SKELETAL MUSCLE

Skeletal muscle consists of muscle fibers, bundles of very long (up to 30 cm) cylindrical multinucleated cells with a diameter of 10–100 m . Multinucleation results from the fusion of embryonic mononucleated myoblasts (muscle cell precursors). The oval nuclei are usually found at the periphery of the cell under the cell membrane. This characteristic nuclear location is helpful in distinguishing skeletal muscle from cardiac and smooth muscle, both of which have centrally located nuclei.

MEDICAL APPLICATION

The variation in diameter of skeletal muscle fibers depends on factors such as the specific muscle and the age and sex, state of nutrition, and physical training of the individual. It is a common observation that exercise enlarges the musculature and decreases fat depots. The increase in muscle thus obtained is caused by formation of new myofibrils and a pronounced growth in the diameter of individual muscle fibers. This process, characterized by augmentation of cell volume, is called hypertrophy (Gr. hyper, above, + trophe, nourishment); tissue growth by an increase in the number of cells is termed hyperplasia (hyper + Gr. plasis, molding). Hyperplasia does not occur in either skeletal or cardiac muscle but does take place in smooth muscle, whose cells have not lost the capacity to divide by mitosis. Hyperplasia is rather frequent in organs such as the uterus, where both hyperplasia and hypertrophy occur during pregnancy.

Organization of Skeletal Muscle

The masses of fibers that make up the various types of muscle are not grouped in random fashion but are arranged in regular bundles surrounded by the epimysium (Gr. epi, upper, + mys, muscle), an external sheath of dense connective tissue surrounding the entire muscle (Figures 10–2, 10–3, and 10–4). From the epimysium, thin septa of connective tissue extend inward, surrounding the bundles of fibers within a muscle. The connective tissue around each bundle of muscle fibers is called the perimysium (Gr. peri, around, + mys). Each muscle fiber is itself surrounded by a delicate layer of connective tissue, the endomysium (Gr. endon, within, + mys), composed mainly of a basal lamina and reticular fibers.

One of the most important roles of connective tissue is to mechanically transmit the forces generated by contracting muscle cells, because in most instances, individual muscle cells do not extend from one end of a muscle to the other.

Blood vessels penetrate the muscle within the connective tissue septa and form a rich capillary network (Figure 10–5) that runs between and parallel to the muscle fibers. The capillaries are of the continuous type, and lymphatic vessels are found in the connective tissue.

Some muscles taper off at their extremities, where a myotendinous junction is formed. The electron microscope shows that in this transitional region, collagen fibers of the tendon insert themselves into complex infoldings of the plasmalemma of the muscle fibers (Figure 10–7).

Organization of Skeletal Muscle Fibers

As observed with the light microscope, longitudinally sectioned muscle fibers show cross-striations of alternating light and dark bands (Figures 10–6, 10–7, 10–8, and 10–9). The darker bands are called A bands (anisotropic, ie, are birefringent in polarized light); the lighter bands are called I bands (isotropic, ie, do not alter polarized light). In the electron microscope, each I band is bisected by a dark transverse line, the Z line. The smallest repetitive subunit of the contractile apparatus, the sarcomere (sarkos + Gr. mere, part), extends from Z line to Z line (Figures 10–10 and 10–11) and is about 2.5 m long in resting muscle.

The sarcoplasm is filled with long cylindrical filamentous bundles called myofibrils. The myofibrils, which have a diameter of 1–2 m and run parallel to the long axis of the muscle fiber, consist of an end-to-end chainlike arrangement of sarcomeres (Figures 10–10 and 10–11). The lateral registration of sarcomeres in adjacent myofibrils causes the entire muscle fiber to exhibit a characteristic pattern of transverse striations.

Studies with the electron microscope reveal that this sarcomere pattern is due mainly to the presence of two types of filaments—thick and thin—that lie parallel to the long axis of the myofibrils in a symmetric pattern.

The thick filaments are 1.6 m long and 15 nm wide; they occupy the A band, the central portion of the sarcomere. The thin filaments run between and parallel to the thick filaments and have one end attached to the Z line (Figures 10–10 and 10–11). Thin filaments are 1.0 m long and 8 nm wide. As a result of this arrangement, the I bands consist of the portions of the thin filaments that do not overlap the thick filaments. The A bands are composed mainly of thick filaments in addition to portions of overlapping thin filaments. Close observation of the A band shows the presence of a lighter zone in its center, the H band, that corresponds to a region consisting only of the rodlike portions of the myosin molecule (Figures 10–10 and 10–11). Bisecting the H band is the M line, a region at which lateral connections are made between adjacent thick filaments (Figure 10–11). The major protein of the M line is creatine kinase. Creatine kinase catalyzes the transfer of a phosphate group from phosphocreatine (a storage form of high-energy phosphate groups) to adenosine diphosphate (ADP), thus supplying adenosine triphosphate (ATP) for muscle contraction.

Thin and thick filaments overlap for some distance within the A band. As a consequence, a cross section in the region of filament overlap shows each thick filament surrounded by six thin filaments in the form of a hexagon (Figures 10–11 and 10–12).

Striated muscle filaments contain several proteins; the four main proteins are actin, tropomyosin, troponin, and myosin. Thin filaments are composed of the first three proteins, whereas thick filaments consist primarily of myosin. Myosin and actin together represent 55% of the total protein of striated muscle.

Actin is present as long filamentous (F-actin) polymers consisting of two strands of globular (G-actin) monomers, 5.6 nm in diameter, twisted around each other in a double helical formation (Figure 10–11). G-actin molecules are structurally asymmetric. When G-actin molecules polymerize to form F-actin, they bind back to front, producing a filament with distinguishable polarity (Figure 10–13). Each G-actin monomer contains a binding site for myosin (Figure 10–14). Actin filaments, which anchor perpendicularly on the Z line, exhibit opposite polarity on each side of the line (Figure 10–11). The protein -actinin, a major component of the Z line, is thought to anchor the actin filaments to this region. -Actinin and desmin (an intermediate filament protein) are believed to tie adjacent sarcomeres together, thus keeping the myofibrils in register.

Tropomyosin, a long, thin molecule about 40 nm in length, contains two polypeptide chains. These molecules are bound head to tail, forming filaments that run over the actin subunits alongside the outer edges of the groove between the two twisted actin strands (Figure 10–13).

Troponin is a complex of three subunits: TnT, which strongly attaches to tropomyosin; TnC, which binds calcium ions; and TnI, which inhibits the actin–myosin interaction. A troponin complex is attached at one specific site on each tropomyosin molecule (Figure 10–13).

In thin filaments, each tropomyosin molecule spans seven G-actin molecules and has one troponin complex bound to its surface (Figure 10–13).

Myosin, a much larger complex (molecular mass 500 kDa), can be dissociated into two identical heavy chains and two pairs of light chains. Myosin heavy chains are thin, rodlike molecules (150 nm long and 2–3 nm thick) made up of two heavy chains twisted together. Small globular projections at one end of each heavy chain form the heads, which have ATP-binding sites as well as the enzymatic capacity to hydrolyze ATP (ATPase activity) and the ability to bind to actin. The four light chains are associated with the head (Figure 10–11). Several hundred myosin molecules are arranged within each thick filament with their rodlike portions overlapping and their globular heads directed toward either end (Figure 10–11).

Analysis of thin sections of striated muscle shows the presence of cross-bridges between thin and thick filaments. These bridges, which are known to be formed by the head of the myosin molecule plus a short part of its rodlike portion, are involved in the conversion of chemical energy into mechanical energy (Figure 10–14).

Sarcoplasmic Reticulum & Transverse Tubule System

The depolarization of the sarcoplasmic reticulum membrane, which results in the release of Ca²⁺ ions, is initiated at a specialized myoneural junction on the surface of the muscle cell. Surface-initiated depolarization signals would have to diffuse throughout the cell to effect the release of Ca²⁺ from internal sarcoplasmic reticulum cisternae. In larger muscle cells, the diffusion of the depolarization signal would lead to a wave of contraction, with peripheral myofibrils contracting before more centrally positioned myofibrils. To provide for a uniform contraction, skeletal muscle possesses a system of transverse (T) tubules (Figure 10–15). These fingerlike invaginations of the sarcolemma form a complex anastomosing network of tubules that encircles the boundaries of the A-I bands of each sarcomere in every myofibril (Figures 10–16 and 10–17).

Adjacent to opposite sides of each T tubule are expanded terminal cisternae of the sarcoplasmic reticulum. This specialized complex, consisting of a T tubule with two lateral portions of sarcoplasmic reticulum, is known as the triad (Figures 10–10, 10–16, and 10–17). At the triad, depolarization of the sarcolemma-derived T tubules is transmitted to the sarcoplasmic reticulum membrane.

As described above, muscle contraction depends on the availability of Ca²⁺ ions, and muscle relaxation is related to an absence of Ca²⁺. The sarcoplasmic reticulum specifically regulates calcium flow, which is necessary for rapid contraction and relaxation cycles. The sarcoplasmic reticulum system consists of a branching network of smooth endoplasmic reticulum cisternae surrounding each myofibril (Figure 10–17). After a neurally mediated depolarization of the sarcoplasmic reticulum membrane, Ca²⁺ ions concentrated within the sarcoplasmic reticulum cisternae are passively released into the vicinity of the overlapping thick and thin filaments, whereupon they bind to troponin and allow bridging between actin and myosin. When the membrane depolarization ends, the sarcoplasmic reticulum acts as a calcium sink and actively transports the Ca²⁺ back into the cisternae, resulting in the cessation of contractile activity.

Mechanism of Contraction

Resting sarcomeres consist of partially overlapping thick and thin filaments. During contraction, both the thick and thin filaments retain their original length. Because contraction is not caused by a shortening of individual filaments, it must be the result of an increase in the amount of overlap between the filaments. The sliding filament hypothesis of muscle contraction has received the most widespread acceptance.

The following is a brief description of how actin and myosin interact during a contraction cycle. At rest, ATP binds to the ATPase site on the myosin heads, but the rate of hydrolysis is very slow. Myosin requires actin as a cofactor to break down ATP rapidly and release energy. In a resting muscle, myosin cannot associate with actin, because the binding sites for myosin heads on actin molecules are covered by the troponin–tropomyosin complex on the F-actin filament (Figure 10–14, top). When sufficiently high concentrations of calcium ions are available, however, they bind to the TnC subunit of troponin. The spatial configuration of the three troponin subunits changes and drives the tropomyosin molecule deeper into the groove of the actin helix (Figure 10–14). This exposes the myosin-binding site on the globular actin components, so that actin is free to interact with the head of the myosin molecule.

The binding of calcium ions to the TnC unit corresponds to the stage at which myosin–ATP is converted into the active complex. As a result of bridging between the myosin head and the G-actin subunit of the thin filament, the ATP is split into ADP and Pi (phosphate ion), and energy is released. This activity leads to a deformation, or bending, of the head and a part of the rodlike portion (hinge region) of the myosin (Figure 10–14). Because the actin is bound to the myosin, movement of the myosin head pulls the actin past the myosin filament. The result is that the thin filament is drawn farther into the A band.

Although a large number of myosin heads extends from the thick filament, at any one time during the contraction only a small number of heads aligns with available actin-binding sites. As the bound myosin heads move the actin, however, they provide for alignment of new actin–myosin bridges. The old actin–myosin bridges detach only after the myosin binds a new ATP molecule; this action also resets the myosin head and prepares it for another contraction cycle. If no ATP is available, the actin–myosin complex becomes stable; this accounts for the extreme muscular rigidity (rigor mortis) that occurs after death. A single muscle contraction is the result of hundreds of bridge-forming and bridge-breaking cycles. The contraction activity that leads to a complete overlap between thin and thick filaments continues until Ca²⁺ ions are removed and the troponin–tropomyosin complex again covers the myosin-binding site.

During contraction, the I band decreases in size as thin filaments penetrate the A band. The H band—the part of the A band with only thick filaments—diminishes in width as the thin filaments completely overlap the thick filaments. A net result is that each sarcomere, and consequently the whole cell (fiber), is greatly shortened (Figure 10–18).

Innervation

Myelinated motor nerves branch out within the perimysial connective tissue, where each nerve gives rise to several terminal twigs. At the site of innervation, the nerve loses its myelin sheath and forms a dilated termination that sits within a trough on the muscle cell surface. This structure is called the motor end plate, or myoneural junction (Figure 10–18). At this site, the axon is covered by a thin cytoplasmic layer of Schwann cells. Within the axon terminal are numerous mitochondria and synaptic vesicles, the latter containing the neurotransmitter acetylcholine. Between the axon and the muscle is a space, the synaptic cleft, in which an amorphous basal lamina matrix lies. At the junction, the sarcolemma is thrown into numerous deep junctional folds. In the sarcoplasm below the folds lie several nuclei and numerous mitochondria, ribosomes, and glycogen granules.

When an action potential invades the motor end plate, acetylcholine is liberated from the axon terminal, diffuses through the cleft, and binds to acetylcholine receptors in the sarcolemma of the junctional folds. Binding of the transmitter makes the sarcolemma more permeable to sodium, which results in membrane depolarization. Excess acetylcholine is hydrolyzed by the enzyme cholinesterase bound to the synaptic cleft basal lamina. Acetylcholine breakdown is necessary to avoid prolonged contact of the transmitter with receptors present in the sarcolemma.

The depolarization initiated at the motor end plate is propagated along the surface of the muscle cell and deep into the fibers via the transverse tubule system. At each triad, the depolarization signal is passed to the sarcoplasmic reticulum and results in the release of Ca²⁺, which initiates the contraction cycle. When depolarization ceases, the Ca²⁺ is actively transported back into the sarcoplasmic reticulum cisternae, and the muscle relaxes.

MEDICAL APPLICATION

Myasthenia gravis is an autoimmune disorder characterized by progressive muscular weakness caused by a reduction in the number of functionally active acetylcholine receptors in the sarcolemma of the myoneural junction. This reduction is caused by circulating antibodies that bind to the acetylcholine receptors in the junctional folds and inhibit normal nerve–muscle communication. As the body attempts to correct the condition, membrane segments with affected receptors are internalized, digested by lysosomes, and replaced by newly formed receptors. These receptors, however, are again made unresponsive to acetylcholine by the same antibodies, and the disease follows its progressive course.

A single nerve fiber (axon) can innervate one muscle fiber, or it may branch and be responsible for innervating 160 or more muscle fibers. In the case of multiple innervation, a single nerve fiber and all the muscles it innervates constitute a motor unit.Individual striated muscle fibers do not show graded contraction—they contract either all the way or not at all. To vary the force of contraction, the fibers within a muscle bundle should not all contract at the same time. Because muscles are broken up into motor units, the firing of a single nerve motor axon will generate tension proportional to the number of muscle fibers innervated by that axon. Thus, the number of motor units and the variable size of each unit can control the intensity of a muscle contraction. The ability of a muscle to perform delicate movements depends on the size of its motor units. For example, because of the fine control required by eye muscles, each of their fibers is innervated by a different nerve fiber. In larger muscles exhibiting coarser movements, such as those of the limb, a single, profusely branched axon innervates a motor unit that consists of more than 100 individual muscle fibers.

Muscle Spindles & Golgi Tendon Organs

All human striated muscles contain encapsulated proprioceptors (L. proprius, one's own, + capio, to take) known as muscle spindles (Figure 10–19). These structures consist of a connective tissue capsule surrounding a fluid-filled space that contains a few long, thick muscle fibers and some short, thinner fibers (collectively called intrafusal fibers). Several sensory nerve fibers penetrate the muscle spindles, where they detect changes in the length (distention) of extrafusal muscle fibers and relay this information to the spinal cord. Here, reflexes of varying complexity are activated to maintain posture and to regulate the activity of opposing muscle groups involved in motor activities such as walking.

In tendons, near the insertion sites of muscle fibers, a connective tissue sheath encapsulates several large bundles of collagen fibers that are continuous with the collagen fibers that make up the myotendinous junction. Sensory nerves penetrate the connective tissue capsule. These structures, known as Golgi tendon organs (Figure 10–20), contribute to proprioception by detecting tensional differences in tendons.

Because these structures are sensitive to increases in tension, they help to regulate the amount of effort required to perform movements that call for variable amounts of muscular force.

System of Energy Production

Skeletal muscle cells are highly adapted for discontinuous production of intense mechanical work through the release of chemical energy and must have depots of energy to cope with bursts of activity. The most readily available energy is stored in the form of ATP and phosphocreatine, both of which are energy-rich phosphate compounds. Chemical energy is also available in glycogen depots, which constitute about 0.5–1% of muscle weight. Muscle tissue obtains energy to be stored in phosphocreatine and ATP from the breakdown of fatty acids and glucose. Fatty acids are broken down to acetate by the enzymes of -oxidation, located in the mitochondrial matrix. Acetate is then further oxidized by the citric acid cycle, with the resulting energy being conserved in the form of ATP. When skeletal muscles are subjected to a short-term (sprint) exercise, they rapidly metabolize glucose (coming mainly from muscle glycogen stores) to lactate, causing an oxygen debt that is repaid during the recovery period. The lactate formed during this type of exercise causes cramping and pain in skeletal muscles.

Based on their morphological, histochemical, and biochemical characteristics, muscle fibers can be classified as type I (slow) and type II (quick). Type I fibers are rich in sarcoplasm, which contains myoglobin (accounting for the dark red color; see below). They are related to continuous contraction, and their energy is derived from oxidative phosphorylation of fatty acids. Type II fibers are related to rapid discontinuous contraction. They contain less myoglobin (producing a light red color). Type II fibers can be further divided into types IIA, IIB, and IIC, according to their activity and chemical characteristics (mainly, the stability of the actomyosin–ATPase they contain). Type IIB fibers have the fastest action and depend more than the others on glycolysis as a source of energy. The classification of muscle fibers has clinical significance for the diagnosis of muscle diseases, or myopathies (mys + Gr. pathos, suffering). In humans, skeletal muscles are frequently composed of mixtures of these various types of fibers.

The differentiation of muscle into red, white, and intermediate fiber types is controlled by its innervation. In experiments in which the nerves to red and white fibers are cut, crossed, and allowed to regenerate, the myofibers change their morphological and physiological characteristics to conform to the innervating nerve. Simple denervation of muscle will lead to fiber atrophy and paralysis.

Other Components of the Sarcoplasm

Glycogen is found in abundance in the sarcoplasm in the form of coarse granules (Figure 10–15). It serves as a depot of energy that is mobilized during muscle contraction.

Another component of the sarcoplasm is myoglobin (Figure 10–21); this oxygen-binding protein, which is similar to hemoglobin, is principally responsible for the dark red color of some muscles. Myoglobin acts as an oxygen-storing pigment, which is necessary for the high oxidative phosphorylation level in this type of fiber. For obvious reasons, it is present in great amounts in the muscle of deep-diving ocean mammals (eg, seals, whales). Muscles that must maintain activity for prolonged periods usually are red and have a high myoglobin content.

Mature muscle cells have negligible amounts of rough endoplasmic reticulum and ribosomes, an observation that is consistent with the low level of protein synthesis in this tissue.

CARDIAC MUSCLE

During embryonic development, the splanchnic mesoderm cells of the primitive heart tube align into chainlike arrays. Rather than fusing into syncytial (Gr. syn, together, + kytos, cell) cells, as in the development of skeletal muscle, cardiac cells form complex junctions between their extended processes. Cells within a chain often bifurcate, or branch, and bind to cells in adjacent chains. Consequently, the heart consists of tightly knit bundles of cells, interwoven in a fashion that provides for a characteristic wave of contraction that leads to a wringing out of the heart ventricles.

Mature cardiac muscle cells are approximately 15 m in diameter and from 85 to 100 m in length. They exhibit a cross-striated banding pattern identical to that of skeletal muscle. Unlike multinucleated skeletal muscle, however, each cardiac muscle cell possesses only one or two centrally located pale-staining nuclei. Surrounding the muscle cells is a delicate sheath of endomysial connective tissue containing a rich capillary network.

A unique and distinguishing characteristic of cardiac muscle is the presence of dark-staining transverse lines that cross the chains of cardiac cells at irregular intervals (Figures 10–22 and 10–23). These intercalated disks represent junctional complexes found at the interface between adjacent cardiac muscle cells (Figures 10–24, 10–25, and 10–26). The junctions may appear as straight lines or may exhibit a steplike pattern. Two regions can be distinguished in the steplike junctions—a transverse portion, which runs across the fibers at right angles, and a lateral portion, which runs parallel to the myofilaments. There are three main junctional specializations within the disk. Fasciae adherentes, the most prominent membrane specialization in transverse portions of the disk, serve as anchoring sites for actin filaments of the terminal sarcomeres. Essentially, they represent hemi-Z bands.Maculae adherentes (desmosomes) are also present in the transverse portion and bind the cardiac cells together, preventing them from pulling apart under constant contractile activity. On the lateral portions of the disk, gap junctions provide ionic continuity between adjacent cells (Figure 10–26). The significance of ionic coupling is that chains of individual cells act as a syncytium, allowing the signal to contract to pass in a wave from cell to cell.

The structure and function of the contractile proteins in cardiac cells are almost the same as in skeletal muscle. The T tubule system and sarcoplasmic reticulum, however, are not as regularly arranged in the cardiac myocytes. The T tubules are more numerous and larger in ventricular muscle than in skeletal muscle. Cardiac T tubules are found at the level of the Z band rather than at the A–I junction (as in mammalian skeletal muscle). The sarcoplasmic reticulum is not as well developed and wanders irregularly through the myofilaments. As a consequence, discrete myofibrillar bundles are not present.

Triads are not common in cardiac cells, because the T tubules are generally associated with only one lateral expansion of sarcoplasmic reticulum cisternae. Thus, heart muscle characteristically possesses diads composed of one T tubule and one sarcoplasmic reticulum cisterna.

Cardiac muscle cells contain numerous mitochondria, which occupy 40% or more of the cytoplasmic volume (Figure 10–27), reflecting the need for continuous aerobic metabolism in heart muscle. By comparison, only about 2% of skeletal muscle fiber is occupied by mitochondria. Fatty acids, transported to cardiac muscle cells by lipoproteins, are the major fuel of the heart. Fatty acids are stored as triglycerides in the numerous lipid droplets seen in cardiac muscle cells. A small amount of glycogen is present and can be broken down to glucose and used for energy production during periods of stress. Lipofuscin pigment granules (aging pigment), often seen in long-lived cells, are found near the nuclear poles of cardiac muscle cells.

A few differences in structure exist between atrial and ventricular muscle. The arrangement of myofilaments is the same in the two types of cardiac muscle, but atrial muscle has markedly fewer T tubules, and the cells are somewhat smaller. Membrane-limited granules, each about 0.2–0.3 m in diameter, are found at both poles of cardiac muscle nuclei and in association with Golgi complexes in this region. These granules (Figure 10–28) are most abundant in muscle cells of the right atrium (approximately 600 per cell), but they are also found in the left atrium, the ventricles, and several other places in the body. These atrial granules contain the high-molecular-weight precursor of a polypeptide hormone known as atrial natriuretic factor, which acts on the kidneys to cause sodium and water loss (natriuresis and diuresis). This hormone thus opposes the actions of aldosterone and antidiuretic hormone, whose effects on kidneys result in sodium and water conservation.

The rich autonomic nerve supply to the heart and the rhythmic impulse-generating and conducting structures are discussed in Chapter 11: The Circulatory System.

SMOOTH MUSCLE

Smooth muscle is composed of elongated, nonstriated cells (Figure 10–29), each of which is enclosed by a basal lamina and a network of reticular fibers (Figures 10–30, 10–31, and 10–32). The last two components serve to combine the force generated by each smooth muscle fiber into a concerted action, eg, peristalsis in the intestine.

Smooth muscle cells are fusiform, ie, they are largest at their midpoints and taper toward their ends. They may range in size from 20 m in small blood vessels to 500 m in the pregnant uterus. During pregnancy, uterine smooth muscle cells undergo a marked increase in size and number. Each cell has a single nucleus located in the center of the broadest part of the cell. To achieve the tightest packing, the narrow part of one cell lies adjacent to the broad parts of neighboring cells. Such an arrangement viewed in cross section shows a range of diameters, with only the largest profiles containing a nucleus (Figure 10–29). The borders of the cell become scalloped when smooth muscle contracts, and the nucleus becomes folded or has the appearance of a corkscrew (Figure 10–33).

Concentrated at the poles of the nucleus are mitochondria, polyribosomes, cisternae of rough endoplasmic reticulum, and the Golgi complex. Pinocytotic vesicles are frequent near the cell surface (Figure 10–32).

A rudimentary sarcoplasmic reticulum is present; it consists of a closed system of membranes, similar to the sarcoplasmic reticulum of striated muscle. T tubules are not present in smooth muscle cells.

The characteristic contractile activity of smooth muscle is related to the structure and organization of its actin and myosin filaments, which do not exhibit the paracrystalline organization present in striated muscles. In smooth muscle cells, bundles of myofilaments crisscross obliquely through the cell, forming a latticelike network. These bundles consist of thin filaments (5–7 nm) containing actin and tropomyosin and thick filaments (12–16 nm) consisting of myosin. Both structural and biochemical studies reveal that smooth muscle actin and myosin contract by a sliding filament mechanism similar to what occurs in striated muscles.

An influx of Ca²⁺ is involved in the initiation of contraction in smooth muscle cells. The myosin of smooth muscle, however, interacts with actin only when its light chain is phosphorylated. For this reason, and because the tropomyosin complex of skeletal muscle is absent, the contraction mechanism in smooth muscle differs somewhat from skeletal and cardiac muscle. Ca²⁺ in a smooth muscle complexes with calmodulin, a calcium-binding protein that is also involved in the contraction of nonmuscle cells. The Ca²⁺–calmodulin complex activates myosin light-chain kinase, the enzyme responsible for the phosphorylation of myosin.

Factors other than calcium affect the activity of myosin light-chain kinase and thus influence the degree of contraction of smooth muscle cells. Contraction or relaxation may be regulated by hormones that act via cyclic adenosine monophosphate (cAMP). When levels of cAMP increase, myosin light-chain kinase is activated, myosin is phosphorylated, and the cell contracts. A decrease in cAMP has the opposite effect, decreasing contractility. The action of sex hormones on uterine smooth muscle is another example of nonneural control. Estrogens increase cAMP and promote the phosphorylation of myosin and the contractile activity of uterine smooth muscle. Progesterone has the opposite effect: It decreases cAMP, promotes dephosphorylation of myosin, and relaxes uterine musculature.

Smooth muscle cells have an elaborate array of 10-nm intermediate filaments coursing through their cytoplasm. Desmin (skeletin) has been identified as the major protein of intermediate filaments in all smooth muscles, and vimentin is an additional component in vascular smooth muscle. Two types of dense bodies (Figure 10–33) appear in smooth muscle cells. One is membrane associated; the other is cytoplasmic. Both contain -actinin and are thus similar to the Z lines of striated muscles. Both thin and intermediate filaments insert into dense bodies that transmit contractile force to adjacent smooth muscle cells and their surrounding network of reticular fibers.

The degree of innervation in a particular bundle of smooth muscle depends on the function and the size of that muscle. Smooth muscle is innervated by both sympathetic and parasympathetic nerves of the autonomic system. Elaborate neuromuscular junctions such as those in skeletal muscle are not present in smooth muscle. Frequently, autonomic nerve axons terminate in a series of dilatations in the endomysial connective tissue.

In general, smooth muscle occurs in large sheets such as those found in the walls of hollow viscera, eg, the intestines, uterus, and ureters. Their cells possess abundant gap junctions and a relatively poor nerve supply. These muscles function in syncytial fashion and are called visceral smooth muscles. In contrast, the multiunit smooth muscles have a rich innervation and can produce precise and graded contractions such as those occurring in the iris of the eye.

Smooth muscle usually has spontaneous activity in the absence of nervous stimuli. Its nerve supply, therefore, has the function of modifying activity rather than, as in skeletal muscle, initiating it. Smooth muscle receives both adrenergic and cholinergic nerve endings that act antagonistically, stimulating or depressing its activity. In some organs, the cholinergic endings activate and the adrenergic nerves depress; in others, the reverse occurs.

In addition to contractile activity, smooth muscle cells also synthesize collagen, elastin, and proteoglycans, which are extracellular products normally associated with the function of fibroblasts.

REGENERATION OF MUSCLE TISSUE

The three types of adult muscle have different potentials for regeneration after injury.

Cardiac muscle has almost no regenerative capacity beyond early childhood. Defects or damage (eg, infarcts) in heart muscle are generally replaced by the proliferation of connective tissue, forming myocardial scars.

In skeletal muscle, although the nuclei are incapable of undergoing mitosis, the tissue can undergo limited regeneration. The source of regenerating cells is believed to be the satellite cells. The latter are a sparse population of mononucleated spindle-shaped cells that lies within the basal lamina surrounding each mature muscle fiber. Because of their intimate apposition with the surface of the muscle fiber, they can be identified only with the electron microscope. They are considered to be inactive myoblasts that persist after muscle differentiation. After injury or certain other stimuli, the normally quiescent satellite cells become activated, proliferating and fusing to form new skeletal muscle fibers. A similar activity of satellite cells has been implicated in muscle hypertrophy, where they fuse with their parent fibers to increase muscle mass after extensive exercise. The regenerative capacity of skeletal muscle is limited, however, after major muscle trauma or degeneration.

Smooth muscle is capable of an active regenerative response. After injury, viable mononucleated smooth muscle cells and pericytes from blood vessels (see Chapter 11: The Circulatory System) undergo mitosis and provide for the replacement of the damaged tissue.

REFERENCES