. The red muscles use oxidative phosphorylation to obtain ATP. Oxidative phosphorylation occurs in the red muscles because the process requires a lot of oxygen, and the red muscles contain high amounts of myoglobin. The process is slower than glycolysis, but much more efficient, which is why slow-twitch muscles do not tire easily. Although it is still being debated, scientists believe that individuals are born with a set amount of fast-twitch fibers and slow-twitch fibers. Sprinting everyday will not convert some of the slow-twitch muscle into fast-twitch muscle, and vice versa. Marathon runners become marathon runners because they naturally have more slow-twitch fibers, allowing them to be effective in the sport. Likewise, sprinters are born with more fast-twitch muscles than others. Although this may be true, exercise can make both fast and slow-twitch muscles bigger, leading to better fitness results.

## Reference

<http://cwx.prenhall.com/bookbind/pubbooks/martinidemo/chapter11/medialib/CH11/html/ch11_2_2.html>
<http://library.thinkquest.org/2935/Natures_Best/Nat_Best_Low_Level/Muscular_page.L.html#Muscles_Types-cardiac>
Human Physiology: An integrated approach (Fourth edition) by Dee Unglaub Silverthorn