Characteristics of the skeletal muscle cell or fiber

Skeletal muscle cells are formed in the embryo by the fusion of myoblasts that produce a postmitotic, multinucleated myotube. The myotube matures into the long muscle cell with a diameter of 10 to 100 μm and a length of up to several centimeters.

The plasma membrane (called the sarcolemma) of the muscle cell is surrounded by a basal lamina and satellite cells (Figure 7-2). We discuss the significance of satellite cells in muscle regeneration. The sarcolemma projects long, finger-like processes—called transverse tubules or T tubules—into the cytoplasm of the cell—the sarcoplasm. T tubules make contact with membranous sacs or channels, the sarcoplasmic reticulum. The sarcoplasmic reticulum contains high concentrations of Ca²⁺. The site of contact of the T tubule with the sarcoplasmic reticulum cisternae is called a triad because it consists of two lateral sacs of the sarcoplasmic reticulum and a central T tubule.

Figure 7-2 Skeletal muscle (striated)

The many nuclei of the muscle fiber are located at the periphery of the cell, just under the sarcolemma.

About 80% of the sarcoplasm is occupied by myofibrils surrounded by mitochondria (called sarcosomes). Myofibrils are composed of two major filaments formed by contractile proteins: thin filaments contain actin, and thick filaments are composed of myosin (see Figure 7-2).

Depending on the type of muscle, mitochondria may be found parallel to the long axis of the myofibrils, or they may wrap around the zone of thick filaments. Thin filaments insert into each side of the Z disk (also called band, or line) and extend from the Z disk into the A band, where they alternate with thick filaments.

The myofibril: A repeat of sarcomere units

The sarcomere is the basic contractile unit of striated muscle (Figure 7-3). Sarcomere repeats are represented by myofibrils in the sarcoplasm of skeletal and cardiac muscle cells.

Figure 7-3 Sarcomere

The arrangement of thick (myosin) and thin (actin) myofilaments of the sarcomere is largely responsible for the banding pattern observed under light and electron microscopy (see Figures 7-2 and 7-3). Actin and myosin interact and generate the contraction force. The Z disk forms a transverse sarcomeric scaffold to ensure the efficient transmission of the generated force.

Thin myofilaments measure 7 nm in width and 1 μm in length and form the I band. Thick filaments measure 15 nm in width and 1.5 μm in length and are found in the A band.

The A band is bisected by a light region called the H band (see Figures 7-3; 7-4). The major component of the H band is the enzyme creatine kinase, which catalyzes the formation of ATP from creatine phosphate and adenosine diphosphate (ADP). We discuss later how creatine phosphate maintains steady levels of ATP during prolonged muscle contraction.

Figure 7-4 Skeletal muscle cell

Running through the midline of the H band is the M line. M-line striations correspond to a series of bridges and filaments linking the bare zone of thick filaments. Thin filaments insert into each side of the Z disk, whose components include α-actinin.

Components of the thin and thick filaments of the sarcomere

F-actin, the thin filament of the sarcomere, is double-stranded and twisted. F-actin is composed of globular monomers (G-actin; see Cytoskeleton in Chapter 1, Epithelium). G-actin monomers bind to each other in a head-to-tail fashion, giving the filament polarity, with barbed (plus) and pointed (minus) ends. The barbed end of actin filaments inserts into the Z disk.

Tropomyosin consists of two nearly identical α-helical polypeptides twisted around each other. Tropomyosin runs in the groove formed by F-actin strands. Each molecule of tropomyosin extends for the length of seven actin monomers and binds the troponin complex (Figure 7-5).

Figure 7-5 Troponin and tropomyosin

Troponin is a complex of three proteins: troponin I, C, and T. Troponin T binds the complex to tropomyosin. Troponin I inhibits the binding of myosin to actin. Troponin C binds Ca²⁺ and is found only in striated muscle.

Myosin II, the major component of the thick filament, has adenosine triphosphatase (ATPase) activity (it hydrolyzes ATP) and binds to F-actin—the major component of the thin filament—in a reversible fashion.

Myosin II consists of two identical heavy chains and two pairs of light chains (Figure 7-6; see Cytoskeleton in Chapter 1, Epithelium). At one end, each heavy chain forms a globular head. Two different light chains are bound to each head: the essential light chain and the regulatory light chain. The globular head has three distinct regions: (1) an actin-binding region; (2) an ATP-binding region; and (3) a light chain–binding region. Myosin II, like the other molecular motors kinesins and dyneins, use the chemical energy of ATP to drive conformational changes that generate motile force. As you recall, kinesins and dyneins move along microtubules. Myosins move along actin filaments to drive muscle contraction.

Figure 7-6 Myosin II

Nebulin (Figure 7-7) is associated with thin (actin) filaments; it inserts into the Z disk and acts as a template for determining the length of actin filaments.

Figure 7-7 Sarcomere: Nebulin and titin

Titin (see Figure 7-7) is a very large protein with a molecular mass in the range of millions. Each molecule associates with thick (myosin) myofilaments and inserts into the Z disk, extending to the bare zone of the myosin filaments, close to the M line. Titin controls the assembly of the myosin myofilament by acting as a template. Titin has a role in sarcomere elasticity by forming a spring-like connection between the end of the thick myofilament and the Z disk.

Z disks are the insertion site of actin filaments of the sarcomere. A component of the Z disk, α-actinin, anchors the barbed end of actin filaments to the Z disk.

Desmin is a 55-kd protein that forms intermediate (10-nm) filaments. Desmin filaments encircle the Z disks of myofibrils and are linked to the Z disk and to each other by plectin filaments (Figure 7-8). Desmin filaments extend from the Z disk of one myofibril to the adjacent myofibril, forming a supportive latticework. Desmin filaments also extend from the sarcolemma to the nuclear envelope.

Figure 7-8 Cytoskeletal protective network of a skeletal muscle cell

Desmin inserts into specialized sarcolemma-associated plaques, called costameres. Costameres, acting in concert with the dystrophin-associated protein complex, transduce contractile force from the Z disk to the basal lamina, maintain the structural integrity of the sarcolemma, and stabilize the position of myofibrils in the sarcoplasm.

The heat shock protein αB-crystallin protects desmin filaments from stress-induced damage. Desmin, plectin, and αB-crystallin form a mechanical stress protective network at the Z-disk level. Mutations in these three proteins lead to the destruction of myofibrils after repetitive mechanical stress.

Mechanism of muscle contraction

During muscle contraction, the muscle shortens about one third of its original length. The relevant aspects of muscle shortening are summarized in Figure 7-9 as follows:

Figure 7-9 Sarcomere: Muscle contraction and relaxation

Creatine phosphate: A back up energy source

Creatine phosphate is a back up mechanism to maintain steady levels of ATP during muscle contraction. Consequently, the concentration in muscle of free ATP during prolonged contraction does not change too much.

Figure 7-10 provides a summary of the mechanism of regeneration of creatine phosphate, which takes place in mitochondria and diffuses to the myofibrils, where it replenishes ATP during muscle contraction.

Figure 7-10 Creatine cycle during muscle contraction

A depolarization signal travels inside the muscle by T tubules

We discussed that the triad consists of a transverse T tubule flanked by sacs of the sarcoplasmic reticulum, and that the sarcoplasm of a skeletal muscle cell is packed with myofibrils (each consisting of a linear repeat of sarcomeres) with abundant mitochondria between them. How does a nerve impulse reach and deliver contractile signals to myofibrils located in the interior of the muscle cell?

An excitation-contraction signal is generated by acetylcholine, a chemical transmitter released from a nerve terminal in response to an action potential. Acetylcholine diffuses into a narrow gap, called the neuromuscular junction, between the muscle and a nerve terminal (Figure 7-11). The action potential spreads from the sarcolemma to the T tubules, which transport the excitation signal to the interior of the muscle cell. Remember that T tubules form rings around every sarcomere of every myofibril at the A-I junction.

Figure 7-11 Neuromuscular junction

We discuss later that the companions of the T tubule, the channels of the sarcoplasmic reticulum, contain calcium ions. Calcium ions are released inside the cytosol to activate muscle contraction when the action potential reaches the T tubule. This excitation-contraction sequence occurs in about 15 milliseconds.

Clinical significance: Disorders of neuromuscular transmission

Synaptic transmission at the neuromuscular junction can be affected by curare and botulinum toxin (see Figure 7-11).

Curare binds to the acetylcholine receptor and prevents binding of acetylcholine. Curare derivatives are used in surgical procedures in which muscle paralysis is necessary.

Botulinum toxin, an exotoxin from the bacterium Clostridium botulinum, prevents the release of acetylcholine at the presynaptic end. Muscle paralysis and dysfunction of the autonomous nervous system occur in cases of food poisoning mediated by botulinum toxin.

Myasthenia gravis is an autoimmune disease in which antibodies are produced against acetylcholine receptors (Figure 7-12). Autoantibodies bind to the receptor, preventing the binding of acetylcholine. This blocks normal nerve-muscle interaction and results in progressive muscle weakness.

Figure 7-12 Myasthenia gravis

Calcium controls muscle contraction

In the absence of Ca²⁺, muscle is relaxed and the troponin-tropomyosin complex blocks the myosin binding site on the actin filament.

When a depolarization signal arrives, Ca²⁺ exits the terminal cisternae of the sarcoplasmic reticulum with the help of the ryanodine-sensitive Ca²⁺ channel (Figure 7-13). In the sarcomere, Ca²⁺ binds to troponin C and causes a change in configuration of the troponin-tropomyosin complex. As a result, the myosin-binding site on the actin filament is exposed. Myosin heads bind to the actin filament, and hydrolysis of ATP occurs. We have seen that steady levels of ATP rely on the mitochondrial supply of creatine phosphate and the availability of creatine kinase (see Figure 7-10).

Figure 7-13 Muscle contraction

Creatine kinase is an enzyme found in soluble form in the sarcoplasm and also is a component of the M-line region of the H band. Creatine kinase catalyzes the transfer of phosphate from creatine phosphate to ADP.

The energy of hydrolysis of ATP produces a change in the position of the myosin head, and the thin filaments are pulled past the thick filaments. Contraction results in the complete overlap of the A and I bands (see Figure 7-9). The contraction continues until Ca²⁺ is removed.

In summary, the sarcoplasmic reticulum, a network of smooth endoplasmic reticulum surrounding each myofibril (see Figure 7-4), stores Ca²⁺. In response to depolarization signals, the sarcoplasmic reticulum releases Ca²⁺. When membrane depolarization ends, Ca²⁺ is pumped back into the sarcoplasmic reticulum with the help of Ca²⁺-dependent ATPase, and binds to the protein calsequestrin (see Figure 7-13). Contraction can no longer take place.

Clinical significance: Muscular dystrophies

Muscular dystrophies are a group of congenital muscular diseases characterized by muscle weakness, atrophy, elevation of serum levels of muscle enzymes, and destructive changes of muscle tissue (Figure 7-14).

Figure 7-14 Muscular dystrophies

Muscular dystrophies are caused by a deficiency in the dystrophin-associated protein (DAP) complex. The DAP complex consists of dystrophin and two subcomplexes: the dystroglycan complex (α and β subunits), and the sarcoglycan complex (α, β, γ, δ, , and ζ subunits; for simplicity, only four subunits are shown in Figure 7-14). Additional proteins include syntrophins (α β1, β2, γ1, and γ2 subunits), dystrobrevin, and sarcospan. Dystrophin, syntrophins, and dystrobrevin are located in the sarcoplasm; dystroglycans, sarcoglycans, and sarcospan are transmembrane glycoproteins. Patients with a primary defect in dystroglycans and syntrophins have not been identified.

The most important muscle protein involved in muscular dystrophies is dystrophin, a 427-kd cytoskeletal protein associated to F-actin, dystroglycans, and syntrophins (see Figure 7-14). The absence of dystrophin determines the loss of components of the DAP complex. The function of dystrophin is to reinforce and stabilize the sarcolemma during the stress of muscle contraction by maintaining a mechanical link between the cytoskeleton and the extracellular matrix. Deficiencies of dystrophin are characteristic of Duchenne’s muscular dystrophy (DMD). Most patients die young (in their late teens or early twenties) due to an involvement of the diaphragm and other respiratory muscles.

DMD is an X chromosome–linked recessive disorder caused by a mutation in the dystrophin gene. The disorder is detected in affected boys after they begin to walk. Progressive muscle weakness and wasting, sudden episodes of vomiting (caused by delayed gastric emptying), and abdominal pain are observed. A typical laboratory finding is increased serum creatine kinase levels.

Muscle biopsies reveal muscle destruction, absence of dystrophin, and a substantial reduction of sarcoglycans, and other components of the DAP complex, detected by immunohistochemistry.

Heterozygote female carriers may be asymptomatic or have mild muscle weakness, muscle cramps, and elevated serum creatine kinase levels. Women with these mutations may give birth to affected males or carrier females.

Sarcoglycanopathies in limb-girdle muscular dystrophies have mutations in the genes for α-, β-, γ-, and δ-sarcoglycan that cause defective assembly of the sarcoglycans, thus disrupting their interaction with the other dystroglycan complex proteins and the association of the sarcolemma with the extracellular matrix.

Clinical significance: Satellite cells and muscle regeneration

Muscle development involves the chain-like alignment and fusion of committed muscle cell precursors, the myoblasts, to form multinucleated myotubes.

Two important events occur during the commitment of the muscle cell precursor to myogenesis: (1) the cessation of proliferation of the precursor cell—determined by the up regulated expression of myogenic regulatory factors (MRFs), Myf5 and MyoD, and the downregulation of Pax7, a transcription factor, and (2) the terminal differentiation of the muscle cell precursor—triggered by myogenin and MRF4.

Satellite cells are a stem cell population distinct from the myoblasts. They attach to the surface of the myotubes before a basal lamina surrounds the satellite cell and myotube (Figure 7-15). Satellite cells are of considerable significance in muscle maintenance, repair, and regeneration in the adult. The function of satellite cells is regulated by their specific niche. A niche is a specific site where stem cells reside for an indefinite period of time and produce a cell progeny while self-renewing. The basis for the regulation of the satellite cell population is the attachment within the niche. Satellite cells express α7β1 integrin, linking F-actin to the basal lamina, and M-cadherin, a calcium-dependent adhesion molecule attaching the satellite cell to the sarcolemma of the adjacent muscle fiber. Capillaries are located close to the satellite cells.

Figure 7-15 Satellite cells and muscle regeneration

Satellite cells are mitotically quiescent in the adult, but can reassume self-renewal and proliferation in response to stress or trauma. MyoD expression induces the proliferation of satellite cells. The descendants of the activated satellite cells—called myogenic precursor cells—undergo multiple rounds of cell division before they can fuse with existing or new myofibers.

Quiescent satellite cells express a receptor on their surface encoded by the proto-oncogene c-Met. The c-Met receptor has strong binding affinity for the chemotactic agent HGF (hepatocyte growth factor) bound to proteoglycans of the basal lamina. The HGF–c-Met complex up regulates a signaling cascade leading to proliferation of the satellite cells and the expression of Myf5 and MyoD.

In addition to satellite cells as progenitors of the myogenic cells in adult skeletal muscle, a population of stem cells in adult skeletal muscle—called side-population cells—has the capacity to differentiate into all major blood cell lineages as well as myogenic satellite cells. Side-population cells are present in bone marrow and may give rise to myogenic cells that can participate in muscle regeneration.

The pluripotent nature of satellite cells and side-population cells raises the possibility of stem cell therapy of a number of muscle injuries and degenerative diseases, including muscular dystrophy.

Clinical significance: Transport proteins on the sarcolemma of cardiocytes

The sarcolemma of the cardiocyte contains specific transport proteins (see Figure 7-17) controlling the release and reuptake of ions critical for systolic contractile function and diastolic relaxation.

Active transport of Ca²⁺ into the lumen of the sarcoplasmic reticulum by Ca²⁺-dependent ATPase is controlled by phospholamban. The activity of phospholamban is regulated by phosphorylation. Changes in the amount and activity of phospholamban—regulated by thyroid hormone—may alter diastolic function during heart failure and thyroid disease. An increase in heart rate and cardiac output is observed in hyperthyroidism. We discuss the role of phospholamban in Graves’ disease (hyperthyroidism) in Chapter 19, Endocrine System.

Additional transporters, including the Na⁺-Ca²⁺ exchanger and voltage-gated K⁺ channels, regulate the intracellular levels of K⁺ and Na⁺. β-Adrenergic receptor is also present in the sarcolemma.

Clinical significance: Myocardial infarction

Myocardial infarction is the consequence of a loss of blood supply to the myocardium caused by an obstruction of an atherosclerotic coronary artery. The clinical outcome depends on the anatomic region affected and the extent and duration of disrupted blood flow.

Irreversible damage of cardiocytes occurs when the loss of blood supply lasts more than 20 minutes. If blood flow is restored in less than 20 minutes—an event known as reperfusion—cardiocyte cell viability is maintained. Timing is critical for implementing early therapy to reestablish blood flow by using thrombolytic agents. The histologie changes of myocardial infarction are summarized in Figure 7-20.

Figure 7-20 Myocardial infarction

Creatine kinase and its MB isoenzyme (CK-MB) are conventional markers of myocardial necrosis. A more sensitive marker is cardiocyte-specific troponin I not expressed in skeletal muscle. An increase of troponin I in the serum of patients with acute coronary syndromes provides prognostic information on increased risk of death and enables treatment to decrease further myocardial necrosis.

Mechanism of smooth muscle contraction

Both the arrangement of the contractile proteins and the mechanism of contraction of smooth muscle differ from those of skeletal and cardiac muscle:

We have seen that the sliding of the myosin-actin complex in striated muscle is the basis for contraction (see Figure 7-9). In smooth muscle, actin filaments and associated myosin attach to cytoplasmic and plasma membrane dense bodies, representing the equivalent of the Z disk of striated muscle. Dense bodies are attached to the plasma membrane through desmin and vimentin intermediate filaments. When the actin-myosin complex contracts, their attachment to the dense bodies determines cell shortening.

Calcium-dependent phosphorylation of myosin regulatory light chains is responsible for the contraction of smooth muscle. We have already discussed this mechanism in Chapter 1, Epithelium, when we analyzed the role of different myosins in the cell (review Figure 1-32).

Smooth muscle myosin is a type II myosin, consisting of two heavy chains and two pairs of light chains. The myosin molecule is folded when dephosphorylated.

When type II myosin phosphorylates, it unfolds and assembles into filaments, the actin binding site on the myosin head is exposed, and myosin can then bind to actin filaments to cause cell contraction.

Smooth muscle can be stimulated to contract by nervous stimulation, hormonal stimulation, or stretch. For example, intravenous oxytocin stimulates uterine muscle contractions during labor.

In response to an appropriate stimulus, there is an increase in cytoplasmic Ca²⁺. Ca²⁺ binds to calmodulin. The Ca²⁺-calmodulin complex activates myosin light-chain kinase, which catalyzes phosphorylation of the myosin light chain. When Ca²⁺ levels decrease, the myosin light chain is enzymatically dephosphorylated, and the muscle relaxes.

Concept mapping

Muscle Tissue

Muscle Tissue

Essential concepts

• There are three types of muscle: skeletal, cardiac, and smooth muscle.

Skeletal muscle is surrounded by the epimysium, a layer of dense connective tissue. The perimysium, derived from the epimysium, surrounds bundles or fascicles of muscle cells, also called muscle fibers. Each muscle fiber within a fascicle is surrounded by the endomysium, a thin layer of reticular fibers and extracellular matrix closely associated to a basal lamina enveloping each muscle cell.

Skeletal muscle cells are multinucleated cells, resulting from the fusion of myoblasts. Each skeletal muscle cell is surrounded by a plasma membrane (called sarcolemma). The sarcolemma is surrounded by a basal lamina and satellite cells. The sarcolemma projects long processes, called transverse tubules or T tubules, deep into the cytoplasm (called sarcoplasm). The sarcoplasm contains mitochondria (called sarcosomes). Each T tubule is flanked by sacs of the endoplasmic reticulum (called sarcoplasmic reticulum) forming a tripartite structure called a triad, found at the junction of the A band and I band. The nuclei are located at the periphery of the cell. An important component of the sarcoplasm is the myofibril.

A myofibril is a linear repeat of sarcomeres. Each sarcomere consists of two major cytoskeletal myofilaments: actin and myosin. Note the difference between myofibril and myofilament. The arrangement of these two myofilaments generates a banding pattern (or striation), characteristic of skeletal and cardiac muscle tissue. There is an A band (dark) and I band (light). The A band is at the center of the sarcomere; the Z disk bisects the I band. The A band is bisected by the H band, which contains creatine kinase. The M line runs through the midline of the H band.

A sarcomere is limited by two adjacent Z disks. Actin inserts into each side of the Z disk. Myosin myofilaments do not attach to the Z disk. Actin is associated with the tropomyosin-troponin complex (formed by troponins I, C, and T) and nebulin. Myosin (called myosin II) consists of two identical heavy chains (with a globular head) and two pairs of light chains. The globular heads have an actin-binding region, and ATP-binding region, and a light chain-binding region. Titin is associated with myosin.

Each Z disk is encircled by the intermediate filament desmin. Desmin filaments are linked to each other by plectin. The desmin-plectin complex forms a lattice with the opposite ends attached to costameres in the sarcolemma. This arrangement stabilizes the myofibrils in the sarcoplasm during muscle contraction.

• During muscle contraction, the length of myosin and actin myofilaments does not change. The length of the sarcomere decreases because actin and myosin slide past each other, represented by a reduction in the width of the I band and H band. ATP is an energy source for muscle contraction. Creatine phosphate (produced in sarcosomes) is a back up mechanism to maintain steady levels of ATP during muscle contraction. Creatine kinase catalyzes a reversible reaction generating creatine and ATP from the hydrolysis of creatine phosphate.

The neuromuscular junction is a specialized structure formed by a nerve associated with a target muscle. Inside the muscle, a motor nerve gives rise to numerous branches, each innervating a single muscle cell. The motor nerve and its innervating branches form a motor unit.

An excitation-contraction signal is produced by the release of acetylcholine from a presynaptic button into a primary synaptic cleft, an invagination on the surface of a muscle cell coated with basal lamina containing acetylcholinesterase. The primary synaptic cleft forms secondary synaptic clefts, also covered by basal lamina. Crests of the secondary synaptic clefts contain acetylcholine receptors.

An action potential depolarizes the sarcolemma, and the action potential travels inside the muscle cell along T tubules, which are in contact with channels of the sarcoplasmic reticulum containing calcium. Calcium ions are released, bind to troponin C, and initiate contraction by regulating myosin-actin interaction. When depolarization ends, calcium ions are pumped back into the sarcoplasmic reticulum channels and bind to calsequestrin.

Botulinum toxin binds to the presynaptic membrane of the nerve terminal and blocks the release of acetylcholine. Curare binds to the acetylcholine receptor, prevents binding of acetylcholine, and induces muscle paralysis. In myasthenia gravis, an autoimmune disease that produces fatigue with exercise, autoantibodies bind to the acetylcholine receptor and prevent binding of acetylcholine.

• Muscular dystrophies are a group of congenital muscular diseases characterized by muscle weakness, atrophy, serum levels increases of muscle enzymes, and destructive changes in muscle tissue.

The following protein complexes, some of them part of the dystrophin-associated protein (DAP) complex, are present in the sarcoplasm or in the sarcolemma adjacent to the sarcolemma. They provide mechanical stabilization during muscle contraction:

1. Dystroglycan complex consists of dystroglycan-α and dystroglycan-β. Dystroglycan-α binds to the α chain of laminin-2, and dystroglycan-β binds to dystrophin. No primary defects in the dystroglycan complex have been identified.

2. Sarcoglycan complex consists of six transmembrane subunits (α, β, γ, δ, , and ζ). Sarcoglycanopathies (for example, limb-girdle muscular dystrophies) are caused by defects in components of the sarcoglycan complex.

3. Dystrophin binds the dystroglycan complex to actin in the sarcoplasm. Duchenne’s muscular dystrophy, an X-linked recessive condition, is caused by a deficiency in dystrophin. The absence of dystrophin results in the loss of syntrophins and other components of the DAP complex.

4. Dystrobrevin (α and β subunits), present in the sarcoplasm.

5. Syntrophins (α, β1, β2, γ1, and γ2 subunits) are found in the sarcoplasm and bind to dystrophin and dystrobrevin.

6. Sarcospan, a transmembrane protein.

• Satellite cells are closely associated to skeletal muscle cells and are covered by a basal lamina. In mature muscle, satellite cells are quiescent. Activated satellite cells activated by trauma or mechanical stress can self-renew and proliferate. The expression of myogenic regulatory factors (for example, Myf5 and MyoD) activates satellite cells, which become myogenic precursor cells (to form muscle cells) or side-population cells (to differentiate into hematopoietic cells).

• The neuromuscular spindle is a specialized encapsulated sensor of the contraction of various muscles. It contains sensory and motor components and specialized muscle fibers called intrafusal fibers (designated nuclear bag fiber and nuclear chain fiber). Intrafusal fibers are in parallel with the striated extrafusal fibers. When extrafusal fibers contract, the neuromuscular spindle becomes slack. This information is transmitted to the spinal cord, which activates gamma motor neurons that stretch the spindle. In contrast to the neuromuscular spindle, the Golgi tendon organs are located in series with the extrafusal muscle fibers. They provide information about the force of contraction of the skeletal muscle.

• There are three major types of skeletal muscle fibers: red fibers (involved in maintenance of posture), white fibers (responsible for rapid contraction), and intermediate fibers (a combination of the characteristics of red and white fibers). Muscles contain a mixture of the three types of fibers.

• Cardiac muscle consists of branched cylindrical cells called cardiocytes. They contain a central nucleus and myofibrils in the cytoplasm. The organization of the sarcomere is similar to skeletal muscle. The following differences are observed:

(1) T tubules and short portions of the sarcoplasmic reticulum form diads (instead of triads). (2) Diads are found at the level of the Z disk (instead of the A-I band junction). (3) Mitochondria contain abundant cristae. (4) Cardiocytes are joined end-to-end by intercalated disks. (5) Intercalated disks display a steplike arrangement with a transverse portion (containing desmosomes and fasciae adherentes), and a longitudinal portion (where gap junctions are located).

A specialized type of cardiac fiber is the Purkinje fiber, a glycogen-rich cell with fewer myofibrils, involved in conductivity.

• Smooth muscle cells are found in the wall of the alimentary tube, urinary excretory passages, respiratory tract, uterus, and blood vessels.

Smooth muscle cells are spindle-shaped, tapering cells, with a central nucleus and surrounded by a basal lamina. We discussed the ability of smooth muscle cells to synthesize and secrete components of collagen and elastic fibers. The cytoplasm contains actin, myosin, and intermediate filaments.

A typical feature of muscle cells are caveolae, regarded as a primitive T tubule system. Caveolae develop from lipid rafts, a domain in the plasma membrane enriched in cholesterol and sphingolipids. The protein caveolin binds to cholesterol. Caveolae are not seen when the caveolin gene is not expressed. The detachment of caveolae forms pynocytotic vesicles, involved in vesicular trafficking and signaling.

• The contraction of smooth muscle cells differs from skeletal and cardiac muscle cells. Smooth muscle cells lack sarcomeres and troponin, and calcium ions initiate contraction from outside the cell, rather than from the sarcoplasmic reticulum.

Myosin light-chain kinase is responsible for the calcium sensitivity of the contractile actin-myosin component of smooth muscle. An equivalent to the Z disk of striated muscle are the dense bodies.

In response to a stimulus, an increase in cytoplasmic calcium binds to calmodulin. The calcium-calmodulin complex activates myosin light-chain kinase, which catalyzes phosphorylation of the myosin light chain and enables binding of activated myosin to actin.