Physiology 5th Ed.


Contraction of skeletal muscle is under voluntary control. Each skeletal muscle cell is innervated by a branch of a motoneuron. Action potentials are propagated along the motoneurons, leading to release of ACh at the neuromuscular junction, depolarization of the motor end plate, and initiation of action potentials in the muscle fiber.

What events, then, elicit contraction of the muscle fiber? These events, occurring between the action potential in the muscle fiber and contraction of the muscle fiber, are called excitation-contraction coupling. The mechanisms of excitation-contraction coupling in skeletal muscle and smooth muscle are discussed in this chapter, and the mechanisms of excitation-contraction coupling in cardiac muscle are discussed in Chapter 4.

Muscle Filaments

Each muscle fiber behaves as a single unit, is multinucleate, and contains myofibrils. The myofibrils are surrounded by sarcoplasmic reticulum and are invaginated by transverse tubules (T tubules). Each myofibril contains interdigitating thick and thin filaments, which are arranged longitudinally and cross-sectionally in sarcomeres (Fig. 1-21). The repeating units of sarcomeres account for the unique banding pattern seen in striated muscle (which includes both skeletal and cardiac muscle).


Figure 1–21 Structure of thick (A) and thin (B) filaments of skeletal muscle. Troponin is a complex of three proteins: I, troponin I; T, troponin T; and C, troponin C.

Thick Filaments

The thick filaments comprise a large molecular weight protein called myosin, which has six polypeptide chains including one pair of heavy chains and two pairs of light chains (see Figure 1-21A). Most of the heavy-chain myosin has an α-helical structure, in which the two chains coil around each other to form the “tail” of the myosin molecule. The four light chains and the N terminus of each heavy chain form two globular “heads” on the myosin molecule. These globular heads have an actin-binding site, which is necessary for cross-bridge formation, and a site that binds and hydrolyzes ATP (myosin ATPase).

Thin Filaments

The thin filaments are composed of three proteins: actin, tropomyosin, and troponin (see Fig. 1-21B).

Actin is a globular protein and, in this globular form, is called G-actin. In the thin filaments, G-actin is polymerized into two strands that are twisted into an α-helical structure to form filamentous actin, called F-actin. Actin has myosin-binding sites. When the muscle is at rest, the myosin-binding sites are covered by tropomyosin so that actin and myosin cannot interact.

Tropomyosin is a filamentous protein that runs along the groove of each twisted actin filament. At rest, its function is to block the myosin-binding sites on actin. If contraction is to occur, tropomyosin must be moved out of the way so that actin and myosin can interact.

Troponin is a complex of three globular proteins (troponin T, troponin I, and troponin C) located at regular intervals along the tropomyosin filaments. Troponin T (T for tropomyosin) attaches the troponin complex to tropomyosin. Troponin I (I for inhibition), along with tropomyosin, inhibits the interaction of actin and myosin by covering the myosin-binding site on actin. Troponin C (C for Ca2+) is a Ca2+-binding protein that plays a central role in the initiation of contraction. When the intracellular Ca2+ concentration increases, Ca2+ binds to troponin C, producing a conformational change in the troponin complex. This conformational change moves tropomyosin out of the way, permitting the binding of actin to the myosin heads.

Arrangement of Thick and Thin Filaments in Sarcomeres

The sarcomere is the basic contractile unit, and it is delineated by the Z disks. Each sarcomere contains a full A band in the center and one half of two I bands on either side of the A band (Fig. 1-22).


Figure 1–22 Arrangement of thick and thin filaments of skeletal muscle in sarcomeres.

The A bands are located in the center of the sarcomere and contain the thick (myosin) filaments, which appear dark when viewed under polarized light. Thick and thin filaments may overlap in the A band; these areas of overlap are potential sites of cross-bridge formation.

The I bands are located on either side of the A band and appear light when viewed under polarized light. They contain the thin (actin) filaments, intermediate filamentous proteins, and Z disks. They have no thick filaments.

The Z disks are darkly staining structures that run down the middle of each I band, delineating the ends of each sarcomere.

The bare zone is located in the center of each sarcomere. There are no thin filaments in the bare zone; thus, there can be no overlap of thick and thin filaments or cross-bridge formation in this region.

The M line bisects the bare zone and contains darkly staining proteins that link the central portions of the thick filaments together.

Cytoskeletal Proteins

Cytoskeletal proteins establish the architecture of the myofibrils, ensuring that the thick and thin filaments are aligned correctly and at proper distances with respect to each other.

Transverse cytoskeletal proteins link thick and thin filaments, forming a “scaffold” for the myofibrils and linking sarcomeres of adjacent myofibrils. A system of intermediate filaments holds the myofibrils together, side by side. The entire myofibrillar array is anchored to the cell membrane by an actin-binding protein called dystrophin. (In patients with muscular dystrophy, dystrophin is defective or absent.)

Longitudinal cytoskeletal proteins include two large proteins called titin and nebulin. Titin, which is associated with thick filaments, is a large molecular weight protein that extends from the M lines to the Z disks. Part of the titin molecule passes through the thick filament; the rest of the molecule, which is elastic or springlike, is anchored to the Z disk. As the length of the sarcomere changes, so does the elastic portion of the titin molecule. Titin also helps center the thick filaments in the sarcomere. Nebulin is associated with thin filaments. A single nebulin molecule extends from one end of the thin filament to the other. Nebulin serves as a “molecular ruler,” setting the length of thin filaments during their assembly. α-Actinin anchors the thin filaments to the Z disk.

Transverse Tubules and the Sarcoplasmic Reticulum

The transverse (Ttubules are an extensive network of muscle cell membrane (sarcolemmal membrane) that invaginates deep into the muscle fiber. The T tubules are responsible for carrying depolarization from action potentials at the muscle cell surface to the interior of the fiber. The T tubules make contact with the terminal cisternae of the sarcoplasmic reticulum and contain a voltage-sensitive protein called the dihydropyridine receptor, named for the drug that inhibits it (Fig. 1-23).


Figure 1–23 Transverse tubules and sarcoplasmic reticulum of skeletal muscle. The transverse tubules are continuous with the sarcolemmal membrane and invaginate deep into the muscle fiber, making contact with terminal cisternae of the sarcoplasmic reticulum.

The sarcoplasmic reticulum is an internal tubular structure, which is the site of storage and release of Ca2+ for excitation-contraction coupling. As previously noted, the terminal cisternae of the sarcoplasmic reticulum make contact with the T tubules in a triad arrangement. The sarcoplasmic reticulum contains a Ca2+-release channel called the ryanodine receptor (named for the plant alkaloid that opens this release channel). The significance of the physical relationship between the T tubules (and their dihydropyridine receptor) and the sarcoplasmic reticulum (and its ryanodine receptor) is described in the section on excitation-contraction coupling.

Ca2+ is accumulated in the sarcoplasmic reticulum by the action of Ca2+ ATPase (SERCA) in the sarcoplasmic reticulum membrane. The Ca2+ ATPase pumps Ca2+ from the ICF of the muscle fiber into the interior of the sarcoplasmic reticulum, keeping the intracellular Ca2+ concentration low when the muscle fiber is at rest. Within the sarcoplasmic reticulum, Ca2+ is bound to calsequestrin, a low-affinity, high-capacity Ca2+-binding protein. Calsequestrin, by binding Ca2+, helps to maintain a low free Ca2+ concentration inside the sarcoplasmic reticulum, thereby reducing the work of the Ca2+ ATPase pump. Thus, a large quantity of Ca2+ can be stored inside the sarcoplasmic reticulum in bound form, while the intrasarcoplasmic reticulum free Ca2+ concentration remains extremely low.

Excitation-Contraction Coupling in Skeletal Muscle

The mechanism that translates the muscle action potential into the production of tension is excitation-contraction coupling. Figure 1-24 shows the temporal relationships between an action potential in the skeletal muscle fiber, the subsequent increase in intracellular free Ca2+ concentration (which is released from the sarcoplasmic reticulum), and contraction of the muscle fiber. These temporal relationships are critical in that the action potential always precedes the rise in intracellular Ca2+ concentration, which always precedes contraction.


Figure 1–24 Temporal sequence of events in excitation-contraction coupling in skeletal muscle. The muscle action potential precedes a rise in intracellular [Ca2+], which precedes contraction.

The steps involved in excitation-contraction coupling are described as follows and illustrated in Figure 1-25. (Step 6 is illustrated in Fig. 1-26):


Figure 1–25 Steps in excitation-contraction in skeletal muscle. SR, Sarcoplasmic reticulum; T tubules, transverse tubules. See text for explanation of the circled numbers.


Figure 1–26 Cross-bridge cycle in skeletal muscle. Mechanism by which myosin “walks” toward the plus end of the actin filament. A–E, See the discussion in the text. ADP, Adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate.

Video: The cross-bridge cycle

1. Action potentials in the muscle cell membrane are propagated to the T tubules by the spread of local currents. Thus, the T tubules are continuous with the sarcolemmal membrane and carry the depolarization from the surface to the interior of the muscle fiber.

2a. and b. Depolarization of the T tubules causes a critical conformational change in their voltage-sensitive dihydropyridine receptors. This conformational change opens Ca2+-release channels (ryanodine receptors) on the nearby sarcoplasmic reticulum. (As an aside, although the T tubules’ dihydropyridine receptors are L-type voltage-gated Ca2+ channels, Ca2+ influx into the cell through these channels is notrequired for excitation-contraction coupling in skeletal muscle.)

3. When these Ca2+-release channels open, Ca2+ is released from its storage site in the sarcoplasmic reticulum into the ICF of the muscle fiber, resulting in an increase in intracellular Ca2+ concentration. At rest, the intracellular free Ca2+ concentration is less than 10−7 M. After its release from the sarcoplasmic reticulum, intracellular free Ca2+ concentration increases to levels between 10−7 M and 10−6 M.

4. Ca2+ binds to troponin C on the thin filaments, causing a conformational change in the troponin complex. Troponin C can bind as many as four Ca2+ ions per molecule of protein. Because this binding is cooperative, each molecule of bound Ca2+ increases the affinity of troponin C for the next Ca2+. Thus, even a small increase in Ca2+ concentration increases the likelihood that all of the binding sites will be occupied to produce the necessary conformational change in the troponin complex.

5. The conformational change in troponin causes tropomyosin (which was previously blocking the interaction of actin and myosin) to be moved out of the way so that cross-bridge cycling can begin. When tropomyosin is moved away, the myosin-binding sites on actin, previously covered, are exposed.

6. Cross-bridge cycling. With Ca2+ bound to troponin C and tropomyosin moved out of the way, myosin heads can now bind to actin and form so-called cross-bridges. Formation of cross-bridges is associated with hydrolysis of ATP and generation of force.

The sequence of events in the cross-bridge cycle is shown in Figure 1-26A, At the beginning of the cycle, no ATP is bound to myosin, and myosin is tightly attached to actin in a “rigor” position. In rapidly contracting muscle, this state is brief. However, in the absence of ATP, this state is permanent (i.e., rigor mortis). B, The binding of ATP to a cleft on the back of the myosin head produces a conformational change in myosin that decreases its affinity for actin; thus, myosin is released from the original actin-binding site. C, The cleft closes around the bound ATP molecule, producing a further conformational change that causes myosin to be displaced toward the plus end of actin. ATP is hydrolyzed to ADP and Pi, which remain attached to myosin. D, Myosin binds to a new site on actin (toward the plus end), constituting the force-generating, or power, stroke. Each cross-bridge cycle “walks” the myosin head 10 nanometers (10−8 meters) along the actin filament. E, ADP is released, and myosin is returned to its original state with no nucleotides bound (A). Cross-bridge cycling continues, with myosin “walking” toward the plus end of the actin filament, as long as Ca2+ is bound to troponin C.

7. Relaxation occurs when Ca2+ is reaccumulated in the sarcoplasmic reticulum by the Ca2+ ATPase of the sarcoplasmic reticulum membrane (SERCA). When the intracellular Ca2+ concentration decreases to less than 10−7 M, there is insufficient Ca2+ for binding to troponin C. When Ca2+ is released from troponin C, tropomyosin returns to its resting position, where it blocks the myosin-binding site on actin. As long as the intracellular Ca2+ is low, cross-bridge cycling cannot occur and the muscle will relax.

The cross-bridge cycle produces force (tension) at the level of the contractile elements. In order for this force to be transmitted to the muscle surface, the series elastic elements (e.g., titin) must first be stretched out. As a result, there is a delay in transmission of force from the cross-bridges to the muscle surface (see Fig. 1-24). Once cross-bridge cycling has concluded, there is also a delay in the fall of muscle tension; the series elastic elements remain stretched out and thus force transmission to the muscle surface continues after intracellular Ca2+ has fallen and cross-bridge cycling has ceased.

Mechanism of Tetanus

A single action potential results in the release of a fixed amount of Ca2+ from the sarcoplasmic reticulum, which produces a single twitch. The twitch is terminated (relaxation occurs) when the sarcoplasmic reticulum reaccumulates this Ca2+. However, if the muscle is stimulated repeatedly, there is insufficient time for the sarcoplasmic reticulum to reaccumulate Ca2+, and the intracellular Ca2+ concentration never returns to the low levels that exist during relaxation. Instead, the level of intracellular Ca2+ concentration remains high, resulting in continued binding of Ca2+ to troponin C and continued cross-bridge cycling. In this state, there is a sustained contraction called tetanus, rather than just a single twitch.

Length-Tension Relationship

The length-tension relationship in muscle refers to the effect of muscle fiber length on the amount of tension the fiber can develop (Fig. 1-27). The amount of tension is determined for a muscle undergoing an isometric contraction, in which the muscle is allowed to develop tension at a preset length (called preload) but is not allowed to shorten. (Imagine trying to lift a 500-lb barbell. The tension developed would be great, but no shortening or movement of muscle would occur!) The following measurements of tension can be made as a function of preset length (or preload):


Figure 1–27 Length-tension relationship in skeletal muscle. Maximal active tension occurs at muscle lengths where there is maximal overlap of thick and thin filaments.

image Passive tension is the tension developed by simply stretching a muscle to different lengths. (Think of the tension produced in a rubber band as it is progressively stretched to longer lengths.)

image Total tension is the tension developed when a muscle is stimulated to contract at different preloads. It is the sum of the active tension developed by the cross-bridge cycling in the sarcomeres and the passive tension caused by stretching the muscle.

image Active tension is determined by subtracting the passive tension from the total tension. It represents the active force developed during cross-bridge cycling.

    The unusual relationship between active tension and muscle length is the length-tension relationship and can be explained by the mechanisms involved in the cross-bridge cycle (see Fig. 1-27). The active tension developed is proportional to the number of cross-bridges that cycle. Therefore, the active tension is maximal when there is maximal overlap of thick and thin filaments and maximal possible cross-bridges. When the muscle is stretched to longer lengths, the number of possible cross-bridges is reduced and active tension is reduced. Likewise, when muscle length is decreased, the thin filaments collide with each other in the center of the sarcomere, reducing the number of possible cross-bridges and reducing active tension.

Force-Velocity Relationship

The force-velocity relationship, shown in Figure 1-28, describes the velocity of shortening when the force against which the muscle contracts, the afterload, is varied (see Fig. 1-28left). In contrast to the length-tension relationship, the force-velocity relationship is determined by allowing the muscle to shorten. The force, rather than the length, is fixed, and therefore, it is called an isotonic contraction. The velocity of shortening reflects the speed of cross-bridge cycling. As is intuitively obvious, the velocity of shortening will be maximal (Vmax) when the afterload on the muscle is zero. As the afterload on the muscle increases, the velocity will be decreased because cross-bridges can cycle less rapidly against the higher resistance. As the afterload increases to even higher levels, the velocity of shortening is reduced to zero. (Imagine how quickly you can lift a feather as opposed to a ton of bricks!)


Figure 1–28 Initial velocity of shortening as a function of afterload in skeletal muscle.

The effect of afterload on the velocity of shortening can be further demonstrated by setting the muscle to a preset length (preload) and then measuring the velocity of shortening at various levels of afterload (see Fig. 1-28right). A “family” of curves is generated, each one representing a different fixed preload. The curves always intersect at Vmax, the point where afterload is zero and where velocity of shortening is maximal.