Muscle Physiology PDF

CHAPTER 6 UNIT II Cont...

CHAPTER 6 UNIT II Contraction of Skeletal Muscle About 40% of the body is skeletal muscle, and perhaps Note in Figure 6-1E that the myosin and actin fila- another 10% is smooth and cardiac muscle. Some of the ments partially interdigitate and thus cause the myofibrils same basic principles of contraction apply to all these to have alternate light and dark bands, as illustrated in muscle types. In this chapter, we mainly consider skel- Figure 6-2. The light bands contain only actin filaments etal muscle function; the specialized functions of smooth and are called I bands because they are isotropic to polar- muscle are discussed in Chapter 8, and cardiac muscle is ized light. The dark bands contain myosin filaments, as discussed in Chapter 9. well as the ends of the actin filaments, where they over- lap the myosin, and are called A bands because they are anisotropic to polarized light. Note also the small projec- PHYSIOLOGICAL ANATOMY OF tions from the sides of the myosin filaments in Figure SKELETAL MUSCLE 6-1E and L. These projections are cross-bridges. It is the Figure 6-1 shows that skeletal muscles are composed of interaction between these cross-bridges and the actin fila- numerous fibers ranging from 10 to 80 micrometers in ments that causes contraction (Video 6-1). diameter. Each of these fibers is made up of successively Figure 6-1E also shows that the ends of the actin smaller subunits, also shown in Figure 6-1, and described filaments are attached to a Z disk. From this disk, these in subsequent paragraphs. filaments extend in both directions to interdigitate with In most skeletal muscles, each fiber extends the entire the myosin filaments. The Z disk, which is composed of length of the muscle. Except for about 2% of the fibers, filamentous proteins different from the actin and myo- each fiber is usually innervated by only one nerve ending, sin filaments, passes crosswise across the myofibril and located near the middle of the fiber. also crosswise from myofibril to myofibril, attaching the myofibrils to one another all the way across the muscle The Sarcolemma Is a Thin Membrane Enclosing a fiber. Therefore, the entire muscle fiber has light and dark Skeletal Muscle Fiber. The sarcolemma consists of a bands, as do the individual myofibrils. These bands give true cell membrane, called the plasma membrane, and skeletal and cardiac muscle their striated appearance. an outer coat made up of a thin layer of polysaccharide The portion of the myofibril (or of the whole muscle material that contains numerous thin collagen fibrils. At fiber) that lies between two successive Z disks is called a each end of the muscle fiber, this surface layer of the sar- sarcomere. When the muscle fiber is contracted, as shown colemma fuses with a tendon fiber. The tendon fibers, in at the bottom of Figure 6-5, the length of the sarcomere turn, collect into bundles to form the muscle tendons that is about 2 micrometers. At this length, the actin filaments then connect the muscles to the bones.! completely overlap the myosin filaments, and the tips of the actin filaments are just beginning to overlap one Myofibrils Are Composed of Actin and Myosin another. As discussed later, at this length, the muscle is Filaments. Each muscle fiber contains several hun- capable of generating its greatest force of contraction.! dred to several thousand myofibrils, which are illus- trated in the cross-sectional view of Figure 6-1C. Each Titin Filamentous Molecules Keep the Myosin and myofibril (Figure 6-1D and E) is composed of about Actin Filaments in Place. The side-by-side relationship 1500 adjacent myosin filaments and 3000 actin fila- between the myosin and actin filaments is maintained ments, which are large polymerized protein molecules by a large number of filamentous molecules of a protein that are responsible for the muscle contraction. These called titin (Figure 6-3). Each titin molecule has a mo- filaments can be seen in longitudinal view in the elec- lecular weight of about 3 million, which makes it one of tron micrograph of Figure 6-2 and are represented the largest protein molecules in the body. Also, because it diagrammatically in Figure 6-1E through L. The thick is filamentous, it is very springy. These springy titin mol- filaments in the diagrams are myosin, and the thin fila- ecules act as a framework that holds the myosin and ac- ments are actin. tin filaments in place so that the contractile machinery of 79 UNIT II Membrane Physiology, Nerve, and Muscle SKELETAL MUSCLE B Muscle fasciculus A Muscle C Muscle fiber Z disk A I band band Myofibril Z A I disk band band D G-Actin molecules J H zone H zone M line F-Actin filament Z Sarcomere Z K E H L Myofilaments Myosin filament Myosin molecule M N Tail Hinge Head F G H I Figure 6-1 A–E, Organization of skeletal muscle, from the gross to the molecular level. F–I, Cross sections at the levels indicated. 80  Chapter 6 Contraction of Skeletal Muscle UNIT II Figure 6-2 Electron micrograph of muscle myofibrils showing the detailed organization of actin and myosin filaments. Note the mito- Figure 6-4 Sarcoplasmic reticulum in the spaces between the myofi- chondria lying between the myofibrils. (From Fawcett DW: The Cell. brils, showing a longitudinal system paralleling the myofibrils. Also Philadelphia: WB Saunders, 1981.) shown in cross section are T tubules (arrows) that lead to the exterior of the fiber membrane and are important for conducting the electri- Myosin (thick filament) M line cal signal into the center of the muscle fiber. (From Fawcett DW: The Titin Cell. Philadelphia: WB Saunders, 1981.) mic reticulum. This reticulum has a special organization that is extremely important in regulating calcium stor- age, release, reuptake and therefore muscle contraction, as discussed in Chapter 7. The rapidly contracting types of muscle fibers have especially extensive sarcoplasmic Actin (thin filament) Z disk reticula.! Figure 6-3 Organization of proteins in a sarcomere. Each titin mol- ecule extends from the Z disk to the M line. Part of the titin molecule is closely associated with the myosin thick filament, whereas the rest GENERAL MECHANISM OF MUSCLE of the molecule is springy and changes length as the sarcomere con- CONTRACTION tracts and relaxes. The initiation and execution of muscle contraction occur the sarcomere will work. One end of the titin molecule in the following sequential steps. is elastic and is attached to the Z disk, acting as a spring 1. An action potential travels along a motor nerve to and changing length as the sarcomere contracts and re- its endings on muscle fibers. laxes. The other part of the titin molecule tethers it to the 2. At each ending, the nerve secretes a small amount myosin thick filament. The titin molecule may also act as of the neurotransmitter acetylcholine. a template for the initial formation of portions of the con- 3. Acetylcholine acts on a local area of the muscle tractile filaments of the sarcomere, especially the myosin fiber membrane to open acetylcholine-gated cation filaments.! channels through protein molecules floating in the membrane. Sarcoplasm Is the Intracellular Fluid Between 4. The opening of acetylcholine-gated channels al- Myofibrils. Many myofibrils are suspended side by side in lows large quantities of sodium ions to diffuse to each muscle fiber. The spaces between the myofibrils are the interior of the muscle fiber membrane. This ac- filled with intracellular fluid called sarcoplasm, contain- tion causes a local depolarization that in turn leads ing large quantities of potassium, magnesium, and phos- to the opening of voltage-gated sodium channels, phate, plus multiple protein enzymes. Also present are tre- which initiates an action potential at the membrane. mendous numbers of mitochondria that lie parallel to the 5. The action potential travels along the muscle fiber myofibrils. These mitochondria supply the contracting my- membrane in the same way that action potentials ofibrils with large amounts of energy in the form of adeno- travel along nerve fiber membranes. sine triphosphate (ATP) formed by the mitochondria.! 6. The action potential depolarizes the muscle mem- brane, and much of the action potential electricity Sarcoplasmic Reticulum Is a Specialized Endoplasmic flows through the center of the muscle fiber. Here Reticulum of Skeletal Muscle. Also, in the sarcoplasm it causes the sarcoplasmic reticulum to release large surrounding the myofibrils of each muscle fiber, is an quantities of calcium ions that have been stored extensive reticulum (Figure 6-4), called the sarcoplas- within this reticulum. 81 UNIT II Membrane Physiology, Nerve, and Muscle I A I Head Z Z Tail Relaxed Two heavy chains I A I A Light chains Z Z Actin filaments Contracted Figure 6-5 Relaxed and contracted states of a myofibril showing (top) sliding of the actin filaments (pink) into the spaces between Cross-bridges Hinges Body the myosin filaments (red) and (bottom) pulling of the Z membranes toward each other. B Myosin filament Figure 6-6 A, Myosin molecule. B, Combination of many myosin molecules to form a myosin filament. Also shown are thousands of 7. The calcium ions initiate attractive forces between myosin cross-bridges and interaction between the heads of the cross- the actin and myosin filaments, causing them to bridges with adjacent actin filaments. slide alongside each other, which is the contractile process. calcium ions, in turn, activate the forces between the myo- 8. After a fraction of a second, the calcium ions are sin and actin filaments, and contraction begins. However, pumped back into the sarcoplasmic reticulum by a energy is needed for the contractile process to proceed. Ca2+ membrane pump and remain stored in the re- This energy comes from high-energy bonds in the ATP ticulum until a new muscle action potential comes molecule, which is degraded to adenosine diphosphate along; this removal of calcium ions from the myofi- (ADP) to liberate the energy. In the next few sections, we brils causes the muscle contraction to cease. describe these molecular processes of contraction.! We now describe the molecular machinery of the mus- cle contractile process.! Molecular Characteristics of the Contractile Filaments Myosin Filaments Are Composed of Multiple Myosin MOLECULAR MECHANISM OF MUSCLE Molecules. Each of the myosin molecules, shown in CONTRACTION Figure 6-6A, has a molecular weight of about 480,000. Figure 6-6B shows the organization of many molecules Muscle Contraction Occurs by a Sliding Filament to form a myosin filament, as well as interaction of this Mechanism. Figure 6-5 demonstrates the basic mecha- filament on one side with the ends of two actin filaments. nism of muscle contraction. It shows the relaxed state of The myosin molecule (see Figure 6-6A) is composed a sarcomere (top) and the contracted state (bottom). In of six polypeptide chains—two heavy chains, each with a the relaxed state, the ends of the actin filaments extending molecular weight of about 200,000; and four light chains, from two successive Z disks barely overlap one another. with molecular weights of about 20,000 each. The two Conversely, in the contracted state, these actin filaments heavy chains wrap spirally around each other to form a have been pulled inward among the myosin filaments, so double helix, which is called the tail of the myosin mol- their ends overlap one another to their maximum extent. ecule. One end of each of these chains is folded bilaterally Also, the Z disks have been pulled by the actin filaments into a globular polypeptide structure called a myosin head. up to the ends of the myosin filaments. Thus, muscle con- Thus, there are two free heads at one end of the double- traction occurs by a sliding filament mechanism. helix myosin molecule. The four light chains are also part of But what causes the actin filaments to slide inward the myosin head, two to each head. These light chains help among the myosin filaments? This action is caused by control the function of the head during muscle contraction. forces generated by interaction of the cross-bridges from The myosin filament is made up of 200 or more individ- the myosin filaments with the actin filaments. Under ual myosin molecules. The central portion of one of these resting conditions, these forces are inactive, but when an filaments is shown in Figure 6-6B, displaying the tails of action potential travels along the muscle fiber, this causes the myosin molecules bundled together to form the body the sarcoplasmic reticulum to release large quantities of of the filament, while many heads of the molecules hang calcium ions that rapidly surround the myofibrils. The outward to the sides of the body. Also, part of the body 82  Chapter 6 Contraction of Skeletal Muscle Active sites Troponin complex Each actin filament is about 1 micrometer long. The bases of the actin filaments are inserted strongly into the Z disks; the ends of the filaments protrude in both direc- tions to lie in the spaces between the myosin molecules, as shown in Figure 6-5.! F-actin Tropomyosin UNIT II Figure 6-7 Actin filament composed of two helical strands of F-actin Tropomyosin Molecules. The actin filament also con- molecules and two strands of tropomyosin molecules that fit in the tains another protein, tropomyosin. Each molecule of tro- grooves between the actin strands. Attached to one end of each tro- pomyosin has a molecular weight of 70,000 and a length pomyosin molecule is a troponin complex that initiates contraction. of 40 nanometers. These molecules are wrapped spirally around the sides of the F-actin helix. In the resting state, of each myosin molecule hangs to the side along with the the tropomyosin molecules lie on top of the active sites of head, thus providing an arm that extends the head out- the actin strands so that attraction cannot occur between ward from the body, as shown in the figure. The protrud- the actin and myosin filaments to cause contraction. Con- ing arms and heads together are called cross-bridges. Each traction occurs only when an appropriate signal causes a cross-bridge is flexible at two points called hinges—one conformation change in tropomyosin that “uncovers” ac- where the arm leaves the body of the myosin filament and tive sites on the actin molecule and initiates contraction, the other where the head attaches to the arm. The hinged as explained later.! arms allow the heads either to be extended far outward from the body of the myosin filament or brought close to Troponin and Its Role in Muscle Contraction. Attached the body. The hinged heads, in turn, participate in the con- intermittently along the sides of the tropomyosin mol- traction process, as discussed in the following sections. ecules are additional protein molecules called troponin. The total length of each myosin filament is uniform, These protein molecules are actually complexes of three almost exactly 1.6 micrometers. Note, however, that there loosely bound protein subunits, each of which plays a are no cross-bridge heads in the center of the myosin fila- specific role in controlling muscle contraction. One of the ment for a distance of about 0.2 micrometer because the subunits (troponin I) has a strong affinity for actin, an- hinged arms extend away from the center. other (troponin T) for tropomyosin, and a third (troponin Now, to complete the picture, the myosin filament is C) for calcium ions. This complex is believed to attach the twisted so that each successive pair of cross-bridges is axi- tropomyosin to the actin. The strong affinity of the tro- ally displaced from the previous pair by 120 degrees. This ponin for calcium ions is believed to initiate the contrac- twisting ensures that the cross-bridges extend in all direc- tion process, as explained in the next section.! tions around the filament.! Interaction of One Myosin Filament, Two Adenosine Triphosphatase Activity of the Myosin Actin Filaments, and Calcium Ions to Head. Another feature of the myosin head that is es- Cause Contraction sential for muscle contraction is that it functions as an Inhibition of the Actin Filament by the Troponin- adenosine triphosphatase (ATPase) enzyme. As explained Tropomyosin Complex. A pure actin filament without later, this property allows the head to cleave ATP and use the presence of the troponin-tropomyosin complex (but the energy derived from the ATP’s high-energy phosphate in the presence of magnesium ions and ATP) binds in- bond to energize the contraction process.! stantly and strongly with the heads of the myosin mol- ecules. Then, if the troponin-tropomyosin complex is Actin Filaments Are Composed of Actin, Tropomyosin, added to the actin filament, the binding between myosin and Troponin. The backbone of the actin filament is a and actin does not take place. Therefore, it is believed double-stranded F-actin protein molecule, represented that the active sites on the normal actin filament of the by the two lighter-colored strands in Figure 6-7. The two relaxed muscle are inhibited or physically covered by the strands are wound in a helix in the same manner as the troponin-tropomyosin complex. Consequently, the sites myosin molecule. cannot attach to the heads of the myosin filaments to Each strand of the double F-actin helix is composed cause contraction. Before contraction can take place, the of polymerized G-actin molecules, each having a molecu- inhibitory effect of the troponin-tropomyosin complex lar weight of about 42,000. Attached to each one of the must itself be inhibited.! G-actin molecules is one molecule of ADP. These ADP molecules are believed to be the active sites on the actin Activation of the Actin Filament by Calcium Ions. filaments with which the cross-bridges of the myosin fila- In the presence of large amounts of calcium ions, the ments interact to cause muscle contraction. The active inhibitory effect of the troponin- tropomyosin on the sites on the two F-actin strands of the double helix are actin filaments is itself inhibited. The mechanism of staggered, giving one active site on the overall actin fila- this inhibition is not known, but one suggestion has ment about every 2.7 nanometers. been presented. When calcium ions combine with 83 UNIT II Membrane Physiology, Nerve, and Muscle Movement Active sites Actin filament Each of the cross-bridges is believed to operate inde- pendently of all the others, with each attaching and pulling in a continuous repeated cycle. Therefore, the Hinges Power greater the number of cross-bridges in contact with the stroke actin filament at any given time, the greater the force of contraction.! ATP Is the Energy Source for Contraction—Chemical Myosin filament Events in the Motion of the Myosin Heads. When a muscle contracts, work is performed, and energy is re- Figure 6-8 The walk-along mechanism for contraction of the muscle. quired. Large amounts of ATP are cleaved to form ADP during the contraction process, and the more work per- troponin C, each molecule of which can bind strongly formed by the muscle, the more ATP that is cleaved; this with up to four calcium ions, the troponin complex phenomenon is called the Fenn effect. The following se- then undergoes a conformational change that in some quence of events is believed to be the means whereby this way tugs on the tropomyosin molecule and moves it effect occurs: deeper into the groove between the two actin strands. 1. Before contraction begins, the heads of the cross- This action uncovers the active sites of the actin, thus bridges bind with ATP. The ATPase activity of the allowing these active sites to attract the myosin cross- myosin head immediately cleaves the ATP but bridge heads and allow contraction to proceed. Al- leaves the cleavage products, ADP plus phosphate though this mechanism is hypothetical, it emphasizes ion, bound to the head. In this state, the conforma- that the normal relationship between the troponin- tion of the head is such that it extends perpendic- tropomyosin complex and actin is altered by calcium ularly toward the actin filament but is not yet at- ions, producing a new condition that leads to contrac- tached to the actin. tion.! 2. When the troponin-tropomyosin complex binds with calcium ions, active sites on the actin filament Interaction of the Activated Actin Filament and the are uncovered, and the myosin heads then bind Myosin Cross-Bridges—The Walk-Along Theory of with these sites, as shown in Figure 6-8. Contraction. As soon as the actin filament is activated 3. The bond between the head of the cross-bridge and by the calcium ions, the heads of the cross-bridges from the active site of the actin filament causes a confor- the myosin filaments become attracted to the active sites mational change in the head, prompting the head to of the actin filament and initiate contraction. Although tilt toward the arm of the cross-bridge and provid- the precise manner in which this interaction between ing the power stroke for pulling the actin filament. the cross-bridges and the actin causes contraction is still The energy that activates the power stroke is the partly theoretical, one hypothesis for which considerable energy already stored, like a cocked spring, by the evidence exists is the walk-along (or ratchet) theory of conformational change that occurred in the head contraction. when the ATP molecule was cleaved earlier. Figure 6-8 demonstrates this postulated walk-along 4. Once the head of the cross-bridge tilts, release of mechanism for contraction. The figure shows the heads the ADP and phosphate ion that were previously of two cross-bridges attaching to and disengaging from attached to the head is allowed. At the site of re- active sites of an actin filament. When a head attaches lease of the ADP, a new molecule of ATP binds. This to an active site, this attachment simultaneously causes binding of new ATP causes detachment of the head profound changes in the intramolecular forces between from the actin. the head and arm of its cross-bridge. The new align- 5. After the head has detached from the actin, the ment of forces causes the head to tilt toward the arm new molecule of ATP is cleaved to begin the next and to drag the actin filament along with it. This tilt of cycle, leading to a new power stroke. That is, the the head is called the power stroke. Immediately after energy again cocks the head back to its perpen- tilting, the head then automatically breaks away from dicular condition, ready to begin the new power the active site. Next, the head returns to its extended stroke cycle. direction. In this position, it combines with a new 6. When the cocked head (with its stored energy de- active site farther down along the actin filament; the rived from the cleaved ATP) binds with a new active head then tilts again to cause a new power stroke, and site on the actin filament, it becomes uncocked and the actin filament moves another step. Thus, the heads once again provides a new power stroke. of the cross-bridges bend back and forth and, step by Thus, the process proceeds again and again until the step, walk along the actin filament, pulling the ends of actin filaments pull the Z membrane up against the ends two successive actin filaments toward the center of the of the myosin filaments or until the load on the muscle myosin filament. becomes too great for further pulling to occur.! 84  Chapter 6 Contraction of Skeletal Muscle D Normal range of contraction B C C 100 B Tension during A contraction Tension of muscle A Tension developed Increase in tension (percent) UNIT II during contraction 50 Tension before contraction D 0 0 0 1 2 3 4 1/2 Normal 2× Length of sarcomere (micrometers) normal normal Figure 6-9 Length-tension diagram for a single fully contracted sar- Length comere showing the maximum strength of contraction when the sar- Figure 6-10 Relationship of muscle length to tension in the muscle comere is 2.0 to 2.2 micrometers in length. At the upper right are both before and during muscle contraction. the relative positions of the actin and myosin filaments at different sarcomere lengths from point A to point D. (Modified from Gordon AM, Huxley AF, Julian FJ: The length-tension diagram of single verte- has a large amount of connective tissue in it; in addition, brate striated muscle fibers. J Physiol 171:28P, 1964.) the sarcomeres in different parts of the muscle do not always contract the same amount. Therefore, the curve Amount of Actin and Myosin Filament has somewhat different dimensions from those shown Overlap Determines Tension Developed for the individual muscle fiber, but it exhibits the same by the Contracting Muscle general form for the slope in the normal range of contrac- Figure 6-9 shows the effect of sarcomere length and the tion, as shown in Figure 6-10. amount of myosin-actin filament overlap on the active ten- Note in Figure 6-10 that when the muscle is at its sion developed by a contracting muscle fiber. To the right normal resting length, which is at a sarcomere length of are different degrees of overlap of the myosin and actin about 2 micrometers, it contracts on activation with the filaments at different sarcomere lengths. At point D on the approximate maximum force of contraction. However, diagram, the actin filament has pulled all the way out to the increase in tension that occurs during contraction, the end of the myosin filament, with no actin-myosin over- called active tension, decreases as the muscle is stretched lap. At this point, the tension developed by the activated beyond its normal length—that is, to a sarcomere length muscle is zero. Then, as the sarcomere shortens, and the greater than about 2.2 micrometers. This phenomenon is actin filament begins to overlap the myosin filament, the demonstrated by the decreased length of the arrow in the tension increases progressively until the sarcomere length figure at greater than normal muscle length.! decreases to about 2.2 micrometers. At this point, the actin filament has already overlapped all the cross-bridges of the Relation of Velocity of Contraction to Load myosin filament but has not yet reached the center of the A skeletal muscle contracts rapidly when it contracts myosin filament. With further shortening, the sarcomere against no load to a state of full contraction in about 0.1 maintains full tension until point B is reached, at a sar- second for the average muscle. When loads are applied, the comere length of about 2 micrometers. At this point, the velocity of contraction decreases progressively as the load ends of the two actin filaments begin to overlap each other increases, as shown in Figure 6-11. When the load has been increased to equal the maximum force that the muscle in addition to overlapping the myosin filaments. As the can exert, the velocity of contraction becomes zero, and no sarcomere length decreases from 2 micrometers to about contraction results, despite activation of the muscle fiber. 1.65 micrometers at point A, the strength of contraction This decreasing velocity of contraction with load occurs decreases rapidly. At this point, the two Z disks of the sar- because a load on a contracting muscle is a reverse force comere abut the ends of the myosin filaments. Then, as that opposes the contractile force caused by muscle con- contraction proceeds to still shorter sarcomere lengths, the traction. Therefore, the net force that is available to cause ends of the myosin filaments are crumpled and, as shown in the velocity of shortening is correspondingly reduced.! the figure, the strength of contraction approaches zero, but the sarcomere has now contracted to its shortest length. ENERGETICS OF MUSCLE CONTRACTION Effect of Muscle Length on Force of Contraction in the Whole Intact Muscle. The top curve of Figure 6-10 is similar to that in Figure 6-9, but the curve in Work Output During Muscle Contraction Figure 6-10 depicts tension of the intact whole muscle When a muscle contracts against a load, it performs work. rather than of a single muscle fiber. The whole muscle To perform work means that energy is transferred from 85 UNIT II Membrane Physiology, Nerve, and Muscle ADP to reconstitute the ATP. However, the total amount Velocity of contraction (cm/sec) 30 of phosphocreatine in the muscle fiber is also small, only about 5 times as great as the ATP. Therefore, the com- bined energy of both the stored ATP and the phosphocre- 20 atine in the muscle is capable of causing maximal muscle contraction for only 5 to 8 seconds. The second important source of energy, which is 10 used to reconstitute both ATP and phosphocreatine, is a process called glycolysis—the breakdown of glycogen previously stored in the muscle cells. Rapid enzymatic 0 breakdown of the glycogen to pyruvic acid and lactic 0 1 2 3 4 acid liberates energy that is used to convert ADP to ATP; Load-opposing contraction (kg) the ATP can then be used directly to energize additional Figure 6-11 Relationship of load to velocity of contraction in a skel- muscle contraction and also to re-form the stores of etal muscle with a cross section of 1 square centimeter and a length phosphocreatine. of 8 centimeters. The importance of this glycolysis mechanism is twofold. First, glycolytic reactions can occur even in the absence of the muscle to the external load to lift an object to a greater oxygen, so muscle contraction can be sustained for many height or to overcome resistance to movement. seconds and sometimes up to more than 1 minute, even In mathematical terms, work is defined by the follow- when oxygen delivery from the blood is not available. Sec- ing equation: ond, the rate of ATP formation by glycolysis is about 2.5 W = L ×D times as rapid as ATP formation in response to cellular foodstuffs reacting with oxygen. However, so many end in which W is the work output, L is the load, and D is products of glycolysis accumulate in the muscle cells that the distance of movement against the load. The energy glycolysis also loses its capability to sustain maximum required to perform the work is derived from the chemi- muscle contraction after about 1 minute. cal reactions in the muscle cells during contraction, as The third and final source of energy is oxidative metab- described in the following sections.! olism, which means combining oxygen with the end prod- ucts of glycolysis and with various other cellular foodstuffs Three Sources of Energy for Muscle to liberate ATP. More than 95% of all energy used by the Contraction muscles for sustained long-term contraction is derived Most of the energy required for muscle contraction is from oxidative metabolism. The foodstuffs that are con- used to trigger the walk-along mechanism whereby the sumed are carbohydrates, fats, and protein. For extremely cross-bridges pull the actin filaments, but small amounts long-term maximal muscle activity—over a period of are required for the following: (1) pumping calcium ions many hours—the greatest proportion of energy comes from the sarcoplasm into the sarcoplasmic reticulum from fats but, for periods of 2 to 4 hours, as much as one after the contraction is over; and (2) pumping sodium and half of the energy can come from stored carbohydrates. potassium ions through the muscle fiber membrane to The detailed mechanisms of these energetic processes maintain an appropriate ionic environment for the propa- are discussed in Chapters 68 through 73. In addition, the gation of muscle fiber action potentials. importance of the different mechanisms of energy release The concentration of ATP in the muscle fiber, about during performance of different sports is discussed in 4 millimolar, is sufficient to maintain full contraction Chapter 85.! for only 1 to 2 seconds at most. The ATP is split to form ADP, which transfers energy from the ATP molecule to Efficiency of Muscle Contraction. The efficiency of an the contracting machinery of the muscle fiber. Then, as engine or a motor is calculated as the percentage of energy described in Chapter 2, the ADP is rephosphorylated to input that is converted into work instead of heat. The per- centage of the input energy to muscle (the chemical energy form new ATP within another fraction of a second, which in nutrients) that can be converted into work, even under allows the muscle to continue its contraction. There are the best conditions, is less than 25%, with the remainder three sources of the energy for this rephosphorylation. becoming heat. The reason for this low efficiency is that The first source of energy that is used to reconstitute about one-half of the energy in foodstuffs is lost during the the ATP is the substance phosphocreatine, which carries a formation of ATP and, even then, only 40% to 45% of the high-energy phosphate bond similar to the bonds of ATP. energy in ATP itself can later be converted into work. The high-energy phosphate bond of phosphocreatine has Maximum efficiency can be realized only when the a slightly higher amount of free energy than that of each muscle contracts at a moderate velocity. If the muscle con- ATP bond, as discussed in more detail in Chapters 68 and tracts slowly or without any movement, small amounts of 73. Therefore, phosphocreatine is instantly cleaved, and its maintenance heat are released during contraction, even released energy causes bonding of a new phosphate ion to though little or no work is performed, thereby decreasing 86  Chapter 6 Contraction of Skeletal Muscle the conversion efficiency to as little as zero. Conversely, if Isotonic contraction contraction is too rapid, much of the energy is used to over- come viscous friction within the muscle itself, and this too reduces the efficiency of contraction. Ordinarily, maximum efficiency occurs when the velocity of contraction is about Muscle 30% of maximum.! Contracts UNIT II CHARACTERISTICS OF WHOLE MUSCLE CONTRACTION Relaxes Many features of muscle contraction can be demonstrated by eliciting single muscle twitches. This can be accom- Weight plished by electrical excitation of the nerve to a muscle or by passing a short electrical stimulus through the muscle Weight itself, giving rise to a single sudden contraction lasting a fraction of a second. Isometric contraction Isometric Contractions Do Not Shorten Muscle, Whereas Isotonic Contractions Shorten Muscle at a Constant Tension. Muscle contraction is said to be iso- Muscle metric when the muscle does not shorten during contrac- tion and isotonic when it shortens but the tension on the Contracts muscle remains constant throughout the contraction. Systems for recording the two types of muscle contrac- tion are shown in Figure 6-12. In the isometric system, the muscle contracts against Relaxes a force transducer without decreasing the muscle length, as shown in the bottom panel of Figure 6-12. In the isotonic system, the muscle shortens against a fixed load, which is illustrated in the top panel of the Low tension High tension figure, showing a muscle lifting a weight. The char- acteristics of isotonic contraction depend on the load against which the muscle contracts, as well as the iner- Heavy Heavy weight weight tia of the load. However, the isometric system records changes in force of muscle contraction independently of load inertia. Therefore, the isometric system is often Figure 6-12 Isotonic and isometric systems for recording muscle con- used when comparing the functional characteristics of tractions. Isotonic contraction occurs when the force of the muscle con- different muscle types.! traction is greater than the load, and the tension on the muscle remains constant during the contraction. When the muscle contracts, it shortens and moves the load. Isometric contraction occurs when the load is great- Characteristics of Isometric Twitches Recorded from er than the force of the muscle contraction; the muscle creates tension Different Muscles. The human body has many sizes of when it contracts, but the overall length of the muscle does not change. skeletal muscles—from the small stapedius muscle in the middle ear, measuring only a few millimeters long and 1 Duration of millimeter or so in diameter, up to the large quadriceps depolarization muscle, a half-million times as large as the stapedius. Fur- Force of contraction thermore, the fibers may be as small as 10 micrometers Soleus in diameter or as large as 80 micrometers. Finally, the energetics of muscle contraction vary considerably from one muscle to another. Therefore, it is no wonder that the Gastrocnemius mechanical characteristics of muscle contraction differ among muscles. Ocular muscle Figure 6-13 shows records of isometric contractions of three types of skeletal muscle—an ocular muscle, which 0 40 80 120 160 200 has a duration of isometric contraction of less than 1/50 Milliseconds second; the gastrocnemius muscle, which has a dura- Figure 6-13 Duration of isometric contractions for different types tion of contraction of about 1/15 second; and the soleus of mammalian skeletal muscles showing a latent period between the muscle, which has a duration of contraction of about 1/5 action potential (depolarization) and muscle contraction. 87 UNIT II Membrane Physiology, Nerve, and Muscle second. These durations of contraction are highly adapted Spinal cord to the functions of the respective muscles. Ocular move- ments must be extremely rapid to maintain fixation of the eyes on specific objects to provide accuracy of vision. The gastrocnemius muscle must contract moderately rapidly to provide sufficient velocity of limb movement for run- Motor unit ning and jumping, and the soleus muscle is concerned principally with slow contraction for continual, long-term support of the body against gravity.! Muscle Somatic motor neuron Fast Versus Slow Muscle Fibers. As will be discussed more fully in Chapter 85 on sports physiology, every mus- cle of the body is composed of a mixture of so-called fast Motor unit and slow muscle fibers, with still other fibers gradated between these two extremes. Muscles that react rapidly, including the anterior tibialis, are composed mainly of fast fibers, with only small numbers of the slow variety. Somatic Conversely, muscles such as soleus that respond slowly motor axon but with prolonged contraction are composed mainly of Motor unit slow fibers. The differences between these two types of fibers are described in the following sections.! Neuromuscular junctions Slow Fibers (Type 1, Red Muscle). The following are Skeletal muscle fibers characteristics of slow fibers: 1. Slow fibers are smaller than fast fibers. Figure 6-14 A motor unit consists of a motor neuron and the group 2. Slow fibers are also innervated by smaller nerve fibers. of skeletal muscle fibers it innervates. A single motor axon may branch to innervate several muscle fibers that function together as 3. Slow fibers have a more extensive blood vessel sys- a group. Although each muscle fiber is innervated by a single motor tem and more capillaries to supply extra amounts of neuron, an entire muscle may receive input from hundreds of differ- oxygen compared with fast fibers, ent motor neurons. 4. Slow fibers have greatly increased numbers of mi- tochondria to support high levels of oxidative me- MECHANICS OF SKELETAL MUSCLE tabolism. CONTRACTION 5. Slow fibers contain large amounts of myoglobin, an iron-containing protein similar to hemoglobin in Motor Unit—All the Muscle Fibers Innervated by a red blood cells. Myoglobin combines with oxygen Single Nerve Fiber. Each motoneuron that leaves the and stores it until needed, which also greatly speeds spinal cord innervates multiple muscle fibers, with the oxygen transport to the mitochondria. The myoglo- number of fibers innervated depending on the type of bin gives the slow muscle a reddish appearance— muscle. All the muscle fibers innervated by a single nerve hence, the name red muscle.! fiber are called a motor unit (Figure 6-14). In general, small muscles that react rapidly and whose control must Fast Fibers (Type II, White Muscle). The following are be exact have more nerve fibers for fewer muscle fibers characteristics of fast fibers: (e.g., as few as two or three muscle fibers per motor unit 1. Fast fibers are large for great strength of contrac- in some of the laryngeal muscles). Conversely, large mus- tion. cles that do not require fine control, such as the soleus 2. Fast fibers have an extensive sarcoplasmic reticu- muscle, may have several hundred muscle fibers in a mo- lum for rapid release of calcium ions to initiate con- tor unit. An average figure for all the muscles of the body traction. is questionable, but a reasonable guess would be about 80 3. Large amounts of glycolytic enzymes are present in to 100 muscle fibers to a motor unit. fast fibers for rapid release of energy by the glyco- The muscle fibers in each motor unit are not all lytic process. bunched together in the muscle but overlap other motor 4. Fast fibers have a less extensive blood supply than units in microbundles of 3 to 15 fibers. This interdigitation slow fibers because oxidative metabolism is of sec- allows the separate motor units to contract in support of ondary importance. one another rather than entirely as individual segments.! 5. Fast fibers have fewer mitochondria than slow fib- ers, also because oxidative metabolism is secondary. Muscle Contractions of Different Force—Force A deficit of red myoglobin in fast muscle gives it the Summation. Summation means the adding together of name white muscle.! individual twitch contractions to increase the intensity 88  Chapter 6 Contraction of Skeletal Muscle completely smooth and continuous, as shown in the fig- Strength of muscle contraction ure. This process is called tetanization. At a slightly higher Tetanization frequency, the strength of contraction reaches its maxi- mum, so any additional increase in frequency beyond that point has no further effect in increasing contractile force. Tetany occurs because enough calcium ions are main- UNIT II tained in the muscle sarcoplasm, even between action po- tentials, so that a full contractile state is sustained without allowing any relaxation between the action potentials.! 5 10 15 20 25 30 35 40 45 50 55 Maximum Strength of Contraction. The maximum Rate of stimulation (times per second) strength of tetanic contraction of a muscle operating at a Figure 6-15 Frequency summation and tetanization. normal muscle length averages between 3 and 4 kg/cm2 of muscle, or 50 pounds/inch2. Because a quadriceps muscle can have up to 16 square inches of muscle belly, as much of overall muscle contraction. Summation occurs in two as 800 pounds of tension may be applied to the patellar ways: (1) by increasing the number of motor units con- tendon. Thus, one can readily understand how it is pos- tracting simultaneously, which is called multiple fiber sible for muscles to pull their tendons out of their inser- summation; and (2) by increasing the frequency of con- tions in bone.! traction, which is called frequency summation and can lead to tetanization.! Changes in Muscle Strength at the Onset of Contraction—the Staircase Effect (Treppe). When a Multiple Fiber Summation. When the central nerv- muscle begins to contract after a long period of rest, its ous system sends a weak signal to contract a muscle, the initial strength of contraction may be as little as one-half smaller motor units of the muscle may be stimulated in its strength 10 to 50 muscle twitches later. That is, the preference to the larger motor units. Then, as the strength strength of contraction increases to a plateau, a phenom- of the signal increases, larger and larger motor units begin enon called the staircase effect, or treppe. to be excited, with the largest motor units often having Although all the possible causes of the staircase effect as much as 50 times the contractile force of the smallest are not known, it is believed to be caused primarily by units. This phenomenon, called the size principle, is im- increasing calcium ions in the cytosol because of the portant because it allows the gradations of muscle force release of more and more ions from the sarcoplasmic during weak contraction to occur in small steps, where- reticulum with each successive muscle action poten- as the steps become progressively greater when large tial and failure of the sarcoplasm to recapture the ions amounts of force are required. This size principle occurs immediately.! because the smaller motor units are driven by small mo- tor nerve fibers, and the small motoneurons in the spinal Skeletal Muscle Tone. Even when muscles are at rest, a cord are more excitable than the larger ones, so naturally certain amount of tautness usually remains, called muscle they are excited first. tone. Because normal skeletal muscle fibers do not con- Another important feature of multiple fiber summa- tract without an action potential to stimulate the fibers, tion is that the different motor units are driven asyn- skeletal muscle tone results entirely from a low rate of chronously by the spinal cord; as a result, contraction nerve impulses coming from the spinal cord. These nerve alternates among motor units one after the other, thus impulses, in turn, are controlled partly by signals trans- providing smooth contraction, even at low frequencies of mitted from the brain to the appropriate spinal cord an- nerve signals.! terior motoneurons and partly by signals that originate in muscle spindles located in the muscle. Both these signals Frequency Summation and Tetanization. Figure 6-15 are discussed in relationship to muscle spindle and spinal shows the principles of frequency summation and tetani- cord function in Chapter 55.! zation. Individual twitch contractions occurring one after another at low frequency of stimulation are displayed on Muscle Fatigue. Prolonged strong contraction of a mus- the left. Then, as the frequency increases, there comes a cle leads to the well-known state of muscle fatigue. Stud- point when each new contraction occurs before the pre- ies in athletes have shown that muscle fatigue increases in ceding one is over. As a result, the second contraction is almost direct proportion to the rate of depletion of mus- added partially to the first, and thus the total strength of cle glycogen. Therefore, fatigue results mainly from the contraction rises progressively with increasing frequency. inability of the contractile and metabolic processes of the When the frequency reaches a critical level, the successive muscle fibers to continue supplying the same work out- contractions eventually become so rapid that they fuse to- put. However, experiments have also shown that trans- gether, and the whole muscle contraction appears to be mission of the nerve signal through the neuromuscular 89 UNIT II Membrane Physiology, Nerve, and Muscle Positioning of a Body Part by Contraction of Agonist and Antagonist Muscles on Opposite Sides of a Joint. Virtually all body movements are caused by simultaneous contrac- tion of agonist and antagonist muscles on opposite sides of joints. This process is called coactivation of the agonist and antagonist muscles, and it is controlled by the motor control centers of the brain and spinal cord. The position of each separate part of the body, such as Biceps muscle an arm or a leg, is determined by the relative degrees of con- traction of the agonist and antagonist sets of muscles. For example, let us assume that an arm or a leg is to be placed in Lever a midrange position. To achieve this position, agonist and antagonist muscles are excited to about an equal degree. Remember that an elongated muscle contracts with more force than does a shortened muscle, which was illustrated in Figure 6-10, showing maximum strength of contraction at full functional muscle length and almost no strength of contraction at half-normal length. Therefore, the elongated Fulcrum Load muscle on one side of a joint can contract with far greater force than the shorter muscle on the opposite side. As an Figure 6-16 Lever system activated by the biceps muscle. arm or leg moves toward its midposition, the strength of the longer muscle decreases, but the strength of the shorter junction, discussed in Chapter 7, can diminish at least muscle increases until the two strengths equal each other. a small amount after intense prolonged muscle activity, At this point, movement of the arm or leg stops. Thus, by thus further diminishing muscle contraction. Interrup- varying the ratios of the degree of activation of the agonist tion of blood flow through a contracting muscle leads to and antagonist muscles, the nervous system directs the po- almost complete muscle fatigue within 1 or 2 minutes be- sitioning of the arm or leg. cause of the loss of nutrient supply, especially the loss of We discuss in Chapter 55 that the motor nervous sys- tem has additional important mechanisms to compensate oxygen.! for different muscle loads when directing this positioning process.! Lever Systems of the Body. Muscles operate by applying tension to their points of insertion into bones, and the bones in turn form various types of lever systems. Fig- REMODELING OF MUSCLE TO MATCH ure 6-16 shows the lever system activated by the biceps FUNCTION muscle to lift the forearm against a load. If we assume The muscles of the body continually remodel to match that a large biceps muscle has a cross-sectional area of 6 the functions required of them. Their diameters, lengths, square inches, the maximum force of contraction would strengths, and vascular supplies are altered, and even the be about 300 pounds. When the forearm is at right an- gles with the upper arm, the tendon attachment of the types of muscle fibers are altered, at least slightly. This biceps is about 2 inches anterior to the fulcrum at the remodeling process is often quite rapid, occurring within elbow, and the total length of the forearm lever is about a few weeks. Experiments in animals have shown that 14 inches. Therefore, the amount of lifting power of the muscle contractile proteins in some smaller, more active biceps at the hand would be only one-seventh of the 300 muscles can be replaced in as little as 2 weeks. pounds of muscle force, or about 43 pounds. When the arm is fully extended, the attachment of the biceps is Muscle Hypertrophy and Muscle Atrophy. The in- much less than 2 inches anterior to the fulcrum, and the crease of the total mass of a muscle is called muscle hy- force with which the hand can be brought forward is also pertrophy. When the total mass decreases, the process is much less than 43 pounds. called muscle atrophy. In short, an analysis of the lever systems of the body de- Virtually all muscle hypertrophy results from an pends on knowledge of the following: (1) the point of muscle increase in the number of actin and myosin filaments insertion; (2) its distance from the fulcrum of the lever; (3) the length of the lever arm; and (4) the position of the lever. in each muscle fiber, causing enlargement of the indi- Many types of movement are required in the body, some of vidual muscle fibers; this condition is called simply fiber which need great strength and others that need large dis- hypertrophy. Hypertrophy occurs to a much greater tances of movement. For this reason, there are many dif- extent when the muscle is loaded during the contrac- ferent types of muscle; some are long and contract a long tile process. Only a few strong contractions each day are distance, and some are short but have large cross-sectional required to cause significant hypertrophy within 6 to 10 areas and can provide extreme strength of contraction over weeks. short distances. The study of different types of muscles, le- The manner in which forceful contraction leads to ver systems, and their movements is called kinesiology and hypertrophy is poorly understood. It is known, however, is an important scientific component of human physiology.! that the rate of synthesis of muscle contractile proteins is 90  Chapter 6 Contraction of Skeletal Muscle far greater when hypertrophy is developing, leading also fatty tissue. The fibers that do remain are composed of a to progressively greater numbers of both actin and myo- long cell membrane with a lineup of muscle cell nuclei but sin filaments in the myofibrils, often increasing as much with few or no contractile properties and little or no capa- as 50%. Some of the myofibrils have been observed to split bility of regenerating myofibrils if a nerve does regrow. within hypertrophying muscle to form new myofibrils, The fibrous tissue that replaces the muscle fibers dur- but the importance of this process in the usual enlarge- ing denervation atrophy also has a tendency to continue UNIT II ment of skeletal muscle is still unknown. shortening for many months, a process called contracture. Along with the increasing size of myofibrils, the enzyme Therefore, one of the most important problems in the systems that provide energy also increase, especially the practice of physical therapy is to keep atrophying muscles enzymes for glycolysis, allowing for a rapid supply of from developing debilitating and disfiguring contractures. energy during short-term forceful muscle contraction. This goal is achieved by daily stretching of the muscles or When a muscle remains unused for many weeks, the use of appliances that keep the muscles stretched during rate of degradation of the contractile proteins is more the atrophying process.! rapid than the rate of replacement. Therefore, muscle atrophy occurs. The pathway that appears to account for Recovery of Muscle Contraction in Poliomyelitis: much of the protein degradation in a muscle undergo- Development of Macromotor Units. When some but not ing atrophy is the ATP-dependent ubiquitin-proteasome all nerve fibers to a muscle are destroyed, as occurs in po- liomyelitis, the remaining nerve fibers branch off to form pathway. Proteasomes are large protein complexes that new axons that then innervate many of the paralyzed mus- degrade damaged or unneeded proteins by proteolysis, a cle fibers. This process results in large motor units called chemical reaction that breaks peptide bonds. Ubiquitin is macromotor units, which can contain as many as five times a regulatory protein that basically labels which cells will the normal number of muscle fibers for each motoneuron be targeted for proteosomal degradation.! coming from the spinal cord. The formation of large mo- tor units decreases the fineness of control one has over the Adjustment of Muscle Length. Another type of hyper- muscles but allows the muscles to regain varying degrees trophy occurs when muscles are stretched to greater than of strength.! normal length. This stretching causes new sarcomeres to Rigor Mortis. Several hours after death, all the muscles be added at the ends of the muscle fibers, where they at- of the body go into a state of contracture called rigor mortis; tach to the tendons. In fact, new sarcomeres can be added that is, the muscles contract and become rigid, even with- as rapidly as several per minute in newly developing mus- out action potentials. This rigidity results from loss of all the ATP, which is required to cause separation of the cross- cle, illustrating the rapidity of this type of hypertrophy. bridges from the actin filaments during the relaxation pro- Conversely, when a muscle continually remains short- cess. The muscles remain in rigor until the muscle proteins ened to less than its normal length, sarcomeres at the deteriorate about 15 to 25 hours later, which presumably ends of the muscle fibers can actually disappear. It is by results from autolysis caused by enzymes released from these processes that muscles are continually remodeled lysosomes. All these events occur more rapidly at higher so they have the appropriate length for proper muscle temperatures.! contraction.! Muscular Dystrophy. The muscular dystrophies include several inherited disorders that cause progressive weakness Hyperplasia of Muscle Fibers. Under rare conditions and degeneration of muscle fibers, which are replaced by of extreme muscle force generation, the actual number of fatty tissue and collagen. muscle fibers has been observed to increase (but only by a One of the most common forms of muscular dystro- few percent), in addition to the fiber hypertrophy process. phy is Duchenne muscular dystrophy (DMD). This disease affects only males because it is transmitted as an X-linked This increase in fiber number is called fiber hyperplasia. recessive trait and is caused by mutation of the gene that When it does occur, the mechanism is linear splitting of encodes for a protein called dystrophin, which links actins to previously enlarged fibers.! proteins in the muscle cell membrane. Dystrophin and as- sociated proteins form an interface between the intracellular Muscle Denervation Causes Rapid Atrophy. When contractile apparatus and extracellular connective matrix. a muscle loses its nerve supply, it no longer receives the Although the precise functions of dystrophin are not contractile signals that are required to maintain normal completely understood, lack of dystrophin or mutated muscle size. Therefore, atrophy begins almost immedi- forms of the protein cause muscle cell membrane desta- ately. After about 2 months, degenerative changes also bilization and activation of multiple pathophysiological begin to appear in the muscle fibers. If the nerve supply to processes, including altered intracellular calcium handling the muscle grows back rapidly, full return of function can and impaired membrane repair after injury. One important effect of abnormal dystrophin is an increase in membrane occur in as little as 3 months but, from then onward, the permeability to calcium, thus allowing extracellular calci- capability of functional return becomes less and less, with um ions to enter the muscle fiber and initiate changes in in- no further return of function after 1 to 2 years. tracellular enzymes that ultimately lead to proteolysis and In the final stage of denervation atrophy, most of the muscle fiber breakdown. muscle fibers are destroyed and replaced by fibrous and 91 UNIT II Membrane Physiology, Nerve, and Muscle Symptoms of DMD include muscle weakness that be- Gunning P, O’Neill G, Hardeman E: Tropomyosin-based regulation of gins in early childhood and rapidly progresses, so that the the actin cytoskeleton in time and space. Physiol Rev 88:1, 2008. patient is usually in wheelchairs by age 12 years and often Heckman CJ, Enoka RM: Motor unit. Compr Physiol 2:2629, 2012. dies of respiratory failure before age 30 years. A milder form Henderson CA, Gomez CG, Novak SM, Mi-Mi L, Gregorio CC. Over- view of the muscle cytoskeleton. Compr Physiol 7:891-944, 2017. of this disease, called Becker muscular dystrophy (BMD), is Jungbluth H, Treves S, Zorzato F, Sarkozy A, Ochala J, Sewry C, also caused by mutations of the gene that encodes for dys- Phadke R, Gautel M, Muntoni F. Congenital myopathies: disorders trophin but has a later onset and longer survival. It is esti- of excitation-contraction coupling and muscle contraction. Nat Rev mated that DMD and BMD affect 1 of every 5,600 to 7,700 Neurol 14:151-167, 2018. males between the ages of 5 through 24 years. Currently, Larsson L, Degens H, Li M, Salviati L, Lee YI, Thompson W, Kirkland no effective treatment exists for DMD or BMD, although JL, Sandri M. Sarcopenia: Aging-related loss of muscle mass and characterization of the genetic basis for these diseases has function. Physiol Rev 99:427-511, 2019. provided the potential for gene therapy in the future. Lin BL, Song T, Sadayappan S. Myofilaments: Movers and rulers of the sarcomere. Compr Physiol 7:675-692, 2017. Mercuri E, Muntoni F: Muscular dystrophies. Lancet 381:845, 2013. Murach KA, Fry CS, Kirby TJ, Jackson JR, Lee JD, White SH, Dupont- Bibliography Versteegden EE, McCarthy JJ, Peterson CA. Starring or supporting Adams GR, Bamman MM: Characterization and regulation of me- role? Satellite cells and skeletal muscle fiber size regulation. Physi- chanical loading-induced compensatory muscle hypertrophy. Com- ology (Bethesda) 33:26-38, 2018. pr Physiol 2:2829, 2012. Olsen LA, Nicoll JX, Fry AC. The skeletal muscle fiber: a mechanically Allen DG, Lamb GD, Westerblad H: Skeletal muscle fatigue: cellular sensitive cell. Eur J Appl Physiol 119:333-349, 2019. mechanisms. Physiol Rev 88:287, 2008. Patikas DA, Williams CA, Ratel S. Exercise-induced fatigue in young Blake DJ, Weir A, Newey SE, Davies KE: Function and genetics of people: advances and future perspectives. Eur J Appl Physiol dystrophin and dystrophin-related proteins in muscle. Physiol Rev 118:899-910, 2018. 82:291, 2002. Schaeffer PJ, Lindstedt SL: How animals move: comparative lessons Damas F, Libardi CA, Ugrinowitsch C. The development of skeletal on animal locomotion. Compr Physiol 3:289, 2013. muscle hypertrophy through resistance training: the role of muscle Schiaffino S, Reggiani C: Fiber types in mammalian skeletal muscles. damage and muscle protein synthesis. Eur J Appl Physiol 118:485- Physiol Rev 91:1447, 2011. 500, 2019. Tsianos GA, Loeb GE. Muscle and limb mechanics. Compr Physiol Fitts RH: The cross-bridge cycle and skeletal muscle fatigue. J Appl 7:429-462, 2017. Physiol 104:551, 2008. van Breemen C, Fameli N, Evans AM: Pan-junctional sarcoplasmic Francaux M, Deldicque L. Exercise and the control of muscle mass in reticulum in vascular smooth muscle: nanospace Ca2+ transport human. Pflugers Arch 471:397-411, 2019. for site- and function-specific Ca2+ signalling. J Physiol 591:2043, Glass DJ: Signaling pathways that mediate skeletal muscle hypertro- 2013. phy and atrophy. Nat Cell Biol 5:87, 2003. Vandenboom R. Modulation of skeletal muscle contraction by myosin Gorgey AS, Witt O, O’Brien L, Cardozo C, Chen Q, Lesnefsky EJ, Gra- phosphorylation. Compr Physiol 7:171-212, 2016. ham ZA. Mitochondrial health and muscle plasticity after spinal cord injury. Eur J Appl Physiol 119:315-331, 2019. 92  CHAPTER 7 UNIT II Excitation of Skeletal Muscle: Neuromuscular Transmission and Excitation-Contraction Coupling NEUROMUSCULAR JUNCTION AND in the cytoplasm of the terminal but is absorbed rap- TRANSMISSION OF IMPULSES FROM idly into many small synaptic vesicles, about 300,000 of NERVE ENDINGS TO SKELETAL MUSCLE which are normally in the terminals of a single end plate. FIBERS In the synaptic space are large quantities of the enzyme Skeletal muscle fibers are innervated by large myelinated acetylcholinesterase, which destroys acetylcholine a few nerve fibers that originate from large motoneurons in the milliseconds after it has been released from the synaptic anterior horns of the spinal cord. As discussed in Chap- vesicles.! ter 6, each nerve fiber, after entering the muscle belly, normally branches and stimulates from three to several SECRETION OF ACETYLCHOLINE BY THE hundred skeletal muscle fibers. Each nerve ending makes NERVE TERMINALS a junction, called the neuromuscular junction, with the muscle fiber near its midpoint. The action potential initi- When a nerve impulse reaches the neuromuscular junc- ated in the muscle fiber by the nerve signal travels in both tion, about 125 vesicles of acetylcholine are released from directions toward the muscle fiber ends. With the excep- the terminals into the synaptic space. Some of the details tion of about 2% of the muscle fibers, there is only one of this mechanism can be seen in Figure 7-2, which such junction per muscle fiber. shows an expanded view of a synaptic space with the neu- ral membrane above and the muscle membrane and its subneural clefts below. PHYSIOLOGIC ANATOMY OF THE On the inside surface of the neural membrane are lin- NEUROMUSCULAR JUNCTION—THE ear dense bars, shown in cross section in Figure 7-2. To MOTOR END PLATE each side of each dense bar are protein particles that pen- Figure 7-1A and B shows the neuromuscular junction etrate the neural membrane; these are voltage-gated cal- from a large myelinated nerve fiber to a skeletal muscle cium channels. When an action potential spreads over the fiber. The nerve fiber forms a complex of branching nerve terminal, these channels open and allow calcium ions to terminals that invaginate into the surface of the muscle diffuse from the synaptic space to the interior of the nerve fiber but lie outside the muscle fiber plasma membrane. terminal. The calcium ions, in turn, are believed to acti- The entire structure is called the motor end plate. It is cov- vate Ca2+-calmodulin–dependent protein kinase, which, ered by one or more Schwann cells that insulate it from in turn, phosphorylates synapsin proteins that anchor the surrounding fluids. the acetylcholine vesicles to the cytoskeleton of the pre- Figure 7-1C shows the junction between a single axon synaptic terminal. This process frees the acetylcholine terminal and the muscle fiber membrane. The invaginated vesicles from the cytoskeleton and allows them to move membrane is called the synaptic gutter or synaptic trough, to the active zone of the presynaptic neural membrane and the space between the terminal and the fiber mem- adjacent to the dense bars. The vesicles then dock at the brane is called the synaptic space or synaptic cleft, which release sites, fuse with the neural membrane, and empty is 20 to 30 nanometers wide. At the bottom of the gut- their acetylcholine into the synaptic space by the process ter are numerous smaller folds of the muscle membrane of exocytosis. called subneural clefts, which greatly increase the surface Although some of the aforementioned details are spec- area at which the synaptic transmitter can act. ulative, it is known that the effective stimulus for causing In the axon terminal are many mitochondria that sup- acetylcholine release from the vesicles is entry of calcium ply adenosine triphosphate (ATP), the energy source used ions and that acetylcholine from the vesicles is then emp- for synthesis of a transmitter, acetylcholine, which excites tied through the neural membrane adjacent to the dense the muscle fiber membrane. Acetylcholine is synthesized bars. 93 UNIT II Membrane Physiology, Nerve, and Muscle Myelin Axon sheath Terminal nerve branches Teloglial cell Myofibrils Muscle nuclei A B Axon terminal in Synaptic vesicles synaptic trough C Subneural clefts Figure 7-1. Different views of the motor end plate. A, Longitudinal section through the end plate. B, Surface view of the end plate. C, Electron micrographic appearance of the contact point between a single axon terminal and the muscle fiber membrane. Release Neural Vesicles the subneural clefts lying immediately below the dense sites membrane bar areas, where the acetylcholine is emptied into the syn- aptic space. The voltage-gated sodium channels also line the subneural clefts. Dense bar Each acetylcholine receptor is a protein complex that Calcium channels has a total molecular weight of approximately 275,000. The fetal acetylcholine receptor complex is composed of Basal lamina and five subunit proteins, two alpha proteins and one each of acetylcholinesterase beta, delta, and gamma proteins. In the adult, an epsilon protein substitutes for the gamma protein in this recep- Acetylcholine receptors tor complex. These protein molecules penetrate all the way through the membrane, lying side by side in a circle to form a tubular channel, illustrated in Figure 7-3. The Subneural cleft channel remains constricted, as shown in part A of the Voltage-activated Na+ channels figure, until two acetylcholine molecules attach respec- tively to the two alpha subunit proteins. This attachment causes a conformational change that opens the channel, Muscle