Chapter 13 - Muscle Physiology

Skeletal Muscle Structure
   Skeletal muscles generally are connected to the bones of the skeleton by tendons. The part of the muscle generating the force is the body. The body contains bundles (fascicles) of muscle cells. Muscle cells are called muscle fibers and are multinucleate. The plasma membrane is called the sarcolemma.
   The contractile component of muscle cells is contained within rodlike elements called myofibrils. Myofibrils have overlapping thick and thin filaments myosin and actin. The smooth endoplasmic reticulum surrounding the myofibrils is called sarcoplasmic reticulum which is closely associated with inward extensions of the sarcolemma called transverse tubules.
   Skeletal muscle is striated muscle due to the orderly arrangement of thick and thin filaments that run parallel to the long axis of the fiber. Myofibrils are also composed of repeating units called sarcomeres. Each sarcomere is bordered by Z lines that anchor the thin filaments. M lines are in the center of the sarcomeres.
   The sarcomere is banded with the following:
A band - appears dArk and is the length of the thick filaments
H zone - light region in the center of the A band
I band - lIght band where only thin filaments are located
   Actin (thin) and myosin (thick) filaments are attached by cross bridges. Thin filaments are composed of globular actin linked to form helical strands. Two regulatory proteins are associated with actin. Tropomyosin extends over and covers binding sites on actin subunits. Troponin, a complex of three proteins, uncovers binding sites when bound to calcium (Fig. 13.4).
   Each myosin molecule is composed of two parts (dimer) each part consisting of a tail twisted around the other and a head (Fig. 13.5a). A thick filament consists of pairs of myosin molecules with each pair attached by the ends of their tails. These pairs of myosin molecules are bundled together so that their heads protrude in a helical pattern at either end with a bare zone in the center. The head of the myosin molecule has a site that binds to actin to form crossbridges, and an ATPase site that hydrolyzes ATP.
   Extending along the length of each thick filament from the M link to each Z line is an elastic protein called titin. Titin gives the sarcomere elasticity so that when it is stretched it returns to its original position when it is relaxed. Titin also anchors the thick filaments in the proper position (Fig. 13.5d). .
Mechanism of Force Generation
   Sliding-filament model
     This model explains muscle contraction by the sliding of thick and thin filaments over one another. This model best explains the changes that occur in the bands and the zones when a muscle contracts (Fig. 13.6).
   Cross Bridge Cycle (Fig. 13.7)
1. Binding of myosin to actin
   The myosin head is in its high-energy conformation. In this form the myosin head is bound to ADP and Pi  and binds to an actin subunit in the adjacent thin filament. 
2. Power stroke
   The binding of the myosin head to actin causes the release of ADP and Pi. During this release the energy contained in the high-energy form is released as the myosin head pivots toward the middle of the sarcomere and pulls the attached actin filament with it. 
3. Rigor
   The myosin head in its low-energy form and the actin subunit remain bound to one another until the myosin head binds ATP. 
4. Unbinding of myosin and actin
   After ATP binds to the myosin head a conformational change occurs that causes the myosin head to detach from actin. 
5. Cocking of the myosin head
   The ATP is soon hydrolyzed by the ATPase associated with the myosin head and the energy that is released forces the myosin head into its high-energy conformation from where the cycle can repeat itself. 
   The smooth contraction of the muscle results from the fact that the crossbridges going through the cycle are in different stages of the cycle. The cross bridges on either side of the M line bend towards one another and towards the middle of the sarcomere causing the actin filaments to slide toward the middle. This results in the sarcomere getting shorter.

 

Excitation-Contraction Coupling
   Excitation-contraction coupling refers to the sequence of events that link the action potential generated in a muscle cell by the motor neuron to contraction.
   Role of Neuromuscular Junction (Fig. 13.8)
     Each muscle fiber is innervated by only one motor neuron. An action potential in the motor neuron causes acetylcholine to be released at the neuromuscular junction. Acetylcholine travels across the synaptic cleft and attaches to receptors in the highly folded plasma membrane of the motor end plate. The end plate potential that results is always followed by an action potential in the muscle cell. The action potential travels along the sarcolemma and travels through the T tubules. The change in potential of the membrane of the T tubule triggers the release of calcium ion from the nearby sarcoplasmic reticulum. Calcium ion initiates the crossbridge cycle.
   Role of Calcium, Troponin and Tropomyosin
     The calcium concentration in the sarcoplasmic reticulum is high due to the presence of Ca++ pumps. Ca++ channels open to allow Ca++ to rush into the cytosol and initiate the crossbridge cycle. Some of the Ca++ channels are voltage-gated in an unusual way. 
     Where T-tubules are in close contact with the sarcoplasmic reticulum, the Ca++ channels are linked to proteins in the membrane of the T-tubule. The Ca++ channel of the sarcoplasmic reticulum is called a ryanodine receptor (foot structure) and the protein in the T-tubule is called a dihydropyridine receptor (DHP receptor). A depolarization in the membrane of the T- tubule causes the DHP receptor to open the Ca++ channel of the ryanodine receptor. The released Ca++ then act as ligands when they bind to ligand-gated Ca++ channels also located in the sarcoplasmic reticulum, releasing more Ca++ (Fig. 13.10).
     When cytosolic calcium increases it binds to the troponin complex which undergoes a change in shape that causes tropomyosin to shift and expose actin binding sites. Myosin binds to the active sites on actin and enters the crossbridge cycle (Fig. 13.9).
   Muscle Cell Metabolism
     When the muscle is stimulated to contract the supply of ATP in the muscle may become rapidly depleted under high exertion. The muscle cell gears up its ATP production to meet the demand but for a few seconds energy is supplied by the creatine/creatine phosphate system. Creatine phosphate in the resting cell can produce ATP by the reaction
creatine phosphate + ADP --->

creatine

+ ATP
<---
The reaction is catalyzed by creatine kinase. There is enough creatine phosphate in the cell to supply four to five times the quantity of preformed ATP.
   Continuous muscle contraction at moderate rates is sustained by the ATP produced by oxidative phosphorylation. After glycogen reserves are used up (first few seconds) glucose and fatty acids are supplied by the blood stream. After 30 minutes fatty acids become the dominant energy source.
   During heavy exercise ATP is produced by glycolysis at a rate that pyruvate builds up too rapidly to undergo oxidative phosphorylation. Excess pyruvate is converted to lactate acid. The build-up of lactic acid is believed to be responsible for the burning sensation experienced in the muscle.

 

Mechanisms of Skeletal Muscle Contraction
   Muscle contraction is based on a twitch of the muscle fiber which is like an action potential in being an all or nothing event. A twitch  is the mechanical response of an individual motor unit to a single action potential. The motor unit consists of a motor neuron and all the muscle fibers it innervates. 
   Phases of the Twitch
     When a stimulus is applied and a fiber contracts the twitch can be divided into phases (Fig. 13.12)
1. Latent period is the delay of a few milliseconds between an action potential and the start of a contraction and reflects the time for excitation-contraction coupling.
2. Contraction phase starts at the end of the latent period and ends when the muscle tension peaks (tension = force expressed in grams). During this time cytosolic calcium levels are increasing as released calcium exceeds uptake. 
3. Relaxation phase is the time between peak tension and the end of the contraction when the tension returns to zero. During this time cytosolic calcium is decreasing as reuptake exceeds release. 
     One feature of a muscle twitch is its reproducibility. Repetitive stimulation produces twitches of the same magnitude and shape. This results from its all or nothing character. Although muscle twitches are reproducible twitches may vary among muscles and muscle fibers. This is due to differences in the size of the muscle fiber and differences in the speed of contraction among fibers. 
Isometric Twitch
   When the load (force opposing contraction) is greater than the force of contraction of the muscle the muscle creates tension when it contracts but does not shorten. This is an isometric (iso- same; metric- length) twitch. An isometric twitch is measured by keeping the muscle immobile while stimulating it and measuring the tension that develops during contraction. The rise and fall of tension traces a bell-shaped curve.
Isotonic Twitch
   When the force of contraction of the muscle is at least equal to the load so that the muscle shortens, the muscle is said to contract isotonically.  An isotonic twitch is measured by attaching the muscle to a moveable load (Fig. 13.14). The tension curve for an isotonic twitch shows a plateau during which the force or tension is constant (iso-same; tonic- tension). 
   The tension curve resulting from an isotonic twitch will look different depending upon the load placed on the muscle (Fig. 13.14). The greater the load the higher the plateau and the greater the time lag between stimuli and the start of muscle shortening. When the load exceeds the amount of force the muscle can generate, an isometric twitch results which is always of the same size and shape. 
   During an isometric contraction the contractile component (cc) of the muscle, that is the sarcomeres, shorten. However, the overall length of the fibers does not change. This is because of the parts of the muscle that do not generate force but passively transfer the force of contraction to the ends of the muscle stretch. This is the part of the muscle called the series elastic component. 
   The laboratory description of an isotonic contraction is an oversimplification of what actually happens in your body. As you move the load your muscles are constantly changing depending upon the position of your bones and your central nervous system adjusts the tension generated to ensure that the muscles generate the appropriate force. 
   
Factors Affecting the Force Generation of Individual Muscle Fibers
1. Frequency of Stimulation
   When a muscle is stimulated at a frequency so that twitches follow one another closely, the peak in tension rises in a step-wise fashion. This phenomenon is called treppe (Fig. 13.15). Treppe may occur because Ca++ released from previous twitches exceeds Ca++ reuptake and this results in an increase in Ca++ concentration. This in turn increases the number of crossbridges that form in the following contractions.
   Because a muscle twitch is fairly slow compared to an action potential (Fig. 13.16) many action potentials can arrive before a single twitch is completed. This causes the twitches to bunch up and results in the generation of a force that is greater than a single twitch. This process is called summation (Fig. 13.17).
   When the frequency of stimulation is so high that Ca++ levels rise to peak levels, summation results in the level of tension reaching a plateau called tetanus. When the frequency of stimuli is high enough to cause tetanus but tension oscillates around an average level, the tetanus is called incomplete or unfused. At greater frequencies of stimulus, levels of Ca++ peak and cause a maximum number of crossbridges to cycle. At this point the tension plateau smoothes out and tetanus is called complete or fused (Fig. 13.17).
    When the muscle is at maximum sustained tension it is said to have reached maximum tetanic tension.
2. Fiber Diameter
   Each muscle has a force generating capacity reflected by the maximum tetanic tension is can generate in an isometric twitch. The number of cross bridges in each sarcomere and the geometrical arrangement of the sarcomeres affect the force generating capacity. Also the greater the number of sarcomeres arranged in parallel, the greater the force generating capacity. The number of sarcomeres arranged in parallel correlates with a fiber's diameter. The greater the cross-sectional area of a fiber, the more force it can generate.
3. Changes in Fiber Length
   For each fiber the maximum force generating capacity occurs over a certain range of lengths. The length-tension curve shown in figure 13.18 illustrates this.
   The sliding-filament model and the cross bridge cycle explains this curve. When the muscle is at the optimum length the number of active cross bridges is the greatest. When the muscle is stretched beyond this length the number of active cross bridges decreases because the overlap between the actin and myosin fibers decrease. As the muscle becomes shorter than the optimum length the thin filaments at opposite ends of the sarcomere first begin to overlap one another and interfere with there movement. This results in a slow decrease in tension as the sarcomeres get shorter. Then as the sarcomeres get shorter the thick filaments come into contact with the Z lines and the decrease in tension with decreasing length becomes even steeper.
   
Regulation of Force Generated by Whole Muscles
   The force of muscle contraction can be increased by increasing the frequency of action potentials to an individual fiber. This force ranges from the force generated by a single twitch to the force generated by maximum tetanic tension. This range in tension, or force, generated by a fiber only accounts for a fraction of the whole range of force that a whole muscle can generate. The whole muscle can generate greater force by increasing the number of individual fibers that contract in a process called recruitment.  
Recruitment
   The nervous system exerts most of its control over muscle force by varying the number of active motor units. Recruitment is the term used to describe an increase in active motor units. Motor units themselves vary in the number of fibers they stimulate (Fig. 13.19) and in the size of the fibers within each unit.
Size Principle
   According to the size principle when a muscle is called upon to generate small forces only smaller motor units are stimulated. When larger forces are needed larger motor units are recruited. This enables fine movements to be controlled by the smaller increments of force generated by the smaller motor units. When greater force is required, the larger increments come from the larger motor units. 
    The gradual recruitment of ever larger motor units is also a reflection of the fact that larger motor units have larger motor neurons which require more stimulation to fire. This is illustrated in Fig. 13.20. As the action potential frequency in the controlling upper motor neuron increases the lower motor neurons become active in order of increasing size. Also, the force of contraction increases as the larger motor units with increasing numbers of fibers are recruited.
    Factors influencing maximum force generated by a muscle is summarized in Fig. 13.21.
Velocity of Shortening
   When a muscle contracts isotonically under increasing loads:
1. The latent period of shortening increases.
2. The duration of shortening decreases.
3. The velocity of shortening decreases (Fig. 13.22).
   When the velocity of shortening is plotted as a function of load, as the load increases the velocity of shortening gradually decreases (Fig. 13.23).
    The velocity of shortening is an important concept because different types of fibers differ in their velocity of shortening. In other words, certain types of muscle fibers can shorten faster than others.
Types of Fibers
   Speed of Contraction
     Under isometric contraction muscles vary in the speed they reach maximum tension (Fig. 13.24). This is because there are fast-twitch and slow-twitch fibers. Certain muscles (e.g. soleus) contain mostly slow twitch fibers and will contract slowly. Some contain predominantly fast-twitch fibers (e.g. extraocular) and contract quickly. Fast-twitch fibers also have higher maximum shortening velocities compared to slow-twitch. 
   The difference between fast-twitch and slow-twitch depends on the type of myosin. Fast myosin hydrolyzes ATP at a faster rate and this leads to more cross bridge cycles per second compared to slow myosin.
   Primary Mode of ATP Production
     Glycolytic fibers have a high cytosolic concentration of glycolytic enzymes and few mitochondria. They produce ATP rapidly by glycolysis but have a lower capacity for producing ATP by oxidative phosphorylation. These fibers are bigger and have fewer capillaries.
     Oxidative fibers are rich in mitochondria and have a high capacity to produce ATP by oxidative phosphorylation. These fibers are smaller and have more capillaries. These fibers also have an oxygen binding protein called myoglobin. This molecule reversibly binds with oxygen like hemoglobin and serves as an oxygen buffer. It supplies oxygen to oxidative fibers when oxygen is temporarily cut off. Myoglobin gives the muscle fibers a reddish-brown color. These fibers are often referred to as red muscle while glycolytic fibers are called white muscle. 
     Glycolytic fibers produce ATP less efficiently by glycolysis but can function with little oxygen. Pyruvate builds up in these fibers and is converted to lactic acid. Oxidative fibers have a greater need for oxygen but are more resistant to fatigue than glycolytic fibers.
Three Types of Skeletal Muscle Fibers
1. Slow oxidative fibers contain slow myosin and produce most of their ATP by oxidative phosphorylation. These fibers also tend to be small in diameter and generate less force.
2. Fast oxidative fibers also have a high oxidative capacity but have fast myosin. In size and force generation these fibers are intermediate.
3. Fast glycolytic fibers contain fast myosin and have a high glycolytic capacity. These fibers tend to be the largest and to generate the most force.
   All muscles have all three types but in different proportions.
Size of Motor Unit and Order of Recruitment
   The three fiber types are segregated into separate motor units. The slow oxidative fibers have smaller fibers and are associated with the smaller motor units that tend to be recruited first for movements requiring a small force. The fast glycolytic fibers have larger fibers and are associated with the larger motor units that tend to be recruited last for movement requiring greater force. The fast oxidative fibers are intermediate between the two.
Resistance to Fatigue
   Muscles differ in their ability to resist fatigue. Fatigue occurs when muscles are stimulated at higher frequencies and when larger forces are generated.
   High Intensity Exercise (e.g. weight lifting, sprinting)
     Fast glycolytic fibers are recruited which tend to build up lactic acid because of low oxidative capacity. Strong contractions constrict blood vessels decreasing oxygen delivery and increase dependence on glycolysis. Lactic acids build up and lowers the pH.
   Low Intensity Exercise (e.g. walking)
     Recruits mostly oxidative fibers that produce little lactic acid. Fatigue develops more slowly and is probably due to depletion of energy reserves.
   Very High Intensity Exercise
     May induce neuromuscular fatigue due to a depletion of acetylcholine at synaptic terminals.
   Complex psychological factors are also involved with fatigue.
Long Term Responses of Muscle to Exercise
   Aerobic exercise (low intensity; long duration) converts some fast glycolytic fibers to fast oxidative fibers. This is associated with an increase in the number of mitochondria, capillaries and a decrease in fiber diameter. High intensity exercise (e.g. weight lifting) converts a portion of the fast oxidative fibers into fast glycolytic fibers. There is a decrease in mitochondria, an increase in glycolytic enzymes and an increase in fiber diameter.
   Muscle growth is due to an increase in fiber diameter due to an increase in the myofibrils in the muscle fiber.

 

Smooth Muscle
   Smooth muscle has thick and thin filaments but they are not arranged in myofibrils. The filaments are arranged in parallel but bundles of them run obliquely in various directions (Fig. 13.28). Dense bodies connect these groups of filaments and connect them to the cell's exterior.
   Excitation-Contraction Coupling
     Smooth muscles contract when voltage-gated calcium channels cause calcium to enter the cytosol from sarcoplasmic reticulum and from outside the cell. Calcium binds reversibly with calmodulin and the calcium-calmodulin complex activates and enzyme myosin kinase. This enzyme catalyzes the phosphorylation of myosin crossbridges and starts crossbridge cycle activity. The activity of another enzyme phosphatase removes phosphate groups from myosin and inactivates myosin.
     In comparison to skeletal muscle, smooth muscle contraction takes longer to initiate and terminate.
   Neural Regulation of Contraction
     Smooth muscles are innervated by autonomic neurons. The neurons can be sympathetic, parasympathetic or both. Autonomic neurons may excite or inhibit smooth muscle cells. Sympathetic and parasympathetic neurons affect smooth muscle in opposite ways. The smooth muscle may also relax or contract in response to the same type of autonomic neuron depending upon differences in neurotransmitter receptors in different locations.
     Autonomic neurons do not form synapses with specific cells but with groups of cells. Neurotransmitter is released at varicosities (swellings) found along the length of the axon. This causes a neighboring group of cells to contract together. Smooth muscle cells contract in groups also because of gap junctions between cells that allow electrical signals to spread from one cell to another.
     Smooth muscle cells may respond to an action potential with a slow-twitch-like contraction. But most smooth muscle cells respond to neural stimulation in a graded fashion with either increasing or decreasing tension depending upon whether the neural stimulation is excitatory or inhibitory.
     Some smooth muscles display a resting degree of tension or tone even in the absence of neural stimulation. Smooth muscle may also respond to the presence of hormones and mechanical stretch.
Organization and Innervation of Smooth Muscle Tissue
   Multi-Unit Smooth Muscle
     In this organization the smooth muscle cells are mostly separate and richly supplied with neurons. These are found in places where fine control of contraction is needed such as respiratory airways and large arteries.
   Single-Unit Smooth Muscle
     In this organization the smooth muscle cells are connected by gap junctions and there are fewer neurons. This organization is present in the wall of the gastrointestinal tract and the uterus.
Pacemaker Activity
   Some smooth muscle cells in single-unit smooth muscle may serve as pacemakers by depolarizing on a regular basis to produce pacemaker potentials. These pacemaker potentials cause smooth muscle cells to contract in unison. Pacemaker potential occur spontaneously but may be regulated by neural input.

 

Cardiac Muscle
   Cardiac muscle has a sarcomere structure and a troponin/tropomyosin system for regulating contractions. Cardiac muscle cells are extensively connected by gap junctions that allow action potentials to spread rapidly. Cardiac action potentials are broad and last for hundreds of milliseconds. This prevents summation and allows cardiac muscle to relax between contractions (Fig. 13.30).
   Some cardiac muscle cells located in the sinoatrial and atrioventricular nodes show pacemaker activity. This enables the heart to beat by itself without neural input. The autonomic nervous system regulates the frequency and force of muscle contraction.