Physiology_Levy

Physiology_Levy. Fig. 12.14A , the lateral rectus of the eye contracts very quickly in response to an action potential, reaching peak tension within 8 msec, and then relaxes quickly, which results in a short duration of contraction. The soleus muscle of the leg, in contrast, requires 90 msec to reach peak tension in response to an action potential, and then it relaxes slowly. The gastrocnemius muscle requires an intermediate time to reach peak tension (40 msec) because of the presence of both fast-twitch and slow-twitch muscle fibers in this muscle. The difference in speed of contraction between fast-twitch and slow-twitch muscles is correlated with myosin ATPase activity (see Fig. 12.14B ), which in turn reflects the type of myosin present in the muscle fiber (Fig. 12.15 Table 12.1 ). Thus fast-twitch muscle fibers contain myosin isoforms that hydrolyze ATP quickly, whereas slow-twitch muscle fibers contain myosin isoforms that hydrolyze ATP


Physiology_Levy

Physiology_Levy. MHC expression: Type I MHC expression: MHC expression: Function: antigravity, IIa, IIx IIb, IIx weight bearing, and Function: sustained Function: burst •Fig. 12.15. Comparisonofthreebasicmotorunitphenotypesinskeletalmuscleofextremitiesandtrunk.MHC,myosinheavychain.(RedrawnfromBaldwinK,HaddadF,PandorfC,etal.Alterationsinmusclemassandcontractilephenotypeinresponsetounloadingmodels:roleoftranscriptional/pretranslationalmechanisms.Front Physiol. 2013;4:284.) *Human“fastglycolytic”skeletalmusclefiberstypicallyexpressthetypeIIxmyosinisoenzymeinsteadofthetypeIIbmyosinisoenzyme.Incontrast,rodentsexpressonetypeofslow-twitchmusclefiber(typeI)andthreetypesoffast-twitchmusclefibers(expressingtypeIIa,typeIIx,ortypeIIbmyosinisoenzymes);thetypeIIxmusclefibersexpressmetabolicpropertiesintermediatebetweenthoseoftypeIIaandtypeIIbmusclefibers.ThetypeIIxmyosinisoenzymemaybecoexpressedwithtypeIIamyosinisoenzymein“fastoxidative”musclefibers.Intext,thesimpledesignationtype II fiber


Physiology_Levy

Physiology_Levy. II fiber referstofastglycolyticmusclefibers.


Physiology_Levy

Physiology_Levy. slowly. These two types of myosin isoforms have the same basic structure described previously, with two heavy chains and two pairs of light chains, although they differ in amino acid composition. It is very difficult to convert a slow-twitch muscle fiber into a fast-twitch fiber, although it can be accomplished by cross-innervation, which involves surgically interconnecting two motor neurons. As shown in Fig. 12.14B , when the soleus muscle and extensor digitorum longus muscle underwent cross-innervation, so that contraction of the soleus muscle was controlled by the extensor digitorum motor neuron (and vice versa), the speed of the contraction and the myosin ATPase activity of the soleus muscle increased (labeled X-SOL in


Physiology_Levy

Physiology_Levy. Fig. 12.14 ), whereas the extensor digitorum longus exhibited a decrease in shortening velocity and myosin ATPase activity (labeled X-EDL). Thus the motor innervation of the muscle fiber plays an important role in determining which type of myosin isoform is expressed in the muscle fiber. Further study showed that the intracellular Ca concentration in the muscle (secondary to differences in the activity pattern of the motor neuron) was an important determinant of whether the muscle fiber expressed the slow myosin isoform or the fast myosin isoform (see the section The myosin isoforms expressed in skeletal muscle can be distinguished on the basis of myosin heavy chain composition (see Fig. 12.15 Table 12.1 ). Slow-twitch muscle fibers express type I myosin heavy chain, whereas fast-twitch skeletal muscle fibers could contain type IIa, type IIx, or type IIb myosin heavy chains. Some fast-twitch muscle fibers may contain a mixture of type II myosin isoforms.


Physiology_Levy

Physiology_Levy. Slow-twitch skeletal muscles are also characterized by a high oxidative capacity (see Table 12.1 ), which in combination with the low myosin ATPase activity contribute to the fatigue resistance of slow-twitch muscle fibers. The oxidative capacity of the fast-twitch muscle fiber ranges from relatively high (in muscle fibers expressing type IIa myosin heavy chain) to low (in muscle fibers expressing type IIb myosin heavy chains). The low oxidative capacity of fast type IIb muscle fibers, coupled with the high myosin ATPase activity, increases the susceptibility of these muscle fibers to fatigue. Humans, however, rarely express the type IIb myosin heavy chain. Type IIb myosins are expressed in small animals such as rabbit and rats. Motor units are generally composed of only one type of muscle fiber ( Table 12.2


Physiology_Levy

Physiology_Levy. Motor units are generally composed of only one type of muscle fiber ( Table 12.2 Fig. 12.15), unless the muscle fibers are undergoing a transition. Conditions that may trigger a change in the type of myosin expressed in a muscle fiber within a motor unit include chronic conditions such as microgravity (in space flight), denervation, and chronic unloading, which are associated with severe atrophy and promote the gradual transition from the expression of slow muscle myosin (type I) in the fiber to the expression of fast muscle myosin (types IIa and IIx). An important function of slow motor units is in the maintenance of posture (see


Physiology_Levy

Physiology_Levy. An important function of slow motor units is in the maintenance of posture (see Fig. 12.15 ). The low ATPase activity of myosin in slow motor units, coupled with their high oxidative capacity, facilitates the ability of these slow motor units to maintain posture at low energy cost and thus resist fatigue. The smaller diameter of slow muscle fibers, and the higher capillary density in slow muscle, also helps slow muscle resist fatigue. Fast muscle, in contrast, is recruited for activities that require faster movements, more force, or both (see Fig. 12.15 ). Weightlifting, for example, can require a lot of power for short duration. In order to meet the demands for more force, additional motor units are recruited. In comparison with slow motor units, the fast motor units typically contain more muscle fibers (see


Physiology_Levy

Physiology_Levy. Table 12.2 ). Fast muscle fibers also have a larger diameter than do slow muscle fibers. Thus recruitment of fast motor units can help meet the increased demands of burst activities such as weightlifting. The high myosin ATPase activity in fast muscle fibers and the increase in diffusion distance (resulting from the large diameter of the fast muscle fibers), however, increase the susceptibility of fast muscle fibers to fatigue. Additional differences between fast and slow muscles include the following: 1. The motor neuron in slow muscle is more easily excited than that in fast muscle, and so slow muscles are typically recruited first. As stated previously, the high oxidative capacity of slow muscle, coupled with the low myosin ATPase activity, helps reduce the susceptibility to fatigue in slow muscle. 2.


Physiology_Levy

Physiology_Levy. 2. The neuromuscular junction of fast muscle differs from that in slow muscle in terms of acetylcholine vesicle content, the amount of acetylcholine released, the density of nicotinic acetylcholine receptors, the acetylcholine esterase activity, and Na channel density, all of which endow the fast muscle with a higher safety factor for initiation of an action potential. During repetitive stimulation, however, the safety factor in fast muscle drops quickly (faster than that seen in slow muscle). 3.


Physiology_Levy

Physiology_Levy. The SR is more highly developed in fast muscle than in slow muscle, with higher levels of RYR, SERCA, lumenal Ca, and a higher DHPR/RYR ratio, all of which promote the development of a larger, faster intracellular Ca transient in fast muscle, which is important for quick, forceful contraction. In addition to the differences between fast and slow fibers just noted, other muscle proteins are also expressed in a fiber type–specific manner. Such proteins include the three troponin subunits, tropomyosin, and C protein. The differential expression of troponin and tropomyosin isoforms influences the dependency of contraction on Ca++ . Slow fibers begin to develop tension at lower [Ca++] than fast fibers do. This difference in sensitivity to Ca++ is related in part to the fact that the troponin C isoform in slow fibers has only a single low-affinity Ca++-binding site, whereas the troponin C of fast fibers has two low-affinity binding sites. Changes in the dependence of contraction on Ca++ ,


Physiology_Levy

Physiology_Levy. C isoform in slow fibers has only a single low-affinity Ca++-binding site, whereas the troponin C of fast fibers has two low-affinity binding sites. Changes in the dependence of contraction on Ca++ , however, are not restricted to differences in the troponin C isoforms. Differences in troponin T and tropomyosin isoforms are also found. Thus regulation of the dependence of contraction on Ca++ is complex and involves contributions from multiple proteins on the thin filament. Phosphorylation of the regulatory light chain of myosin by Ca++/ calmodulin-dependent myosin light chain kinase, however, can increase Ca++ sensitivity of contraction, particularly in fast muscle fibers (partly because of the reported higher activity of myosin light chain kinase in fast muscle fibers).


Physiology_Levy

Physiology_Levy. •Fig. 12.16. Increasing the Frequency of Electrical Stimulation of Skeletal Muscle Results in an Increase in the Force of Contraction. ThisisattributabletoprolongationoftheintracellularCa++transientandistermedtetany. IncompletetetanyresultsfrominitiationofanotherintracellularCa++transientbeforethemusclehascompletelyrelaxed.Thusthereisasummationoftwitchforces.Seetextfordetails.Action potential Time 1 sec Myoplasmic Ca++ Incomplete tetanus Twitch force Tetanus force Modulation of the Force of Contraction


Physiology_Levy

Physiology_Levy. Modulation of the Force of Contraction A simple means of increasing the force of contraction of a muscle is to recruit more muscle fibers. Because all the muscle fibers within a motor unit are activated simultaneously, a muscle recruits more muscle fibers by recruiting more motor units. As already noted, muscle fibers can be classified as fast-twitch or slow-twitch. The type of fiber is determined by its innervation. Because all fibers in a motor unit are innervated by a single α motor neuron, all fibers within a motor unit are of the same type. Slow-twitch motor units tend to be small (100 to 500 muscle fibers) and are innervated by an α motor neuron that is easily excited (see


Physiology_Levy

Physiology_Levy. Table 12.2 ). Fast-twitch motor units, in contrast, tend to be large (containing 1000 to 2000 muscle fibers) and are innervated by α motor neurons that are more difficult to excite. Thus slow-twitch motor units tend to be recruited first. As more and more force is needed, fast-twitch motor units are recruited. The advantage of such a recruitment strategy is that the first muscle fibers recruited are those that have high resistance to fatigue. Moreover, the small size of slow-twitch motor units allows fine motor control at low levels of force. The process of increasing the force of contraction by recruiting additional motor units is termed spatial summation because forces from muscle fibers are being “summed” within a larger area of the muscle. This is in contrast to temporal summation, which is discussed later. Action potentials in skeletal muscles are quite uniform and lead to the release of a reproducible pulse of Ca++ from the SR (


Physiology_Levy

Physiology_Levy. Action potentials in skeletal muscles are quite uniform and lead to the release of a reproducible pulse of Ca++ from the SR ( Fig. 12.16 ). A single action potential releases sufficient Ca++ to cause a twitch contraction. However, the duration of this contraction is very short because Ca++ is very rapidly pumped back into the SR. If the muscle is stimulated a second time before it is fully relaxed, the force of contraction increases (see Fig. 12.16 , middle). Thus twitch forces are amplified as stimulus frequency increases. At a high level of stimulation, intracellular [Ca++] increases and is maintained throughout the period of stimulation (see Fig. 12.16 , right), and the amount of force developed greatly exceeds that observed during a twitch. The response is termed tetany. At intermediate stimulus frequency, intracellular [Ca++] returns to baseline just before the next stimulus. However, there is a gradual rise in force (see


Physiology_Levy

Physiology_Levy. Fig. 12.16 , middle). This phenomenon is termed incomplete tetany. In both cases, the increased frequency of stimulation is said to produce a fusion of twitches.


Physiology_Levy

Physiology_Levy. The low force generation during a twitch, in comparison with that during tetany, may be due to the presence of a series elastic component in the muscle. Specifically, when the muscle is stretched a small amount shortly after initiation of the action potential, the muscle generates a twitch force that approximates the maximal tetanic force. This result, coupled with the observation that the size of the intracellular Ca++ transient during a twitch contraction is comparable with that during tetany, suggests that enough Ca++ is released into the myoplasm during a twitch to allow the actin-myosin interactions to produce maximal tension. However, the duration of the intracellular Ca++ transient during a twitch is sufficiently short that the contractile elements may not have enough time to fully stretch the series elastic components in the fiber and muscle. As a result, the measured tension is submaximal.


Physiology_Levy

Physiology_Levy. An increase in the duration of the intracellular Ca++ transient, as occurs with tetany, provides the muscle with sufficient time to completely stretch the series elastic component and thereby results in expression of the full contractile force of the actin-myosin interactions (i.e., maximal tension). Partial stretching of the series elastic component (as might be expected during a single twitch), followed •Fig. 12.17. Slow-Twitch Muscles Exhibit Tetany at a Lower Stimulation Frequency Than Do Fast-Twitch Muscles. A, Fast-twitchmotorunitinthegastrocnemiusmuscle.B, Slow-twitchmotorunitinthegastrocnemiusmuscle.C, Slow-twitchmuscleunitinthesoleusmuscle.Themotorunitswerestimulatedatthefrequenciesindicatedontheleft.Thecalibrationbarfortension(ingrams)generatedduringconcentrationisindicatedbythevertical brackets underthecurves.Notethelargeforcegeneratedbythefast-twitchmotorunit(A).(FromMontcastleV[ed].Medical Physiology. 12thed.St.Louis:Mosby:1974.) by restimulation of the muscle before


Physiology_Levy

Physiology_Levy. brackets underthecurves.Notethelargeforcegeneratedbythefast-twitchmotorunit(A).(FromMontcastleV[ed].Medical Physiology. 12thed.St.Louis:Mosby:1974.) by restimulation of the muscle before complete relaxation, however, would be expected to yield an intermediate level of tension, similar to that seen with incomplete tetany. The location of the series elastic component in skeletal muscle is not known. One potential source is the myosin molecule itself. In addition, it is likely that there are other sources of the series elastic component, such as the connective tissue and titin.


Physiology_Levy

Physiology_Levy. The stimulus frequency needed to produce tetany depends on whether the motor unit consists of slow or fast fibers ( Fig. 12.17 ). Slow fibers can be tetanized at lower frequencies than can fast fibers. The ability of slow-twitch muscle to tetanize at lower stimulation frequencies reflects, at least in part, the longer duration of contraction seen in slow fibers. As also illustrated in Fig. 12.17 , fast fibers develop a larger maximal force than slow fibers do because fast fibers are larger in diameter than slow fibers and there are more fibers in fast motor units than in slow motor units. Modulation of Force by Reflex Arcs


Physiology_Levy

Physiology_Levy. Skeletal muscles contain sensory fibers (muscle spindles; also called intrafusal fibers) that run parallel to the skeletal muscle fibers. The muscle spindles assess the degree of stretch of the muscle, as well as the speed of contraction. In the stretch reflex, rapid stretching of the muscle (e.g., tapping the tendon) lengthens the spindles in the muscle and results in an increased frequency of action potentials in the afferent sensory neurons of the spindle. These afferent fibers in turn excite the α motor neurons in the spinal cord that innervate the stretched muscle. The result is that the reflex arc is a stretch-induced contraction of the muscle that does not require input from high centers in the brain. As the muscle shortens, efferent output is also sent to the spindle, which thereby takes the slack out of the spindle and ensures its ability to respond to stretch at all muscle lengths. By their action, muscle spindles provide feedback to the muscle in terms of its length and


Physiology_Levy

Physiology_Levy. takes the slack out of the spindle and ensures its ability to respond to stretch at all muscle lengths. By their action, muscle spindles provide feedback to the muscle in terms of its length and thus help maintain a joint at a given angle.


Physiology_Levy

Physiology_Levy. Golgi tendon organs are located in the tendons of muscles and provide feedback regarding contraction of the muscle. The main component of the tendon organ is an elongated fascicle of collagen bundles that is in series with the muscle fibers and can respond to contractions of individual muscle fibers. A given tendon organ may attach to several fast-twitch or slow-twitch muscle fibers (or both) and sends impulses through type Ib afferent nerve fibers in response to muscle contraction. The type Ib afferent impulses enter the spinal cord, which can promote inhibition of α motor neurons to the contracting (and synergistic) muscles while promoting excitation of α motor neurons to antagonistic muscles. The inhibitory actions are mediated through interneurons in the cord that release an inhibitory transmitter to the α motor neuron and create an inhibitory postsynaptic potential. The type Ib afferent impulses are also sent to higher centers of the brain (including the motor cortex and


Physiology_Levy

Physiology_Levy. transmitter to the α motor neuron and create an inhibitory postsynaptic potential. The type Ib afferent impulses are also sent to higher centers of the brain (including the motor cortex and cerebellum). It is hypothesized that feedback from the tendon organs in response to muscle contraction may smooth the progression of muscle contraction by limiting the recruitment of additional motor units. Of interest is that the response of the tendon organ is not linearly related to force; rather, it drops off at higher levels of force, which may facilitate the recruitment of motor units at higher levels of effort.


Physiology_Levy

Physiology_Levy. The skeletal system supports the body in an erect posture with the expenditure of relatively little energy. Nonetheless, even at rest, muscles normally exhibit some level of contractile activity. Isolated (i.e., denervated) unstimulated muscles are in a relaxed state and are said to be flaccid. However, relaxed muscles in the body are comparatively firm. This firmness, or tone, is caused by low levels of contractile activity in some of the motor units and is driven by reflex arcs from the muscle spindles. Interruption of the reflex arc by sectioning of the sensory afferent fibers abolishes this resting muscle tone. The tone in skeletal muscle is distinct from the “tone” in smooth muscle (see


Physiology_Levy

Physiology_Levy. Muscle cells convert chemical energy to mechanical energy. ATP is the energy source used for this conversion. The ATP pool in skeletal muscle is small and capable of supporting only a few contractions if not replenished. This pool, however, is continually replenished during contraction, as described later, so that even when the muscle fatigues, ATP stores are only modestly decreased. Muscle cells contain creatine phosphate, which is used to convert ADP to ATP and thus replenish the ATP store during muscle contraction. The creatine phosphate store represents the immediate high-energy source for replenishing the ATP supply in skeletal muscle, especially during intense exercise. The enzyme creatine phosphokinase catalyzes the reaction:


Physiology_Levy

Physiology_Levy. Although much of the creatine phosphokinase is present in the myoplasm, a small amount is located in the thick filament (near the M line). The creatine phosphokinase in the thick filament may participate in the rapid resynthesis of ATP near the myosin heads during muscle contraction. The phosphate store created, however, is only about five times the size of the ATP store and thus cannot support prolonged periods of contraction (less than a minute of maximal muscle activity). Skeletal muscle fatigue during intense exercise is associated with depletion of the creatine phosphate store, although as described subsequently, this does not necessarily imply that the fatigue is caused by depletion of the creatine phosphate store. Because the creatine phosphokinase–catalyzed reaction is reversible, the muscle cell replenishes the creatine phosphate pool during recovery from fatigue by using ATP synthesized through oxidative phosphorylation.


Physiology_Levy

Physiology_Levy. Muscle cells contain glycogen, which can be metabolized during muscle contraction to provide glucose for oxidative phosphorylation and glycolysis, both of which generate ATP to replenish the ATP store. Muscle cells can also take up glucose from blood, a process that is stimulated by insulin (see


Physiology_Levy

Physiology_Levy. Chapter 39). The cytosolic enzyme phosphory lase releases glucose 1-phosphate residues from glycogen, which are then metabolized by a combination of glycolysis (in the cytosol) and oxidative phosphorylation (in the mitochondria) to yield the equivalent of 37 mol of ATP per mole of glucose 1-phosphate. Blood glucose yields 36 mol of ATP per mole of glucose because 1 ATP is used to phosphorylate glucose at the start of glycolysis. These ATP yields, however, are dependent on an adequate oxygen supply. Under anaerobic conditions, in contrast, metabolism of glycogen and glucose yields only 3 and 2 mol of ATP per mole of glucose 1-phosphate and glucose, respectively (along with 2 mol of lactate). As discussed later, muscle fatigue during prolonged exercise is associated with depletion of glycogen stores in the muscle.


Physiology_Levy

Physiology_Levy. Fatty acids represent an important source of energy for muscle cells during prolonged exercise. Muscle cells contain fatty acids but can also take up fatty acids from blood. In addition, muscle cells can store triglycerides, which can be hydrolyzed when needed to produce fatty acids. The fatty acids are subjected to β oxidation within the mitochondria. For fatty acids to enter the mitochondria, however, they are converted to acylcarnitine in the cytosol and then transported into the mitochondria, where they are converted to acyl coenzyme A (CoA). Within the mitochondria, the acyl CoA is subjected to β oxidation and yields acetyl CoA, which then enters the citric acid cycle and ultimately produces ATP.


Physiology_Levy

Physiology_Levy. If the energy demands of exercise cannot be met by oxidative phosphorylation, an oxygen debt is incurred. After completion of exercise, respiration remains above the resting level in order to “repay” this oxygen debt. The extra oxygen consumption during this recovery phase is used to restore metabolite levels (such as creatine phosphate and ATP) and to metabolize the lactate generated by glycolysis. The increased cardiac and respiratory work during recovery also contributes to the increased oxygen consumption seen at this time and explains why more oxygen has to be “repaid” than was “borrowed.” Some oxygen debt occurs even with low levels of exercise because slow oxidative motor units consume considerable ATP, derived from creatine phosphate or glycolysis, before oxidative metabolism can increase ATP production to meet steady-state requirements. The oxygen debt is much greater with strenuous exercise, when fast glycolytic motor units are used (Fig. 12.18 ). The oxygen debt is


Physiology_Levy

Physiology_Levy. can increase ATP production to meet steady-state requirements. The oxygen debt is much greater with strenuous exercise, when fast glycolytic motor units are used (Fig. 12.18 ). The oxygen debt is approximately equal to the energy consumed during exercise minus that supplied by oxidative metabolism (i.e., the darkand light-colored areas in


Physiology_Levy

Physiology_Levy. Fig. 12.18 are approximately equal). As indicated earlier, the additional oxygen used during recovery from exercise represents the energy requirements for restoring normal cellular metabolite levels. The ability of muscle to meet energy needs is a major determinant of the duration of the exercise. However, fatigue is not the result of depletion of energy stores. Instead, metabolic byproducts seem to be important factors in the onset of fatigue. Fatigue may potentially occur at any of the points involved in muscle contraction, from the brain to the muscle cells, as well as in the cardiovascular and respiratory systems that maintain energy supplies (i.e., fatty acids and glucose) and oxygen delivery to the exercising muscle. Several factors have been implicated in muscle fatigue. During brief periods of tetany, the oxygen supply to the muscle is adequate as long as the circulation is intact. However, the force/stress generated during these brief


Physiology_Levy

Physiology_Levy. Rate of energy expenditure •Fig. 12.18. An Oxygen Debt Is Incurred by the Exercising of Muscle When the Rate of Energy Expenditure Exceeds the Rate of Energy Production by Oxidative Metabolism. Upper panel, Energyexpenditureduringstrenuousexercise.Lower panel, Energyexpenditureduringenduranceexercise.Seetextfordetails. tetanic periods decays rapidly to a level that can be maintained for long periods (


Physiology_Levy

Physiology_Levy. tetanic periods decays rapidly to a level that can be maintained for long periods ( Fig. 12.19 ). This decay represents the rapid and almost total failure of the fast motor units. The decline in force/stress is paralleled by depletion of glycogen and creatine phosphate stores and the accumulation of lactic acid. Of importance is that the decline in force/ stress occurs when the ATP pool is not greatly reduced, so that the muscle fibers do not go into rigor. In contrast, the slow motor units are able to meet the energy demands of fibers under this condition, and they do not exhibit significant fatigue, even after many hours. Evidently, some factor associated with energy metabolism can inhibit contraction (e.g., in the fast fibers), but this factor has not been clearly identified.


Physiology_Levy

Physiology_Levy. During intense exercise, accumulation of inorganic phosphate (Pi) and lactic acid in the myoplasm accounts for muscle fatigue. The accumulation of lactic acid, to levels as high as 15 to 26 mmol/L, decreases myoplasmic pH (from ≈7 to ≈6.2) and inhibits actin-myosin interactions. This decrease in pH reduces the sensitivity of the actin-myosin interaction to Ca++ by altering Ca++ binding to troponin C and by decreasing the maximum number of actin-myosin interactions. Pi has also been implicated as an important factor in the development of fatigue during intense exercise, inasmuch as phosphate concentrations can increase from approximately 2 mmol/L at rest to nearly 40 mmol/L in working muscle. Such an elevation in [Pi] can reduce tension by at least the following three different mechanisms: •Fig. 12.19.


Physiology_Levy

Physiology_Levy. can increase from approximately 2 mmol/L at rest to nearly 40 mmol/L in working muscle. Such an elevation in [Pi] can reduce tension by at least the following three different mechanisms: •Fig. 12.19. Aseriesofbrieftetanicstimulationsofskeletalmuscleresultinarapiddecreaseinforce(tetanicstress,exemplifiedbythe“Wholemuscle”lineinplot)thatisattributabletofatigueoffast-twitch(typeII)motorunitsinthemuscle.Undertheseconditions,however,slow-twitch(typeI)motorunitsareresistanttofatigue.3 2 1 0 10 2 3 4 5 10 20 30 Minutes Tetanus stress (kg/cm2 ) Type 1 motor units Whole muscle Type II motor units (1) inhibition of Ca++ release from the SR, (2) decrease in the sensitivity of contraction to Ca++ , and (3) alteration in actin-myosin binding. A number of other factors, including glycogen depletion from a specialized compartment, a localized increase in [ADP], extracellular elevation of [K+], and generation of oxygen free radicals, have also been implicated in various forms of exercise-induced


Physiology_Levy

Physiology_Levy. from a specialized compartment, a localized increase in [ADP], extracellular elevation of [K+], and generation of oxygen free radicals, have also been implicated in various forms of exercise-induced muscle fatigue. Finally, the central nervous system contributes to fatigue, especially in how fatigue is perceived by the individual.


Physiology_Levy

Physiology_Levy. Regardless of whether the muscle is fatigued as a consequence of high-intensity exercise or prolonged exercise, the myoplasmic ATP level does not decrease substantially. In view of the reliance of all cells on the availability of ATP to maintain viability, fatigue has been described as a protective mechanism to minimize the risk of muscle cell injury or death. Consequently, it is likely that skeletal muscle cells have developed redundant systems to ensure that ATP levels do not drop to dangerously low levels and hence risk the viability of the cell.


Physiology_Levy

Physiology_Levy. Most persons tire and cease exercise long before the motor unit fatigues. General physical fatigue may be defined as a homeostatic disturbance produced by work. The basis for the perceived discomfort (or even pain) probably involves many factors. These factors may include a decrease in plasma glucose levels and accumulation of metabolites. Motor system function in the central nervous system is not impaired. Highly motivated and trained athletes can withstand the discomfort of fatigue and may exercise to the point at which some motor unit fatigue occurs. Part of the enhanced performance observed after training involves motivational factors.


Physiology_Levy

Physiology_Levy. Skeletal muscle fibers differentiate before they are innervated, and some neuromuscular junctions are formed well after birth. Before innervation, the muscle fibers physiologically resemble slow (type I) cells. Acetylcholine receptors are distributed throughout the sarcolemma of these uninnervated cells and are supersensitive to that neurotransmitter. An end plate is formed when the first growing nerve terminal establishes contact with a muscle cell. The cell forms no further association with nerves, and receptors to acetylcholine become concentrated in the end plate membranes. Cells innervated by a small motor neuron form slow (type I) oxidative motor units. Fibers innervated by large motor nerves develop all the characteristics of fast (type II) motor units. Innervation produces major cellular changes, including synthesis of the fast and slow myosin isoforms, which replace embryonic or neonatal variants. Thus muscle fiber type is determined by the nerves that innervate the fiber.


Physiology_Levy

Physiology_Levy. An increase in muscle strength and size occurs during maturation. As the skeleton grows, the muscle cells lengthen. Lengthening is accomplished by the formation of additional sarcomeres at the ends of the muscle cells (


Physiology_Levy

Physiology_Levy. Fig. 12.20 ), a process that is reversible. For example, the length of a cell decreases when terminal sarcomeres are eliminated, which can occur when a limb is immobilized with the muscle in a shortened position or when improper setting of a fracture causes shortening of the limb segment. Changes in muscle length affect the velocity and extent of shortening but do not influence the amount of force that can be generated by the muscle. The gradual increase in strength and diameter of a muscle during growth is achieved mainly by hypertrophy. Doubling the myofibrillar diameter by adding more sarcomeres in parallel (hypertrophy, for example) may double the amount of force generated but has no effect on the maximal velocity of shortening. Resistance exercise can promote hypertrophy by activation of the Akt-mTOR signaling pathway and simultaneous inhibition of the forkhead box O protein (FoxO)–atrogene pathway, which results in an increase in net protein synthesis (


Physiology_Levy

Physiology_Levy. Fig. 12.21A ). The increase in intracellular Ca and decrease in ATP concentration can also stimulate mitochondrial biogenesis and expression of a slow muscle phenotype through activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) signaling (see Fig. 12.21B Skeletal muscles have a limited ability to form new fibers (hyperplasia). These new fibers result from differentiation of satellite cells that are present in the tissues. However, major cellular destruction leads to replacement by scar tissue. Muscles not only must be used to maintain normal growth and development but must also experience loading.


Physiology_Levy

Physiology_Levy. Muscles not only must be used to maintain normal growth and development but must also experience loading. •Fig. 12.20. Effects of Growth on the Mechanical Output of a Muscle Cell. Typically,skeletalmusclecellgrowthinvolveseitherlengthening(addingmoresarcomerestotheendsofthemusclefibers)orincreasingmusclefiberdiameter(hypertrophyasaresultoftheadditionofmoremyofilaments/myofibrilsinparallelwithinthemusclefiber).Theformationofnewmusclefibersiscalledmuscle hyperplasia, anditisinfrequentinskeletalmuscle.


Physiology_Levy

Physiology_Levy. Muscles immobilized in a cast lose mass. In addition, space flight exposes astronauts to a microgravity environment that mechanically unloads their muscles. Such unloading leads to rapid loss of muscle mass (i.e., atrophy) and weakness. Disuse atrophy appears to involve both inhibition of protein synthesis and stimulation of protein degradation (with net activation of the FoxO-atrogene pathway). Other categories of skeletal muscle atrophy include sarcopenia (which is atrophy associated with the aging process) and cachexia (which is atrophy associated with an illness).


Physiology_Levy

Physiology_Levy. Muscles that frequently contract to support the body typically have a high number of slow (type I) oxidative motor units. These slow motor units atrophy more rapidly than the fast (type II) motor units during prolonged periods of unloading. This atrophy of slow motor units is associated with a decrease in maximal tetanic force but also an increase in maximal shortening velocity. The increase in velocity is correlated with expression of the fast myosin isoform in these fibers. An important aspect of space medicine is the design of exercise programs that minimize such phenotypic changes during prolonged space flight.


Physiology_Levy

• Fig.

Physiology_Levy. • Fig.


Physiology_Levy

Physiology_Levy. 12.21. Basic molecular signaling pathways involved in contributing to net protein synthesis (A) and mitochondrial biogenesis (B) in skeletal muscle in response to exercise. AKT, a serine/threonine-specific protein kinase (protein kinase B); AMPK, 5′ adenosine monophosphate–activated protein kinase; ATP, adenosine triphosphate; CaM kinase, Ca++/calmodulin-dependent protein kinase; CREB, cAMP response element binding protein; ERRα, estrogen-related receptor-α; FoxO, forkhead box O class of transcription factors; FoxO-P, phosphorylated FoxO; Glut-4, glucose transporter type 4; HDAC5, histone deacetylase 5; IGF-1, insulin-like growth factor 1; MEF2, myocyte enhancer factor 2; mTOR, mammalian target of rapamycin; Nrf1, Nrf2, and Nrf2α, nuclear respiratory factors 1, 2, and 2α; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α; PI3K, phosphatidylinositol-3-kinase; Tn I, troponin I. (A, From Sandri M, et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing Fo


Physiology_Levy

Physiology_Levy. me proliferator-activated receptor γ coactivator 1α; PI3K, phosphatidylinositol-3-kinase; Tn I, troponin I. (A, From Sandri M, et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. PNAS. 2006;103:16260-16265. B, From Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell


Physiology_Levy

Metab. 2005;1:361-370.)

Physiology_Levy. Metab. 2005;1:361-370.)


Physiology_Levy

Physiology_Levy. Testosterone is a major factor responsible for the greater Denervation, Reinnervation, muscle mass in men because it has both myotrophic action ). A variety of synthetic molecules, called anabolic steroids, As already noted, innervation is crucial for the skeletal have been designed to enhance muscle growth while mini-muscle phenotype. If the motor nerve is cut, muscle fasmizing their androgenic action. These drugs are widely used ciculation occurs. Fasciculation is characterized by small, by bodybuilders and athletes in sports in which strength is irregular contractions caused by release of acetylcholine from important. The doses are typically 10-to 50-fold greater the terminals of the degenerating distal portion of the axon. than might be prescribed therapeutically for individuals Several days after denervation, muscle fibrillation begins. with impaired hormone production. Unfortunately, none Fibrillation is characterized by spontaneous, repetitive of these compounds lack


Physiology_Levy

Physiology_Levy. Several days after denervation, muscle fibrillation begins. with impaired hormone production. Unfortunately, none Fibrillation is characterized by spontaneous, repetitive of these compounds lack androgenic effects. Hence, at the contractions. At this time, the cholinergic receptors have doses used, they induce serious hormone disturbances, spread out over the entire cell membrane, in effect reverting including depression of testosterone production. A major to their preinnervation embryonic arrangement. The muscle issue is whether these drugs do in fact increase muscle and fibrillations reflect supersensitivity to acetylcholine. Affected athletic performance in individuals with normal circulating muscles also atrophy, with a decrease in the size of the levels of testosterone. Although they have been used since muscle and its cells. Atrophy is progressive in humans, with the 1950s, the scientific facts remain uncertain, and most degeneration of some cells 3 or 4 months after


Physiology_Levy

Physiology_Levy. they have been used since muscle and its cells. Atrophy is progressive in humans, with the 1950s, the scientific facts remain uncertain, and most degeneration of some cells 3 or 4 months after denervation. experimental studies in animals have not demonstrated Most of the muscle fibers are replaced by fat and connective any significant effects on muscle development. Reports of tissue after 1 to 2 years. These changes can be reversed if studies in humans remain controversial. Proponents claim reinnervation occurs within a few months. Reinnervation increases in strength that provide advantages in world-class is normally achieved by growth of the peripheral stump of performance. Critics argue that these increases are largely motor nerve axons along the old nerve sheath. placebo effects associated with expectations and motivational Reinnervation of formerly fast (type II) fibers by a small factors. The public debate on abuse of anabolic steroids has motor axon causes that cell to


Physiology_Levy

Physiology_Levy. associated with expectations and motivational Reinnervation of formerly fast (type II) fibers by a small factors. The public debate on abuse of anabolic steroids has motor axon causes that cell to redifferentiate into a slow led to their designation as controlled substances, along with (type I) fiber, and vice versa. This suggests that large and opiates, amphetamines, and barbiturates. small motor nerves differ qualitatively and that the nerves have a specific “trophic” effect on the muscle fibers. This “trophic” effect reflects the rate of fiber stimulation. For example, stimulation via electrodes implanted in the muscle can lessen denervation atrophy. More strikingly, chronic low-frequency stimulation of fast motor units causes these units to be converted to slow units. Some conversion toward a typical fast-fiber phenotype can occur when the frequency of contraction in slow units is greatly decreased by reducing the excitatory input. Excitatory input can be reduced by sectioning the


Physiology_Levy

Physiology_Levy. a typical fast-fiber phenotype can occur when the frequency of contraction in slow units is greatly decreased by reducing the excitatory input. Excitatory input can be reduced by sectioning the appropriate spinal or dorsal root or by severing the tendon, which functionally inactivates peripheral mechanoreceptors.


Physiology_Levy

Physiology_Levy. The frequency of contraction determines fiber development and phenotype through changes in gene expression and protein synthesis. Fibers that undergo frequent contractile activity form many mitochondria and synthesize the slow isoform of myosin. Fibers innervated by large, less excitable axons contract infrequently. Such relatively inactive fibers typically form few mitochondria, have large concentrations of glycolytic enzymes and synthesize the fast isoform of myosin.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Intracellular [Ca++] appears to play an important role in expression of the slow myosin isoform. Slow-twitch muscle fibers have a higher resting level of intracellular Ca++ than do fast-twitch muscle fibers. In addition, chronic electrical stimulation of fast-twitch muscle is accompanied by a 2.5fold increase in resting myoplasmic [Ca++] that precedes the increased expression of slow-twitch myosin and decreased expression of fast-twitch myosin. Similarly, chronic elevation of intracellular Ca++ (approximately fivefold) in muscle cells expressing fast-twitch myosin induces a change in gene expression from the fast muscle myosin isoform to the slow myosin isoform within 8 days. An increase in citrate synthetase activity (an indicator of oxidative capacity) and a decrease in lactate dehydrogenase activity (an indicator of glycolytic capacity) accompany this Ca++-dependent


Physiology_Levy

Physiology_Levy. Muscle: action potential Surface membrane •Fig. 12.22. Molecular Signaling Pathways Contributing to the Transition From Fast-Twitch Muscle to Slow-Twitch Muscle. Chronicelectricalstimulationofafast-twitchmuscleinapatternconsistentwithaslow-twitchmuscleresultsindevelopmentoftheslow-twitchmusclephenotypebecauseofdephosphorylationofthetranscriptionfactornuclearfactorfromactivatedTcells(NFAT)bytheCa++/calmodulin-dependentproteinphosphatasecalcineurin(CaN);thisinturnresultsinnucleartranslocationofNFATandexpressionofslow-twitchmusclefibergenes(A). Activationofthetranscriptionfactormyocyteenhancerfactor2(MEF2)alsoappearstocontributetothisfibertypetransition(B), inwhichactivationofMEF2involvesCa++/calmodulin-dependentphosphorylationofaninhibitor,histonedeacetylase(HDAC).CaMK,Ca++/calmodulin-dependentproteinkinase;ECC,excitation-contractioncoupling;P,phosphorylationofHDAC.(FromLiuY,etal:.Signalingpathwaysinactivity-dependentfibertypeplasticityinadultskeletalmuscle.J Muscle Res Cell Motil.


Physiology_Levy

Physiology_Levy. Muscle Res Cell Motil. 2005;26:13-21.) transition from fast-twitch to slow-twitch myosin. These Ca++-dependent changes are reversible by a reduction of intracellular [Ca++].


Physiology_Levy

Physiology_Levy. Response to Exercise Exercise physiologists identify three categories of training regimens and responses: learning, endurance, and strength training ( Table 12.3). Typically, most athletic endeavors involve elements of all three. The learning aspect of training involves motivational factors, as well as neuromuscular coordination. This aspect of training does not involve adaptive changes in the muscle fibers per se. However, motor skills can persist for years without regular training, unlike the responses of muscle cells to exercise.


Physiology_Levy

Physiology_Levy. All healthy persons can maintain some level of continuous muscular activity that is supported by oxidative metabolism. This level can be greatly increased by a regular exercise regimen that is sufficient to induce adaptive responses. The adaptive response of skeletal muscle fibers to endurance exercise is mainly the result of an increase in the oxidative metabolic capacity of the motor units involved. This demand places an increased load on the cardiovascular and respiratory systems and increases the capacity of the heart and respiratory muscles. The latter effects are responsible for the principal health benefits associated with endurance exercise.


Physiology_Levy

Physiology_Levy. Muscle strength can be increased by regular massive efforts that involve most motor units. Such efforts recruit fast glycolytic motor units, as well as slow oxidative motor units. During these efforts, blood supply to the working muscles may be interrupted as tissue pressures rise above intravascular pressure. The reduced blood flow limits the duration of the contraction. Regular maximal-strength exercise, such as weightlifting, induces the synthesis of more myofibrils and hence hypertrophy of the active muscle cells. The increased stress also induces the growth of tendons and bones. Endurance exercise does not cause fast motor units to become slow, nor does maximal muscular effort produce a shift from slow to fast motor units. Thus any practical exercise regimen, when superimposed on normal daily activities, probably does not alter muscle fiber phenotype.


Physiology_Levy

Physiology_Levy. Activities such as hiking or, in particular, downhill running, in which contracting muscles are stretched and lengthened too vigorously, are followed by more pain and stiffness than after comparable exercise that does not involve vigorous muscle stretching and lengthening (e.g., cycling). The resultant dull, aching pain develops slowly and reaches its peak within 24 to 48 hours. The pain is associated with reduced range of motion, stiffness, and weakness of the affected muscles. The prime factors that cause the pain are swelling and inflammation from injury to muscle cells, most commonly near the myotendinous junction. Type II motor units are affected more than type I motor units because the maximal force is highest in large cells, in which the loads imposed are approximately 60% greater than the maximal force that the cells can develop. Recovery is slow and depends on regeneration of the injured sarcomeres. Biophysical Properties of Skeletal Muscle


Physiology_Levy

Physiology_Levy. Biophysical Properties of Skeletal Muscle The molecular mechanisms of muscle contraction described earlier underlie and are responsible for the biophysical properties of muscle. Historically, these biophysical properties were well described before elucidation of the molecular mechanisms of contraction. They remain important ways of describing muscle function. When muscles contract, they generate force (often measured as tension or stress) and decrease in length. In examination of the biophysical properties of muscle, one of these parameters is usually held constant, and the other is measured after an experimental maneuver. Accordingly, an isometric contraction is one in which muscle length is held constant, and the force generated during the contraction is then measured. An isotonic contraction is one in which the force (or tone) is held constant, and the change in length of the muscle is then measured.


Physiology_Levy

Physiology_Levy. When a muscle at rest is stretched, it resists stretch by a force that increases slowly at first and then more rapidly as the extent of stretch increases (


Physiology_Levy

Physiology_Levy. Fig. 12.23 ). This purely passive property is due to the elasticity of the muscle tissue. If the muscle is stimulated to contract at these various lengths, a different relationship is obtained. Specifically, contractile force increases as muscle length is increased up to a point (designated LO to indicate optimal length). As the muscle is stretched beyond LO, contractile force decreases. This length-tension curve is consistent with the sliding filament theory, described previously. At a very 0 1 201 Length (fraction of optimum) Sarcomere length (µm) •Fig. 12.23. Length-Tension Relationship in Skeletal Muscle. A, Experimentalsetupinwhichmaximalisometrictetanictensionismeasuredatvariousmusclelengths.B, Howactivetensionwascalculatedatvariousmusclelengths(i.e.,bysubtractingpassivetensionfromtotaltensionateachmusclelength).C, Plotofactivetensionasafunctionofmusclelength,withthepredictedoverlapofthickandthinfilamentsatselectedpoints.


Physiology_Levy

Physiology_Levy. •Fig. 12.24. Force-Velocity Relationship of Skeletal Muscle. Theexperimentalsetupisshownontheright.Theinitialmusclelengthwaskeptconstant,buttheamountofweightthatthemusclehadtoliftduringtetanicstimulationvaried.Whilethesevariousamountsofweightwerelifted,muscle-shorteningvelocitywasmeasured.Seetextfordetails.F,force;V,velocity. long sarcomere length (3.7 µm), actin filaments no longer overlap with myosin filaments, and so there is no contraction. As muscle length is decreased toward LO, the amount of overlap increases, and contractile force progressively increases. As sarcomere length decreases below 2 µm, the thin filaments collide in the middle of the sarcomere, the actin-myosin interaction is disturbed, and hence contractile force decreases. For construction of the length-tension curves, muscles were maintained at a given length, and then contractile force was measured (i.e., isometric contraction).


Physiology_Levy

Physiology_Levy. Thus the length-tension relationship supports the sliding filament theory of muscle contraction. The velocity at which a muscle shortens is strongly dependent on the amount of force that the muscle must develop (


Physiology_Levy

Physiology_Levy. Fig. 12.24 ). In the absence of any load, the shortening velocity of the muscle is maximal (denoted as V0). V0 corresponds to the maximal cycling rate of the cross-bridges (i.e., it is proportional to the maximal rate of energy turnover [ATPase activity] by myosin). Thus V0 for fast-twitch muscle is higher than that for slow-twitch muscle. Increasing the load decreases the velocity of muscle shortening until, at maximal load, the muscle cannot lift the load and hence cannot shorten (zero velocity). Further increases in load result in stretching the muscle (negative velocity). The maximal isometric tension (i.e., force at which shortening velocity is zero) is proportional to the number of active cross-bridges between actin and myosin, and it is usually greater for fast-twitch motor units (because of the larger diameter of fast-twitch muscle fibers and greater number of muscle fibers in a typical fast-twitch motor unit). In


Physiology_Levy

Physiology_Levy. Fig. 12.24 , the power-stress curve reflects the rate of work done at each load and shows that the maximal rate of work was done at a submaximal load (namely, when the force of contraction was approximately 30% of the maximal tetanic tension). To calculate the latter curve, the x-and y-coordinates were simply multiplied, and then the product was plotted as a function of the x-coordinate. 1.


Physiology_Levy

Physiology_Levy. 1. Skeletal muscle is composed of numerous muscle cells (muscle fibers) that are typically 10 to 80 µm in diameter and up to 25 cm in length. The appearance of striations in skeletal muscle is due to the highly organized arrangement of thick and thin filaments in the myofibrils of skeletal muscle fibers. The sarcomere is a contractile unit in skeletal muscle. Each sarcomere is approximately 2 µm in length at rest and is bounded by two Z lines. Sarcomeres are arranged in series along the length of the myofibril. Thin filaments, containing actin, extend from the Z line toward the center of the sarcomere. Thick filaments, containing myosin, are positioned in the center of the sarcomere and overlap the actin thin filaments. Muscle contraction results from the Ca++-dependent interaction of myosin and actin, in which myosin pulls the thin filaments toward the center of the sarcomere. 2.


Physiology_Levy

Physiology_Levy. 2. Contraction of skeletal muscle is under control of the central nervous system (i.e., voluntary). Motor centers in the brain control the activity of α motor neurons in the ventral horns of the spinal cord. These α motor neurons, in turn, synapse on skeletal muscle fibers. Whereas each skeletal muscle fiber is innervated by only one motor neuron, a motor neuron innervates several muscle fibers within the muscle. A motor unit refers to all the muscle fibers innervated by a single motor neuron. 3.


Physiology_Levy

Physiology_Levy. 3. The motor neuron initiates contraction of skeletal muscle by producing an action potential in the muscle fiber. As the action potential passes down the T tubules of the muscle fiber, dihydropyridine receptors (DHPRs) in the T tubules undergo conformational changes that result in the opening of neighboring SR Ca++ channels called ryanodine receptors (RYRs), which then release Ca++ to the myoplasm from the SR. The increase in myoplasmic Ca++ promotes muscle contraction by exposing myosin-binding sites on the actin thin filaments (a process that involves binding of Ca++ to troponin C, followed by movement of tropomyosin toward the groove in the thin filament). Myosin cross-bridges then appear to undergo a ratchet action, with the thin filaments pulled toward the center of the sarcomere and contracting the skeletal muscle fiber. Relaxation of the muscle follows as myoplasmic Ca++ is resequestered by Ca++-ATPase (SERCA) in the SR. 4.


Physiology_Levy

Physiology_Levy. 4. The force of contraction can be increased by the activation of more motor neurons (i.e., recruiting of more muscle fibers) or by an increase in the frequency of action potentials in the muscle fiber, which produces tetany. The increase in force during tetanic contractions is due to prolonged elevation of intracellular [Ca++]. 5. The two basic types of skeletal muscle fibers are distinguished on the basis of their speed of contraction (i.e., fast-twitch versus slow-twitch). The difference in speed of contraction is attributed to the expression of different myosin isoforms that differ in myosin ATPase activity. In addition to the difference in myosin ATPase activity, fast-and slow-twitch muscles also differ in metabolic activity, fiber diameter, motor unit size, sensitivity to tetany, and recruitment pattern. 6.


Physiology_Levy

Physiology_Levy. 6. Typically, slow-twitch muscles are recruited before fast-twitch muscle fibers because of the greater excitability of motor neurons innervating slow-twitch muscles. The high oxidative capacity of slow-twitch muscle fibers supports sustained contractile activity. Fast-twitch muscle fibers, in contrast, tend to be large and typically have low oxidative capacity and high glycolytic capacity. The fast-twitch motor units are thus best suited for short periods of activity when high levels of force are required. 7.


Physiology_Levy

Physiology_Levy. 7. Fast-twitch muscle fibers can be converted to slow-twitch muscle fibers (and vice versa), depending on the stimulation pattern. Chronic electrical stimulation of a fast-twitch muscle results in the expression of slow-twitch myosin and decreased expression of fast-twitch myosin, along with an increase in oxidative capacity. The mechanism or mechanisms underlying this change in gene expression are unknown, but the change appears to be secondary to an elevation in resting intracellular [Ca++]. The Ca++-dependent phosphatase calcineurin and the transcription factor NFAT have been implicated in this transition from the fast-twitch to the slow-twitch phenotype. Ca++/calmodulin-dependent kinase and the transcription factor MEF2 may also participate in the phenotype transition. 8.


Physiology_Levy

Physiology_Levy. 8. Skeletal muscle fibers atrophy after denervation. Muscle fibers depend on the activity of their motor nerves for maintenance of the differentiated phenotype. Reinnervation by axon growth along the original nerve sheath can reverse these changes. Skeletal muscle has a limited capacity to replace cells lost as a result of trauma or disease. Inhibition of the PI3K/Akt signaling pathways and activation of the FoxO pathway appears to contribute to the decreased rate of protein synthesis and the increased rate of protein degradation (respectively) observed during disuse atrophy. The increased protein degradation during atrophy is attributed to increases in both protease activity (e.g., activation of caspase 3) and ubiquitination (through elevated levels of ubiquitin ligases). 9.


Physiology_Levy

Physiology_Levy. 9. Skeletal muscle exhibits considerable phenotypic plasticity. Normal growth is associated with cellular hypertrophy, caused by the addition of more myofibrils and more sarcomeres at the ends of the cell to match skeletal growth. Strength training induces cellular hypertrophy, whereas endurance training increases the Allen DG, Whitehead NP, Froehner SC. Absence of dystrophin disrupts skeletal muscle signaling: roles of Ca2+ , reactive oxygen species, and nitric oxide in the development of muscular dystrophy. Physiol Rev. 2016;96(1):253-305. Anderson DM, Anderson KM, Chang CL, et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell. 2015;160(4):595-606. Baldwin KM, Haddad F, Pandorf CE, Roy RR, Edgerton VR. Alterations in muscle mass and contractile phenotype in response to unloading models: role of transcriptional/pretranslational mechanisms. Front Physiol. 2013;4:284.


Physiology_Levy

Physiology_Levy. Burr AR, Molkentin JD. Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy. Cell Death Differ. 2015;22:1402-1412. oxidative capacity of all involved motor units. Training regimens cannot alter fiber type or the expression of myosin isoforms. 10. Muscle fatigue during exercise is not due to depletion of ATP. The mechanism or mechanisms underlying exercise-induced fatigue are not known, although the accumulation of various metabolic products (lactate, Pi, ADP) has been implicated. In view of the importance of preventing depletion of myoplasmic ATP, which would affect the viability of the cell, it is likely that multiple mechanisms may have been developed to induce fatigue and hence lower the rate of ATP hydrolysis before the individual risks injury or death of the skeletal muscle cell. 11.


Physiology_Levy

Physiology_Levy. 11. When the energy demands of an exercising muscle cannot be met by oxidative metabolism, an oxygen debt is incurred. Increased breathing during the recovery period after exercise reflects this oxygen debt. The greater the reliance on anaerobic metabolism to meet the energy requirements of muscle contraction, the greater the oxygen debt. Gordon AM, Homsher E, Regnier M. Regulation of contraction in striated muscle. Physiol Rev. 2000;80(2):853-924. Imbrici P, Altamura C, Pessia M, Mantegazza R, Desaphy JF, Camerino DC. ClC-1 chloride channels: state-of-the-art research and future challenges. Front Cell Neurosci. 2015;9:156. Joyner MJ, Casey DP. Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol Rev. 2015;95(2):549-601.


Physiology_Levy

Physiology_Levy. Joyner MJ, Casey DP. Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol Rev. 2015;95(2):549-601. Nelson CR, Fitts RH. Effects of low cell pH and elevated inorganic phosphate on the pCa-force relationship in single muscle fibers at near-physiological temperatures. Am J Physiol Cell Physiol. 2014;306(7):C670-C678. Sandri M. Protein breakdown in cancer cachexia. Semin Cell Dev Biol. 2016;54:11-19. Schiaffino S, Reggiani C. Fiber types in mammalian skeletal muscles. Physiol Rev. 2011;91(4):1447-1531. Upon completion of this chapter, the student should be able to answer the following questions: 1. Describe the organization of cardiac muscle and how it meets the demands of the organ. 2. Describe the molecular mechanisms involved in excitation-contraction coupling in cardiac muscle and its suitability for this organ. 3.


Physiology_Levy

Physiology_Levy. 2. Describe the molecular mechanisms involved in excitation-contraction coupling in cardiac muscle and its suitability for this organ. 3. Describe the molecular mechanisms that lead to an increase in the force of contraction of the heart. 4. Discuss the length-tension relationship and the force-velocity curve for cardiac muscle, including the molecular basis for both curves. If the student has already completed on skeletal muscle, the student will be able to compare cardiac and skeletal muscle for each of the learning objectives just listed.


Physiology_Levy

Physiology_Levy. If the student has already completed on skeletal muscle, the student will be able to compare cardiac and skeletal muscle for each of the learning objectives just listed. he function of the heart is to pump blood through the circulatory system, and this is accomplished by the highly organized contraction of cardiac muscle cells. Specifically, the cardiac muscle cells are connected together to form an electrical syncytium, with tight electrical and mechanical connections between adjacent cardiac muscle cells. An action potential initiated in a specialized region of the heart (e.g., the sinoatrial node) is therefore able to pass quickly throughout the heart to facilitate synchronized contraction of the cardiac muscle cells, which is important for the pumping action of the heart. Likewise, refilling of the heart requires synchronized relaxation of the heart; abnormal relaxation often results in pathological conditions.


Physiology_Levy

Physiology_Levy. This chapter begins with a description of the organization of cardiac muscle cells within the heart, including discussion of the tight electrical and mechanical connections. The mechanisms that underlie contraction, relaxation, and regulation of the force of contraction of cardiac muscle cells are also addressed. Although cardiac muscle and skeletal muscle are both striated muscles, they are significantly different in terms of organization, electrical and mechanical coupling, excitation-contraction coupling, and mechanisms to regulate the force of contraction. These differences are also highlighted. Basic Organization of Cardiac Muscle Cells Cardiac muscle cells are much smaller than skeletal muscle cells. Typically, cardiac muscle cells measure 10 µm in diameter and approximately 100 µm in length. As shown in


Physiology_Levy

Physiology_Levy. Cardiac muscle cells are much smaller than skeletal muscle cells. Typically, cardiac muscle cells measure 10 µm in diameter and approximately 100 µm in length. As shown in Fig. 13.1A , cardiac cells are connected to each other through intercalated disks, which include a combination of mechanical junctions and electrical connections. The mechanical connections, which keep the cells from pulling apart when contracting, include the fascia adherens and desmosomes. Gap junctions between cardiac muscle cells, on the other hand, provide electrical connections between cells to allow propagation of the action potential throughout the heart. Thus the arrangement of cardiac muscle cells within the heart is said to form an electrical and mechanical syncytium that allows a single action potential (generated within the sinoatrial node) to pass throughout the heart so that the heart can contract in a synchronous, wave-like manner. Blood vessels course through the myocardium.


Physiology_Levy

Physiology_Levy. The basic organization of thick and thin filaments in cardiac muscle cells is comparable with that in skeletal muscle (see ). Electron microscopy reveals repeating light and dark bands that represent I bands and A bands, respectively (see Fig. 13.1B Fig. 12.3 ). Thus cardiac muscle is classified as a striated muscle. The Z line transects the I band and represents the point of attachment of the thin filaments. The region between two adjacent Z lines represents the sarcomere, which is the contractile unit of the muscle cell. The thin filaments are composed of actin, tropomyosin, and troponin and extend into the A band. The A band is composed of thick filaments, along with some overlap of thin filaments. The thick filaments are composed of myosin and extend from the center of the sarcomere toward the Z lines.


Physiology_Levy

Physiology_Levy. Myosin filaments are formed by a tail-to-tail association of myosin molecules in the center of the sarcomere, followed by a head-to-tail association as the thick filament extends toward the Z lines. Thus the myosin filament is polarized and poised for pulling the actin filaments toward the center of the sarcomere. A cross-section view of the sarcomere near the end of the A band shows that each thick filament is surrounded by six thin filaments, and each thin filament receives cross-bridge attachments from three thick filaments. This complex array of thick and thin filaments is characteristic of both cardiac and skeletal muscle and helps • Fig.


Physiology_Levy

Physiology_Levy. each thin filament receives cross-bridge attachments from three thick filaments. This complex array of thick and thin filaments is characteristic of both cardiac and skeletal muscle and helps • Fig. 13.1 A, Photomicrograph of cardiac muscle cells (magnification, ×210). Intercalated disks at either end of a muscle cell are identified in the lower left portion of the micrograph. The intercalated disk physically connects adjacent myocytes and, because of the presence of gap junctions, electrically couples the cells as well so that the muscle functions as an electrical and mechanical syncytium. B, Schematic representation of the organization of a sarcomere within a cardiac muscle cell. (A, From Telser A. Elsevier’s Integrated Histology. St. Louis: Mosby; 2007. B, Redrawn from Fawcett D, McNutt NS. The ultrastructure of the cat myocardium. I. Ventricular papillary muscle. J Cell Biol. 1969;42:1-45.) stabilize the filaments during muscle contraction (see


Physiology_Levy

Physiology_Levy. Fig. 12.3B , for the hexagonal array of thick and thin filaments in the sarcomere of striated muscle). Several proteins may contribute to the organization of the thick and thin filaments, including meromyosin and C protein (in the center of the sarcomere), which appear to serve as a scaffold for organization of the thick filaments. Similarly, nebulin extends along the length of the actin filament and may serve as a scaffold for the thin filament. The actin filament is anchored to the Z line by α-actinin, whereas the protein tropomodulin resides at the end of the actin filament and regulates the length of the thin filament. These proteins are present in both cardiac and skeletal muscle cells.


Physiology_Levy

Physiology_Levy. The thick filaments are tethered to the Z lines by a large elastic protein called titin. Although titin was postulated to tether myosin to the Z lines and thus prevent overstretching of the sarcomere, there is evidence indicating that titin may participate in cell signaling (perhaps by acting as a stretch sensor and thus modulating protein synthesis in response to stress). Such signaling by titin has been observed in both cardiac and skeletal muscle cells. Moreover, genetic defects in titin result in atrophy of both cardiac and skeletal muscle cells and may contribute to both cardiac dysfunction and skeletal muscle dystrophies (termed titinopathies). Titin is also thought to contribute to the ability of cardiac muscle to increase force upon stretch (discussed in the later section “


Physiology_Levy

Physiology_Levy. Although both cardiac muscle and skeletal muscle contain an abundance of connective tissue, there is more connective tissue in the heart. The abundance of connective tissue in the heart helps prevent muscle rupture (as in skeletal muscle), but it also prevents overstretching of the heart. Length-tension analysis of cardiac muscle, for example, shows a dramatic increase in passive tension as cardiac muscle is stretched beyond its resting length. Skeletal muscle, in contrast, tolerates a much greater degree of stretch before passive tension increases to a comparable level. The reason for this difference between cardiac and skeletal muscle is not known, although one possibility is that stretch of skeletal muscle is typically limited by the range of motion of the joint, which in turn is limited by the ligaments/connective tissue surrounding the joint.


Physiology_Levy

Physiology_Levy. The heart, on the other hand, appears to rely on the abundance of connective tissue around cardiac muscle cells to prevent overstretching during periods of increased venous return. During intense exercise, for example, venous return may increase fivefold. However, the heart is capable of pumping this extra volume of blood into the arterial system with only minor changes in the ventricular volume of the heart (i.e., end-diastolic volume increases less than 20%). Although the abundance of connective tissue in the heart limits stretch of the heart during these periods of increased venous return, additional regulatory mechanisms help the heart pump the extra blood that it receives (as discussed in the section “ ”). Conversely, if the heart were to be overstretched, the contractile ability of cardiac muscle cells would be expected to decrease (because of decreased overlap of the thick and thin filaments), which would result in insufficient pumping, increased venous pressure, and perhaps


Physiology_Levy

Physiology_Levy. cardiac muscle cells would be expected to decrease (because of decreased overlap of the thick and thin filaments), which would result in insufficient pumping, increased venous pressure, and perhaps pulmonary edema.


Physiology_Levy

Physiology_Levy. Within cardiac muscle cells, myofibrils are surrounded by the sarcoplasmic reticulum (SR), an internal network of membranes (see Fig. 13.1B ). This is similar to the SR in skeletal muscle except that the SR in the heart is less dense and not as well developed. Terminal regions of the SR abut the T tubule or lie just below the sarcolemma (or both) and play a key role in the elevation of intracellular [Ca++] during an action potential. The mechanism by which an action potential initiates release of Ca++ in the heart, however, differs significantly from that in skeletal muscle (as discussed in the section “ ”). The heart contains an abundance of mitochondria; up to 30% of the volume of the heart is occupied by these organelles. The high density of mitochondria provides the heart with great oxidative capacity, more so than is typical in skeletal muscle.


Physiology_Levy

Physiology_Levy. The sarcolemma of cardiac muscle also contains invaginations (T tubules) comparable to those seen in skeletal muscle. In cardiac muscle, however, T tubules are positioned at the Z lines, whereas in mammalian skeletal muscle, T tubules are positioned at the ends of the I bands. In cardiac muscle, the connections between the T tubules and the SR are fewer than, and not as well developed as, those in skeletal muscle.


Physiology_Levy


Physiology_Levy

Physiology_Levy. Control of Cardiac Muscle Activity Cardiac muscle is an involuntary muscle with an intrinsic pacemaker. The pacemaker represents a specialized cell (located in the sinoatrial node of the right atrium) that is able to undergo spontaneous depolarization and generate action potentials. Of importance is that although several cells in the heart are able to depolarize spontaneously, the fastest spontaneous depolarizations occur in cells in the sinoatrial node. Moreover, once a given cell spontaneously depolarizes and fires an action potential, this action potential is then propagated throughout the heart (by specialized conduction pathways and cell-to-cell contact). Thus depolarization from only one cell is needed to initiate a wave of contraction in the heart (i.e., a heartbeat). The mechanisms underlying this spontaneous depolarization are discussed in depth in


Physiology_Levy

Physiology_Levy. Fig. 16.17 , once an action potential is initiated in the sinoatrial node, it is propagated between atrial cells via gap junctions, as well as through specialized conduction fibers in the atria. The action potential can pass throughout the atria within approximately 70 msec. For the action potential to reach the ventricles, it must pass through the atrioventricular node, after which the action potential passes throughout the ventricle via specialized conduction pathways (the bundle of His and the Purkinje system) and gap junctions in the intercalated disks of adjacent cardiac myocytes. The action potential can pass through the entire heart within 220 msec after initiation in the sinoatrial node. Because contraction of a cardiac muscle cell typically lasts 300 msec, this rapid conduction promotes nearly synchronous contraction of heart muscle cells. This is a very different scenario from that of skeletal muscle, in which cells are grouped into motor units that are recruited


Physiology_Levy

Physiology_Levy. promotes nearly synchronous contraction of heart muscle cells. This is a very different scenario from that of skeletal muscle, in which cells are grouped into motor units that are recruited independently as the force of contraction is increased.


Physiology_Levy

Physiology_Levy. Blood and extracellular fluids typically contain 1 to 2 mmol/L of free Ca++ , and it has been known since the days of the physiologist Sidney Ringer (ca. 1882) that the heart requires extracellular Ca++ to contract. Thus an isolated heart typically continues to beat when perfused with a warm (37°C), oxygenated, physiological salt solution that contains approximately 2 mmol/L Ca++ (e.g., Tyrode’s solution), but it stops beating in the absence of extracellular . This cessation of contractions in Ca++-deficient media is also observed in hearts that are electrically stimulated, which further demonstrates the importance of extracellular Ca++ for contraction of cardiac muscle. This situation is quite different from that of skeletal muscle, which can contract in the total absence of extracellular Ca++ . Action potentials in cardiac muscle are prolonged, lasting 150 to 300 msec (


Physiology_Levy

Physiology_Levy. Fig. 13.2 inset), which is substantially longer than the action potentials in skeletal muscle (≈5 msec). The long duration of the action potential in cardiac muscle is due to a slow inward Ca++ current through a voltage-gated L-type calcium channel in the sarcolemma. The amount of Ca++ coming into the cardiac muscle cell is relatively small and serves as a trigger for release of Ca++ from the SR. In the absence of extracellular Ca++ , an action potential can still be initiated in cardiac muscle, although it • Fig.


Physiology_Levy

Physiology_Levy. is relatively small and serves as a trigger for release of Ca++ from the SR. In the absence of extracellular Ca++ , an action potential can still be initiated in cardiac muscle, although it • Fig. 13.2 Excitation-contraction coupling in the heart requires Ca++ influx through L-type calcium channels in the sarcolemma and T tubules. See text for details. Inset shows time course of action potential (AP), intracellular Ca transient (Ca), and contraction. ATP, adenosine triphosphate; NCX, sarcolemmal 3Na+-Ca++ antiporter; PLN, phospholamban; RYR, ryanodine receptor. (Modified from Bers DM. Cardiac excitation-contraction coupling. Nature. 2002;415:198-205. Inset modified from Mountcastle VB: Medical Physiology, 13 ed. St Louis, Mosby, 1974; Brooks CM, Hoffman BF, Suckling EE, Orias O: Excitability of the Heart. New York, Grune & Stratton, 1955.) is considerably shorter in duration and unable to initiate a contraction. Thus influx of Ca++ during the action potential is crucial for triggering


Physiology_Levy

Physiology_Levy. is considerably shorter in duration and unable to initiate a contraction. Thus influx of Ca++ during the action potential is crucial for triggering release of Ca++ from the SR and thus initiating contraction.


Physiology_Levy

Physiology_Levy. The L-type calcium channel is composed of five subunits (α1, α2, β, γ, and δ). The α1 subunit is also called the dihydropyridine receptor (DHPR) because it binds the dihydropyridine class of calcium channel–blocking drugs (e.g., nitrendipine and nimodipine). Although this channel complex is present in both skeletal and cardiac muscle, it serves very different functions in the two muscle types (discussed in the next paragraph). In each cardiac muscle sarcomere, terminal regions of the SR abut T tubules and the sarcolemma (see


Physiology_Levy

Physiology_Levy. Figs. 13.1B 13.2 ). These junctional regions of the SR are enriched in ryanodine receptors (RYRs; a Ca++ release channel in the SR). The RYR is a Ca++-gated calcium channel, and so influx of Ca++ during an action potential is able to initiate release of Ca++ from the SR in cardiac muscle. The amount of Ca++ released into the cytosol from the SR is much greater than that entering the cytosol from the sarcolemma, although release of Ca++ from the SR does not occur without this entry of “trigger” Ca++ . In contrast, in skeletal muscle, release of Ca++ from the SR does not involve entry of Ca++ across the sarcolemma but instead results from a voltage-induced conformational change in the DHPR. Thus excitation-contraction coupling in cardiac muscle is termed electrochemical coupling (involving Ca++-induced release of Ca++), whereas excitation-contraction coupling in skeletal muscle is termed electromechanical coupling (involving direct interactions between the DHPR in the T tubule and the


Physiology_Levy

Physiology_Levy. Ca++-induced release of Ca++), whereas excitation-contraction coupling in skeletal muscle is termed electromechanical coupling (involving direct interactions between the DHPR in the T tubule and the RYR in the SR). The basis for this difference in Ca++ release mechanisms appears to depend on the DHPR isoform because expression of cardiac DHPR in skeletal muscle cells results in a requirement for extracellular Ca++ for contraction of these modified skeletal muscle cells.


Physiology_Levy

Physiology_Levy. As in skeletal muscle, contraction of cardiac muscle is regulated by thin filaments, and an elevation in intracellular [Ca++] is necessary to promote actin-myosin interaction. At low (<50 nmol/L) intracellular [Ca++], binding of myosin to actin is blocked by tropomyosin. As cytosolic [Ca++] increases during an action potential, however, binding of Ca++ to troponin C results in a conformational change in the troponin/tropomyosin complex in which tropomyosin slips into the groove of the actin filament and exposes myosin binding sites on the actin filament. As long as cytosolic [Ca++] remains elevated, and hence myosin binding sites are exposed, myosin will bind to actin, undergo a ratchet action, and contract the cardiac muscle cell. Note that because myosin binding sites on actin are blocked at low [Ca++] and exposed during a rise in intracellular [Ca++], contraction of cardiac muscle is termed thin filament regulated. This is identical to the situation in skeletal muscle; in smooth


Physiology_Levy

Physiology_Levy. at low [Ca++] and exposed during a rise in intracellular [Ca++], contraction of cardiac muscle is termed thin filament regulated. This is identical to the situation in skeletal muscle; in smooth muscle, in contrast, contraction is thick filament regulated (see


Physiology_Levy

Physiology_Levy. During a rise in intracellular [Ca++] and exposure of myosin-binding sites on actin, the myosin cross-bridges undergo a series of steps that result in contraction of the cardiac muscle cell. At rest, the myosin molecules are energized in that they have partially hydrolyzed adenosine triphosphate (ATP) to “cock the head” and are thus ready to interact with actin. An elevation in intracellular [Ca++] then exposes myosin-binding sites on actin and thus allows myosin to bind actin (step 1). The bound myosin subsequently undergoes a powerstroke in which the actin filament is pulled toward the center of the sarcomere (step 2). Adenosine diphosphate (ADP) and inorganic phosphate (Pi) are released from the myosin head during this step as the energy from ATP is used to contract the muscle. The myosin head moves approximately 70 nm during each ratchet action (cross-bridge cycle). Binding of ATP to myosin decreases the affinity of myosin for actin and thus allows myosin to release from actin


Physiology_Levy

Physiology_Levy. myosin head moves approximately 70 nm during each ratchet action (cross-bridge cycle). Binding of ATP to myosin decreases the affinity of myosin for actin and thus allows myosin to release from actin (step 3). Myosin then partially hydrolyzes the bound ATP to reenergize (“cock”) the head (step 4) and ready the cross-bridge for another cycle. This four-step cycle is identical to that described for skeletal muscle (see


Physiology_Levy

Physiology_Levy. Fig. 12.13). Cardiac muscle and skeletal muscle differ, however, in the level of intracellular [Ca++] attained after an action potential and hence in the number of actin-myosin interactions. In skeletal muscle, intracellular [Ca++] rises and the number of actin-myosin interactions is high after an action potential. In cardiac muscle, the rise in intracellular [Ca++] can be regulated, which affords the heart an important means of modulating the force of contraction without recruiting more muscle cells or undergoing tetany. Recall that in the heart, all the muscle cells are activated during a contraction, and so recruiting more muscle cells is not an option. Moreover, tetany of cardiac muscle cells would prevent any pumping action and thus be fatal. Consequently, the heart relies on different means of increasing the force of contraction, including varying the amplitude of the intracellular Ca++ transient. Relaxation of Cardiac Muscle


Physiology_Levy

Physiology_Levy. Relaxation of skeletal muscle simply requires reaccumulation of Ca++ by the SR through the action of the sarcoplasmic endoplasmic reticulum calcium-ATPase (SERCA), also known as the SR Ca++ pump. Although SERCA plays a key role in the decrease in cytosolic [Ca++] in cardiac muscle, the process is more complex than that in skeletal muscle because some trigger Ca++ enters the cardiac muscle cell through the sarcolemmal calcium channels during each action potential. A mechanism must therefore exist to extrude this trigger Ca++; otherwise, the amount of Ca++ in the SR would continuously increase, and Ca++ overload would result. In particular, some Ca++ is extruded from the cardiac muscle cell though the sarcolemmal 3Na+-Ca++ antiporter and a sarcolemmal Ca++ pump (Fig. 13.2 ). The extracellular [Ca++] is in the millimolar range, whereas the amount of intracellular [Ca++] is submicromolar, and so extrusion of Ca++ is accomplished against a large chemical gradient. Similarly, [Na+] is


Physiology_Levy

Physiology_Levy. [Ca++] is in the millimolar range, whereas the amount of intracellular [Ca++] is submicromolar, and so extrusion of Ca++ is accomplished against a large chemical gradient. Similarly, [Na+] is considerably higher in the extracellular media than within the cell. The antiporter uses the Na+ gradient across the cell to power the uphill movement of Ca++ out of the cell. Because three Na+ ions enter the cell in exchange for one Ca++ ion, the 3Na+-Ca++ antiporter is electrogenic and creates a depolarizing current. The sarcolemmal Ca++ pump, on the other hand, uses the energy in ATP to extrude Ca++ from the cell. Both extrusion mechanisms and SERCA thus contribute to the relaxation of cardiac muscle by decreasing cytosolic [Ca++].


Physiology_Levy

Physiology_Levy. Although the interaction of actin and myosin requires a relatively small increase in free intracellular [Ca++], the abundance of Ca++-binding proteins in the myoplasm necessitates a much larger increase in total intracellular [Ca++]. The resting intracellular [Ca++] is approximately 50 to 100 nmol/L; half-maximal force of contraction requires approximately 600 nmol/L of free Ca++ . However, because of Ca++-binding proteins such as parvalbumin and troponin C, the total myoplasmic concentration must increase by 70 µmol/L. As already noted, much of this increase in total myoplasmic [Ca++] occurs through release of Ca++ from the SR. In a number of species, including rabbits, dogs, cats, guinea pigs, and humans, uptake and release of Ca++ by the SR account for approximately 70% of the intracellular Ca++ transient. Thus up to 30% of the rise in intracellular [Ca++] may be attributable to influx of Ca++ through voltage-gated calcium channels in the sarcolemma, and the 3Na+-Ca++ antiporter


Physiology_Levy

Physiology_Levy. Ca++ transient. Thus up to 30% of the rise in intracellular [Ca++] may be attributable to influx of Ca++ through voltage-gated calcium channels in the sarcolemma, and the 3Na+-Ca++ antiporter contributes significantly to Ca++ extrusion during relaxation.


Physiology_Levy

Physiology_Levy. The sarcolemmal Ca++ pump is in lower abundance than the 3Na+-Ca++ antiporter but has a higher affinity for Ca++ and thus may contribute more to the regulation of resting intracellular [Ca++] (see Fig. 13.2 ). The relative contribution of the Ca++ extrusion mechanisms, however, varies between species. For example, rat and mouse myocytes rely primarily on Ca++ reuptake by the SR (i.e., the SR accounts for 92% of Ca++ transport). Regulation of the Force of Contraction


Physiology_Levy

Physiology_Levy. Regulation of the Force of Contraction Because the heart represents an electrical syncytium, in which all the cardiac muscle cells contract during a single beat, it is not possible to increase the force of contraction by recruiting more muscle cells. Moreover, tetany of the heart would be lethal because it would defeat the critical pumping action of the heart. The heart has therefore developed alternative strategies to increase the force of contraction. The long duration of the action potential found in cardiac muscle, which is due to activation of the voltage-gated L-type calcium channel, results in a long refractory period, which in turn prevents tetany. Modulation of Ca++ influx through L-type calcium channels during an action potential, however, provides the heart with a mechanism to alter cytosolic [Ca++] and hence the force of contraction.


Physiology_Levy

Physiology_Levy. A simple means of modulating the force of contraction of cardiac muscle cells in vitro is to vary extracellular [Ca++]. As noted previously, contraction of the heart requires extracellular Ca++ . Decreasing extracellular [Ca++] from a normal range of 1 to 2 mmol/L to 0.5 mmol/L, for example, reduces the force of the contraction. This reduction in force of contraction is not associated with a change in the duration of the contraction because the kinetic characteristics of Ca++ sequestration by the SR and Ca++ extrusion have not been modified. Although this approach of varying extracellular [Ca++] to alter the force of contraction is demonstrable in vitro, it is not a common means of modulating the force of cardiac contraction in vivo. In vivo, an increase in the size of the intracellular Ca++ transient and hence the force of contraction occurs in response to sympathetic stimulation (see the section


Physiology_Levy

Physiology_Levy. In vivo, an increase in the size of the intracellular Ca++ transient and hence the force of contraction occurs in response to sympathetic stimulation (see the section Chapter 18). Sympathetic stimulation often occurs during periods of excitement or fright and involves activation of β-adrenergic receptors on the heart by norepinephrine (released from nerve terminals in the heart) or epinephrine (released from the adrenal medulla into the bloodstream). As shown in


Physiology_Levy

Physiology_Levy. Fig. 13.3 , the β-adrenergic agonist isoproterenol results in a dramatic increase in the size of the intracellular Ca++ transient and, consequently, a more forceful contraction. An increase in the force of contraction is termed positive inotropy. Typically, the rate of relaxation accompanying this β-adrenergic stimulation also increases, which results in a shorter contraction. The increase in the rate of muscle relaxation is termed positive lusitropy. The frequency of contractions of the heart also increases with β-adrenergic stimulation and is termed positive chronotropy. Thus β-adrenergic stimulation of the heart produces stronger, briefer, and more frequent contractions.


Physiology_Levy

Physiology_Levy. The sympathetic nervous system is stimulated when a human or an animal becomes excited, and it is said to prepare the individual for “fight or flight.” In the case of the heart, increased levels of the adrenal medullary hormone epinephrine or the sympathetic neurotransmitter norepinephrine activate β-adrenergic receptors on the cardiac muscle cells, which in turn activates adenylate cyclase, increases cyclic adenosine monophosphate (cAMP), and thus promotes cAMP-dependent phosphorylation of numerous proteins in cardiac muscle cells ( Fig. 13.4


Physiology_Levy

Physiology_Levy. Fig. 13.4 Both voltage-gated L-type calcium channels (responsible for the trigger Ca++) and a protein associated with SERCA, called phospholamban, are phosphorylated by cAMPdependent protein kinase. The combined action of these phosphorylations increases the amount of Ca++ in the SR. Specifically, phosphorylation of the sarcolemmal calcium channel causes more trigger Ca++ to enter the cell, and phosphorylation of phospholamban increases the activity of SERCA, thereby allowing the SR to accumulate more Ca++ before it is extruded by the 3Na+-Ca++ antiporter and the sarcolemmal Ca++ pump. The net result is that the SR releases more Ca++ into the cytosol during the next action potential, which promotes more actin-myosin interactions and hence greater force of contraction (see


Physiology_Levy

Physiology_Levy. Fig. 13.3 ). The increased activity of SERCA after sympathetic stimulation also results in a shortened contraction because of the rapid reaccumulation of Ca++ by the SR. This in turn allows the heart to increase its rate of relaxation. An additional consequence of sympathetic stimulation is an increase in heart rate through a direct effect on the pacemaker cells (see •Fig. 13.3 Stimulationofβ-adrenergicreceptorsintheheartincreasestheforceofcontraction.Electricalstimulationofmyocardiumresultsinatransientriseinintracellular[Ca++]andproductionofforce(A). Isoproterenol(aβ-adrenergicreceptoragonist)increasestheamplitudeoftheintracellularCa++transientandhencetheamountofforcegenerated(B). A Control B +Isoproterenol Ca Ca Force Force 0.5 sec Additional proteins and some micropeptides also appear to be associated with SERCA and influence SR calcium transport. This includes the 34–amino acid peptide dwarf open reading frame (DWORF), which increases SERCA calcium affinity (


Physiology_Levy

Physiology_Levy. Fig. 13.5 ), apparently by displacing phospholamban. DWORF was identified in putative non-coding RNA. Themechanismsunderlyingtheresponseofthehearttoβ-adrenergicstimulationarecomplexandinvolvecAMPdependentphosphorylationofseveralproteins.AnA kinase anchoring protein (AKAP) hasbeenshowntobecloselyassociatedwiththeL-typecalciumchannelintheheart,therebypositioningcAMP-dependent protein kinase closetothechannelandfacilitatingcAMP-dependentphosphorylationofthischannelduringsympatheticstimulation.HowthesecAMP-dependentphosphorylationsincreasetheamplitudeoftheintracellularCa++ transientand,insodoing,resultinamoreforceful,briefercardiaccontractionisdiscussedingeneraltermslater(seealso


Physiology_Levy


Physiology_Levy

Physiology_Levy. Stretching of the heart increases the force of contraction both in vivo and in vitro and is an intrinsic mechanism for regulating contractile force. In contrast, skeletal muscle typically exhibits maximal tension at resting length. Stretching of the heart in vivo occurs during times of increased venous return of blood to the heart (e.g., during exercise or when the heart rate is slowed, or both). The Frank-Starling law of the heart refers to this ability of the heart to increase its force of contraction when stretched, which occurs at •Fig. 13.4


Physiology_Levy

Physiology_Levy. or when the heart rate is slowed, or both). The Frank-Starling law of the heart refers to this ability of the heart to increase its force of contraction when stretched, which occurs at •Fig. 13.4 Sympatheticstimulationoftheheartresultsinanincreaseincytosoliccyclicadenosinemonophosphate(cAMP)andhencephosphorylationofseveralproteinsbyproteinkinaseA(PKA).AnAkinaseanchorprotein(AKAP)adjacenttotheL-typecalciumchannelfacilitatesphosphorylationofthischannelandpossiblynearbysarcoplasmicreticulumcalciumchannels.OtherproteinsphosphorylatedbyPKAincludephospholamban(PLN)andtroponinI.Muscarinicagonists(e.g.,acetylcholine[ACh]),ontheotherhand,inhibitthissympatheticcascadebyinhibitingtheproductionofcAMPbyadenylatecyclase(AC).β-AR,β-adrenergicreceptor;ATP,adenosinetriphosphate;Gi,inhibitoryGprotein;M2Rec,muscarinicacetylcholineM2receptor;Reg,regeneratinggenereceptor.(RedrawnfromBersDM.Cardiacexcitation-contractioncoupling.Nature 2002;415:198.) times of increased venous return (Fig. 13.6A


Physiology_Levy

Physiology_Levy. The importance of this mechanism is that it helps the heart pump whatever volume of blood it receives. Thus when the heart receives a lot of blood, the ventricles are stretched, and the force of contraction is increased, which ensures ejection of this extra volume of blood. Stretching of cardiac muscle also increases passive tension, which helps prevent overstretching of the heart. This passive resistance in the heart is greater than that in skeletal muscle and is attributed to both extracellular matrix (connective tissue) and intracellular elastic proteins (titin).


Physiology_Levy

Physiology_Levy. This stretch-induced increase in force of contraction of cardiac muscle occurs over a narrow range of sarcomere lengths (ca. 1.6-2.3 um), resulting in a steep length-dependent activation of contraction. This ascending limb of the length-tension relationship in cardiac muscle is much steeper than that seen in skeletal muscle. It is important to note that this stretch-induced increase in force can occur within a singe heart beat. The mechanism(s) underlying this stretch-induced increase in force of contraction of cardiac muscle is controversial, but appears to involve changes in the overlap of the thick and thin filaments as well as stretch-induced increase in the Ca++ sensitivity of contraction (


Physiology_Levy

Physiology_Levy. Fig. 13.6B of the stretch-induced increase in force of contraction has been attributed to an increase in Ca++ sensitivity, whereas the remaining 40% of the stretch-induced increase in force of contraction has been attributed to changes in the overlap of the thick and thin filaments. The changes in myofilament overlap, however, are less likely to contribute to the continued increase in force of cardiac contraction as sarcomere length increases from 2.0um to 2.3 um, as this region is thought to represent a region of optimal overlap of myofilaments (and represents a plateau in the length tension relationship in skeletal muscle). The mechanism(s) contributing to the stretch-induced increase in Ca++ sensitivity of cardiac contraction are not clear, but appears to involve the intracellular elastic protein titin, as well as regulatory proteins (e.g., troponinC).


Physiology_Levy

Physiology_Levy. As in skeletal muscle, myosin uses the energy in ATP to generate force, so the ATP pool, which is small, must be continually replenished. Typically, this replenishment of ATP pools is accomplished by aerobic metabolism, including the oxidation of fats and carbohydrates. During times of ischemia, the creatine phosphate pool, which converts ADP to ATP, may decrease. As in skeletal muscle, the In rat ventricular trabecular muscle, approximately 60% creatine phosphate pool is small.


Physiology_Levy

Physiology_Levy. 276 SECTION3Berne & Levy Physiology ContractionSarcomereCa2˜Ca2˜Ca2˜Sarcomere RelaxationSarcoplasm MyocyteSarcoplasmic reticulum RyRSERCASERCAPLNDWORF A B C 125 100 75 50 25 0 250 200 150 100 50 0 WT Tg KO % Vmax 8.0 7.5 7.0 6.5 6.0 5.5 pCa * * WT Tg KO KCa[Ca2˜]free (nM) •Fig. 13.5 Asmall(34–aminoacid)peptideencodedbyalongnoncodingRNAappearstoimprovesarcoplasmicreticulumfunctionandmyocyteperformancebycounteringtheinhibitoryeffectofphospholamban(PLN)(asdepictedintheworkingmodelshowninpanelA).TheabilityofDWORFtoincreasecardiacSRCauptakeisshowninpanelsBandC,whereoverexpressionofDWORFincardiomyocytes(labeledTg)increasedtheCasensitivityofSRCatransport,whereasknockoutofDWORF(labeledKO)hadthereverseeffect.DWORF,dwarfopenreadingframe;KO,knockout;SERCA,sarcoplasmicendoplasmicreticulumcalcium-ATPase;Tg,transgenic;WT,wild-type.(FromNelsonBR,MakarewichCA,AndersonDM,etal.ApeptideencodedbyatranscriptannotatedaslongnoncodingRNAenhancesSERCAactivityinmuscle.Science. 2016;351:271-275.)


Physiology_Levy

Physiology_Levy. When cardiac muscle is completely deprived of O2 because of occlusion of a coronary vessel (i.e., stopped-flow ischemia), contractions quickly cease (within 30 seconds). This is not due to depletion of either ATP or creatine phosphate because these levels decline more slowly. Even after 10 minutes of stopped-flow ischemia, when creatine phosphate levels are near zero and only 20% of the ATP remains, reperfusion can restore these energy stores, as well as contractile ability. However, prolonging the stopped-flow ischemia for 20 minutes results in further drops in ATP, so that reperfusion has considerably less effect, with only limited restoration of ATP and creatine phosphate levels or contractile activity.