A. Histogenesis and Growth

All skeletal muscle arises from mesodermal mesenchyme cells migrating from the myotomes of the somites.

The mesenchymal cells retract their cytoplasmic processes and assume a spindle shape to become myoblasts; these fuse to form multinucleated myotubes. Myotubes elongate and increase in diameter by incorporating additional myoblasts, accumulating myofilaments and nuclei in their cytoplasm. The myofilaments organize into myofibrils (II.B.1.c) and displace the nuclei and other cytoplasmic components peripherally. Mature muscle fibers cannot divide; therefore, increases in skeletal muscle mass in response to weight bearing and exercise are due to hypertrophy rather than to hyperplasia (division) of the existing cells. Exercise and weight bearing elicit a proliferative response from quiescent stem cells in the muscle tissue, called satellite cells. Some of their progeny become myoblasts and fuse with existing muscle fibers, increasing their size. Because the strength of contraction is directly proportional to muscle fiber diameter, skeletal muscle hypertrophy increases muscle strength. Myostatin is a signaling molecule that slows myogenesis. Loss-of-function myostatin mutants were first discovered in Piedmontese and Belgian cattle with double the muscle mass of normal cattle. Similar mutations in humans are exceedingly rare but have the same effect.

B. Skeletal Muscle Cells

Mature skeletal muscle fibers are long, unbranched, cylindrical, multinucleated cells. The flattened, peripheral nuclei lie just under the sarcolemma (muscle cell plasma membrane); most of the organelles and sarcoplasm (muscle cell cytoplasm) lie near the nuclear poles. The sarcoplasm contains many mitochondria, glycogen granules, and an oxygen-binding protein called myoglobin, and it accumulates lipofuscin pigment with age. Mature skeletal muscle fibers cannot divide.

1. Myofilaments in skeletal muscle fibers are of two major types.

   1. Thin (actin) filaments (Fig. 10–1) have several components.

      1. Filamentous actin (F-actin) is a polymeric chain of globular actin (G-actin) monomers. Each thin filament contains two F-actin strands wound in a double helix.

      2. Tropomyosin is a long, thin, double-helical polypeptide that wraps around the actin double helix, lies in the grooves on its surface, and spans seven G-actin monomers.

      3. Troponin is a complex of three globular proteins. TnT (troponin T) attaches each complex to a specific site on each tropomyosin molecule, TnC (troponin C) binds calcium ions, and TnI (troponin I) covers the myosin-binding site on actin and inhibits interaction between thin and thick filaments.

   2. Thick filaments. A myosin molecule is a long, golf club–shaped polypeptide. A thick (myosin) filament is a bundle of myosin molecules whose shafts point toward and overlap in the bundle's middle and whose heads project from the bundle's ends (Fig. 10–2). This arrangement leaves a headless region in the center of each filament corresponding to the H band (II.B.1.d). Papain (a proteolytic enzyme) cleaves myosin into two pieces at a point near the head. The piece containing most of the thin shaft is termed light meromyosin; the head and associated section of the shaft make up heavy meromyosin. The head portion of heavy meromyosin has an ATP-binding site and an actin-binding site, both of which are necessary for contraction. Heavy and light meromyosins, which are enzyme-generated fragments, should not be confused with heavy and light myosins, which are distinct gene products (proteins) that combine to form a thick myosin filament (Fig. 10–2 [see 13 in the figure]).

   3. Myofilament organization. Skeletal muscle banding (II.B.1.d) reflects the grouping of its thick and thin myofilaments into parallel bundles called myofibrils. Each muscle fiber may contain several myofibrils, depending on its size.

      1. Myofibrils in cross-section. EM images of myofibrils in cross-section reveal large and small dots corresponding to thick and thin filaments, respectively. Sections containing both filament types have six thin filaments in hexagonal array around each thick filament. Each thick filament shares two of its surrounding thin filaments with each adjacent thick filament to form a repeating crystalline pattern (Fig. 10–2 [see 9 in the figure]).

      2. Myofibrils in longitudinal section. At both light and electron microscopic levels, each myofibril exhibits repeating, linearly arranged, functional subunits called sarcomeres,whose bands (striations) run perpendicular to the myofibril's long axis. The sarcomeres of each myofibril lie in register with those in adjacent myofibrils so that their bands appear continuous. The sarcomere is separated from its neighbors at each end by a dense Z line, or Z disk. A major Z-disk protein, α-actinin, anchors one end of the thin filaments and helps maintain spatial distribution. Titin flexibly anchors thick filaments to the Z line while M protein and myomesin anchor these filaments to the M line. These myosin-binding proteins help maintain thick filament position during contraction. The thin filaments extend toward the middle of the sarcomere. The center of each sarcomere is marked by the M line, which holds the thick filaments in place. Desmin-containing intermediate filaments are found in both M lines and Z disks. The thick filament bundles lie at the center of each sarcomere, are bisected by the M line, and overlap the thin filaments’ free ends. The overlap between thick and thin filaments produces the banding pattern and differs depending on the myofibrils’ state of contraction (see Fig. 10–2).

   4. Bands. Under the light microscope, skeletal muscle fibers exhibit alternating light- and dark-staining bands that run perpendicular to the cells’ long axes. The light-staining bands contain only thin filaments and are known as I bands (isotropic) because they do not rotate polarized light. Each I band is bisected by a Z line. Thus, each sarcomere has two half I bands, one at each end (Fig. 10–2 [see 4 and 5 in the figure]). One dark-staining band lies in the middle of each sarcomere and shows the position of the thick filament bundles; this is known as an A band (anisotropic) because it contains the crystalline array of thick and thin filaments and is, therefore, birefringent (rotates polarized light). At the EM level, each A band has a lighter central region, or H band, which is bisected by an M line. The H band lies between the thin filaments’ free ends and contains only the shafts of myosin molecules. The darker peripheral parts of the A bands are regions of overlap between the thick and thin filaments and contain the myosin heads. Interaction between the myosin heads of the thick filaments and the thin filaments’ free ends causes muscle contraction (see Fig. 10–2).

2. Sarcoplasmic reticulum is the SER of striated muscle cells and is specialized to sequester calcium ions. In skeletal muscle, this anastomosing complex of membrane-limited tubules and cisternae ensheathes each myofibril. At each A–I band junction, a tubular invagination of the sarcolemma, termed a transverse tubule (or T tubule), penetrates the muscle fiber and overlies the surface of the myofibrils. On each side of the T tubule lies an expansion of the sarcoplasmic reticulum termed a terminal cisterna. Two terminal cisternae and an intervening T tubule comprise a triad. Triads are important in initiating muscle contraction (II.D).

3. Types of skeletal muscle fibers. The three basic skeletal muscle fiber types differ in myoglobin content, number of mitochondria, and speed of contraction. In humans, most skeletal muscles are mixtures of these fiber types. Initially, muscle fiber types were distinguished by enzyme histochemistry targeting the fiber-type–specific myosin ATPase activity. Currently, immunohistochemistry targeting fiber-type–specific expression of four main myosin heavy chain (MyHC) isotypes (I, IIA, IIB, and IIX) provides more reliable information.

   1. Red fibers contain more myoglobin (red when oxygenated) and mitochondria. Their contraction in response to nervous stimulation is slow and steady, which has resulted in their designation as slow fibers. They predominate in postural muscles and occur in large numbers in certain limb muscles. The ratio of red to white fibers increases with age. Slow fibers are characterized by a predominance of MyHC type I.

   2. White fibers contain less myoglobin and fewer mitochondria. They react quickly, with brief, forceful contractions but cannot sustain contraction for long periods; thus, they are termed fast fibers. These fibers predominate in the extraocular muscles. Fast fibers are characterized by a predominance of one or more MyHC type II isoforms.

   3. Intermediate fibers have structural and functional characteristics between those of red and white fibers but are a subclass of the latter. They are dispersed among the red and white fibers in muscles where either type predominates. As a subclass of fast fibers, intermediate fibers contain mostly MyHC type II isoforms.

C. Motor End-Plates

A motor end-plate, or myoneural junction, is a collection of specialized synapses of a motor neuron's terminal boutons with a skeletal muscle fiber's sarcolemma (Fig. 10–3). It transmits nerve impulses to muscle cells, initiating contraction. Each myoneural junction has three major components:

1. The presynaptic (neural) component is the terminal bouton. Although extensions of Schwann cell cytoplasm cover the bouton, the myelin sheath ends before reaching it. The bouton contains mitochondria and acetylcholine-filled synaptic vesicles. The part of the bouton's plasma membrane directly facing the muscle fiber is the presynaptic membrane.

2. The synaptic cleft lies between the presynaptic membrane and the opposing postsynaptic membrane and contains a continuation of the muscle fiber's basal lamina. It also contains acetylcholinesterase, which degrades the neurotransmitter so that when neural stimulation ends, contraction ends. The primary synaptic cleft lies directly beneath the presynaptic membrane and communicates directly with a series of secondary synaptic clefts created by infoldings of the postsynaptic membrane.

3. The postsynaptic (muscular) component includes the sarcolemma (postsynaptic membrane) and the sarcoplasm directly under the synapse. The postsynaptic membrane contains acetylcholine receptors and is thrown into numerous junctional folds. The sarcoplasm under the folds contains nuclei, mitochondria, ribosomes, and glycogen, but lacks synaptic vesicles.

D. Mechanism of Contraction

According to the sliding-filament hypothesis, skeletal muscle contraction involves rapidly repeating cycles of a multistep cascade whereby the completion of each step initiates the succeeding step (Fig. 10–4). The many steps occur nearly instantaneously. Because each step depends on the one preceding it, a disease process that interferes with even a single step can interrupt the entire cascade and result in paralysis.

E. Relaxation

When neural stimulation ends, all of the membranes repolarize, allowing the sarcoplasmic reticulum to sequester Ca2+from the sarcoplasm by active transport. This removes Ca2+ from the TnC and returns the TnI to the position in which it inhibits binding of the myosin head to the actin filament.

F. Energy Production

Muscles use glucose (from stored glycogen and from the blood) and fatty acids (from the blood) to form the ATP and phosphocreatine that provide chemical energy for contraction. At the end of the each contraction cycle, ATP is also required to release the myosin head from the binding site on actin and recock the contraction mechanism. When ATP is not available, actin–myosin binding stabilizes, accounting for rigor mortis, the muscular rigidity that accompanies death and lasts for 24 hours until enzymatic degradation reduces rigidity.

G. Organization of the Skeletal Muscles

Each muscle (e.g., biceps brachii) is a bundle of muscle fascicles surrounded by a sheath of dense connective tissue termed the epimysium. Each fascicle is a bundle of muscle fibers surrounded by a dense connective tissue sheath called the perimysium, comprising septumlike inward extensions of epimysium. Each muscle fiber is a bundle of myofibrils surrounded by the sarcolemma that is in turn surrounded by a delicate connective tissue sheath termed the endomysium, which consists of a basal lamina and a loose mesh of reticular fibers. Each myofibril is a bundle of myofilaments surrounded by an investment of sarcoplasmic reticulum, with a triad at both A–I junctions of each sarcomere. The connective tissue investments are continuous with one another.

H. Muscle–Tendon Junctions

The attachment of muscle to tendon must be secure to prevent the muscle from tearing away during contraction. The tendon's collagen fibers blend with the epimysium and penetrate the muscle along with the perimysium. Near the junction with the tendon, the ends of the muscle cells taper and exhibit many sarcolemmal infoldings. Collagen and reticular fibers enter the infoldings, penetrate the basal lamina, and attach directly to the outer surface of the sarcolemma. The attachment of actin filaments to the inner surface of the sarcolemma helps stabilize the association between the collagen fibers and the muscle cell.

I. Pattern of Innervation

Each motor neuron has a single axon that may terminate on a single muscle fiber or undergo terminal branching (arborization) and terminate on multiple muscle fibers. A motor neuron and all the muscle fibers it innervates (1 to >100) comprise a motor unit. Muscles responsible for delicate movements (e.g., extraocular muscles) are composed of many small motor units; those responsible for coarser movements (e.g., gluteus maximus) are composed of fewer large motor units.

Muscle cells are structurally and functionally specialized for contraction. Contraction requires two types of special protein filaments called myofilaments; these include thin filaments containing actin and thick filaments containing myosin.

The length of muscle cells, which sometimes reaches 4 cm, is greater than their width. Muscle cells are, therefore, often called muscle fibers or myofibers.

Muscle tissues are groups of muscle cells organized by connective tissue. This arrangement allows the groups to act together or separately, generating mechanical forces of varying strength.