Muscle

*The answer is D.* The basal lamina of a muscle fiber is part of the endomysium.

*The answer is B.* The triad consists of the T-tubule surrounded by two terminal cisternae of the sarcoplasmic reticulum. The sarcoplasmic reticulum is a special structure in muscle cells that holds and releases calcium.

*The answer is C.* Cardiac muscle is often branched.

*The answer is B.* In smooth muscle calcium released by the smooth ER initiates contraction by binding to calmodulin. Calmodulin then binds and activates myosin light-chain kinase, which phosphorylates the light chains of myosin and activates myosin.

*The answer is C.* T-tubules carry depolarization to the muscle fiber interior.

*The answer is C.* In smooth muscle, thin actin filaments attatch to dense bodies.

*The answer is E.* In cardiac muscle, numerous gap junctions, desmosomes, and adherens junctions are specifically localized in intercalaated discs.

*The answer is D.* Rigor mortis is fixed muscular contraction after death caused by an absence of ATP (loss of mitochondrial activity after death), which creates actin-myosin cross bridges that become stable.

*The answer is B.* Skeletal muscle regenerates through the differentiation of muscle satellite cells.

*The answer is A.* The A band remains constant during muscle contraction.

*The answer is B.* Ca²⁺ is responsible for the coupling of excitation and contraction in skeletal muscle. The sarcoplasmic reticulum is a modified endoplasmic reticulum. Ca²⁺ is concentrated in the lumen of the sarcoplasmic reticulum (B). Glycogen is stored as droplets in the cytoplasm (C). The transverse tubule system, or T system, is an extension of the cell membrane of the myofiber (sarcolemma). The T system allows for simultaneous contraction of all myofibrils because it encircles the A-I bands in each sarcomere of every myofibril (A). It is important to note that cardiac muscle also has a T system, although it is not as elaborate and well organized as that found in skeletal muscle (e.g., dyads are present rather than the triads of skeletal muscle, and there are fewer T tubules in the atrial versus ventricular muscle).

*The answer is A.* There is a small amount of production of adenosine triphosphate (ATP) after death through anaerobic and phosphagen pathways. However, there is insufficient ATP to induce the detachment of the myosin heads from actin. Ca²⁺ continues to leak from the extracellular fluid and the sarcoplasmic reticulum (E); however, the sarcoplasmic reticulum is no longer able to retrieve the Ca²⁺ (B). Tropomyosin and troponin are disengaged from the myosin active sites (C). Lactic acid is produced during rigor mortis through anaerobic pathways. The high levels of lactic acid cause deterioration of the skeletal muscle and end the state of rigor mortis (D).

*The answer is B.* Dystrophin is part of a multisubunit complex that links actin filaments in myofibrils to integral membrane proteins in the sarcolemma, which are also bound to the endomysium. This ensures that when the sarcomere shortens, the myofiber shortens, and that the force of shortening is transmitted to the muscle's connective tissue wrappings.

*The answer is D.* When cytoplasmic Ca²⁺ levels are low, tropomyosin blocks the myosin-binding site on actin. Following an action potential, membrane depolarization at the neuromuscular junction rapidly spreads down the T tubules, triggering release of Ca²⁺ from the sarcoplasmic reticulum. Ca²⁺ binds to troponin, releasing the troponin complex from actin, which allows tropomyosin to shift its position on actin and expose the myosin-binding site. This allows myosin heads to bind to actin, activating the myosin adenosine triphosphatase (ATPase). The repeated binding and release of myosin to actin is responsible for filament sliding and muscle contraction.

*The answer is D.* Intercalated discs are complex cellular junctions that provide both mechanical and electrical connections between adjacent cardiac muscle cells. The transverse portions of intercalated discs bond the two cells together and function as hemi Z lines to link the contractile apparatus of the two cells. The longitudinal portions of intercalated discs contain gap junctions, which transmit depolarization to a neighboring cell, synchronizing contraction.

*The answer is A.* Smooth muscle cells lack T tubules. Instead, membrane specializations called caveolae are thought to be involved in Ca²⁺ in these cells. Caveolae are invaginations of the plasma membrane that contain Ca²⁺ pumps, Ca²⁺ channels, and hormone receptors. It is thought that caveolae may be responsible for the direct entry of Ca²⁺ from outside the cells via ion channels and its removal by pumping. They may also signal release and reuptake of Ca²⁺ from the smooth endoplasmic reticulum.

*The answer is D.* The T tubules of skeletal muscle cells are positioned so that they form triads with the terminal cisternae of the SR at the interface of the A and I bands.

*The answer is A.* The T tubules of cardiac muscle cells are wider than those of skeletal muscle cells and are lined by external lamina (a basal lamina-like material). In contrast to skeletal muscle, the T tubules are located at the Z disk, where they often form dyads, not triads.

*The answer is C.* Smooth muscle cells do not have T tubules. Contraction may be initiated by stretching, neural impulses, the intercellular passage of small molecules via gap junctions, or the action of hormones such as oxytocin. Contraction is not dependent on troponin, which is absent from the thin filament of smooth muscle. Instead, Ca²⁺ controlled by sarcolemmal vesicles known as caveolae is released into the cytosol, where it binds with calmodulin. The calcium-calmodulin complex activates myosin light-chain kinase, which participates in the contraction process.

*The answer is C.* Binding of Ca²⁺ to the TnC subunit of troponin leads to the uncovering of myosinbinding sites on actin (thin filaments).

*The answer is C.* Smooth muscle cells contain one centrally located nucleus.

*The answer is C.* Titin forms an elastic lattice that anchors thick filaments to Z disks.

*The answer is A.* The endomysium is a thin connective tissue layer composed of reticular fibers and an external lamina that invests individual muscle fibers (cells). The epimysium surrounds the entire muscle, and the perimysium surrounds bundles (fascicles) of muscle fibers.

*The answer is B.* A triad in skeletal muscle is composed of three components, a T tubule and two terminal cisternae of the SR that flank it. The SR, not the T tubules, sequesters Ca²⁺.

*The answer is D.* Cardiac muscle cells are joined together end to end by a unique junctional specialization called the intercalated disk.

*The answer is C.* Botulism is the only possible consideration, especially since they both had canned food. Duchenne muscular dystrophy is most common in young men but very rare in older women. It would be highly unlikely that both mother and son would show symptoms of amyotrophic lateral sclerosis or myasthenia gravis or have myocardial infarct at the same time.

*The answer is B.* Unlike connective tissue fibers (e.g., collagenous fibers, elastic fibers, reticular fibers), a muscle fiber is actually a muscle cell. These elongated cells (myocytes) are organized into parallel arrays to form muscle tissue. In skeletal muscle, a muscle fiber is a multinucleated syncytium formed by the fusion of several embryonic myoblasts. In longitudinal sections, skeletal muscle cells appear as long cylindrical fibers with multiple, long oval nuclei located at the periphery of the cells. Myofibrils (choice C) are longitudinal arrays of contractile filaments in the cytoplasm of muscle cells. Myofibrils are composed of thick (myosin) and thin (actin) myofilaments (choice D). A sarcomere (choice E) is the segment of a myofibril that forms the basic functional unit of skeletal muscle. Muscle fascicles (choice A) are bundles of muscle fibers bound together by a connective tissue sheath.

*The answer is A.* Skeletal muscles are invested with distinct layers of connective tissue: (1) endomysium surrounds individual muscle fibers (2) perimysium surrounds bundles of muscle fibers; and (3) epimysium surrounds the external surface of muscles. Groups of muscle fibers surrounded by perimysium are referred to as muscle fascicles or muscle bundles. As shown in the image, large blood vessels and nerves (indicated by arrows) travel within the perimysium (indicated by arrowheads) to supply the muscle fascicles. Muscle fibers (choice B) exhibit a polygonal shape in cross section and feature multiple peripheral nuclei. None of the other structures exhibit the distinctive histologic features of muscle fascicles.

*The answer is A.* A delicate connective tissue (indicated by the arrowheads) composed of a basal lamina and reticular fibers surrounds individual muscle fibers (indicated by the arrows). This connective tissue layer is endomysium. Numerous capillaries travel through the endomysium to supply muscle fibers with oxygen and nutrients. Epimysium (choice B) is the dense connective tissue sheath that envelops an entire muscle. It provides the investing fascia that is described in gross anatomy. It is continuous with the tendon or aponeurosis that anchors a muscle to its attachment site. Thin connective tissue septa arising from the epimysium extend into the muscle and surround muscle fascicles. These connective septa form the perimysium (choice D). Sarcoplasmic reticulum (choice E) is a highly organized, tubular network of smooth endoplasmic reticulum that separates bundles of myofilaments into myofibrils (choice C).

*The answer is B.* When examined in cross section at high magnification, skeletal muscle fibers appear stippled because of the presence of numerous myofibrils in the cytoplasm. In longitudinal sections, myofibrils demonstrate cross-striations with alternating regions of light-stained I bands and dark-stained A bands. The precise lateral alignment of light- and dark-stained bands gives skeletal muscle its distinctive striated appearance; hence the term "striated muscle." Myofibrils are bundles of the actin and myosin myofilaments (choice C) that produce muscle fiber contraction. Two types of myofilaments are found in skeletal muscle cells: thick filaments contain myosin (choice D), whereas thin filaments (choice E) contain primarily actin.

*The answer is E.* As described above, alternating A and I bands form cross-striations that are a characteristic feature of skeletal muscle fibers. When examined by polarized light microscopy, the dark A bands (anisotropic bands) exhibit birefringence, whereas the light I bands (isotropic bands) exhibit monorefringence. When examined at high magnification, dense Z lines (Z disks) are observed to bisect the light-stained I bands. The Z lines appear as zigzag lines in longitudinal sections. The major protein found in Z lines is the actin-binding protein, α-actinin. α-Actinin anchors thin filaments to Z lines. A less dense region, termed the H zone (H band), is observed to bisect the dark-stained A bands. A narrow dense line, the M line, is located at the center point of the H zone. H zones and M lines are not visible by light microscopy, but they are revealed when skeletal muscle fibers are examined by electron microscopy.

*The answer is D.* Sarcomeres are the repetitive functional units of striated muscle fibers. They are defined as the segments of myofibrils that lie between adjacent Z lines. Sarcomeres extend about 2.5 μm in resting muscle, but the length of a sarcomere is reduced to about 1 μm during muscle contraction. The explanation for this observation is that during muscle contraction, thin filaments in I bands slide into A bands. Thus, the length of I bands becomes shorter during muscle contraction, whereas the length of A bands remains unchanged. A single skeletal muscle fiber may contain over 100,000 sarcomeres.

*The answer is A.* Thick filaments composed of myosin extend along the entire length of the A band. The center point of the A band is the dense M line that contains a myosin-binding protein, myomesin. This protein links thick filaments together, forming the M line. The less-dense H zone that flanks the M line consists exclusively of thick filaments. The thin filament anchored to the Z line extends over one-half of the I band and, therefore, overlaps with a portion of the A band. Thus, portions of the A band that flank the H zone contain both thin and thick filaments. These thin and thick filaments are organized so that each thick filament is in contact with six thin filaments. During muscle contraction, longer portions of the thin filaments slide into the A bands. As result of these molecular changes, H zones become thinner and I bands become shorter during muscle contraction.

*The answer is E.* Three types of muscle fibers are found in skeletal muscle, namely red, white, and intermediate. These muscle fibers differ in their color, diameter, and enzyme biochemistry. Histochemical reactions detecting myosin ATPase can be used to distinguish type I (slow-twitch) fibers from type II (fast-twitch) fibers. The rationale for this observation is that myosin ATPase activity is positively correlated with muscle contraction velocity. When stained for myosin ATPase, type I fibers appear pale and type II fibers appear dark (shown in the image). In fresh tissue, type I fibers are small and red. They tend to have more mitochondria and more myoglobin. Type I fibers are characterized by a slow velocity of the myosin ATPase reaction, which results in slow/prolonged contractions (i.e., slow-twitch fibers). By contrast, type II fibers exhibit high anaerobic enzyme activity and they produce faster, shorter, and stronger contractions than do type I fibers (fast-twitch fibers). An intermediate muscle fiber was recently identified. Intermediate (type IIa) fibers are fast-twitch, fatigue-resistant motor units. They are not identified in this muscle biopsy. Myofibrils and myofilaments (choices B and C) cannot be resolved in frozen sections examined at low magnification.

*The answer is B.* Muscle fiber diameter varies according to physiologic demand. The size of muscle fibers also varies as a function of age, sex, and nutrition. It is commonly known that physical training and exercise leads to muscle enlargement. This enlargement is caused by increased diameter of individual muscle fibers (i.e., increased cell volume). Exercise stimulates the production of new intracellular myofibrils that increase the diameter of individual muscle fibers. This process, growth by increased cell size, is referred as hypertrophy. Skeletal muscle has limited capacity to regenerate in response to injury, and does not respond to increased workload by increasing the number of muscle fibers (hyperplasia, choice C). Exercise reduces fat deposition in muscles (choice A) and does not increase the abundance of interstitial connective tissue (choices D and E).

*The answer is C.* Dystrophin is a rod-shaped cytoplasmic protein located beneath the sarcolemma (plasma membrane). It links actin filaments of the outmost layer of the myofilaments to the inner surface of the plasma membrane (sarcolemma). It interacts with many other muscle proteins and forms a dystrophin-associated protein complex that links cytoplasmic proteins with extracellular structural proteins. Duchenne muscular dystrophy is a severe, progressive, X-linked, inherited condition characterized by progressive degeneration of muscles, particularly those of the pelvic and shoulder girdles. Dystrophin deficiency leads to impaired force transmission from thin filaments to the sarcolemma. The resulting weakness is noted mainly around the pelvic and shoulder girdles (proximal muscle weakness) and is progressive. Enlargement of the patient's calf muscles is referred to as "pseudohypertrophy." Healthy muscle tissue is replaced gradually with an abundance of fibrofatty connective tissue. None of the other proteins are associated with pathogenesis of Duchenne muscular dystrophy.

*The answer is A.* Neuromuscular junctions (or motor end plates) are functional contactsbetween a motor nerve fiber and a muscle fiber. At this junction, the terminal end of an axon (or terminal twig of an axon) forms a synapse with the plasma membrane (sarcolemma) of the target muscle fiber. Synaptic vesicles stored in the terminal axon bulb contain acetylcholine. Nerve impulses cause acetylcholine to be released into the synaptic cleft. Binding of this neurotransmitter to its receptor initiates muscle cell contraction. Motor nerves containing myelinated axons travel within the perimysium. The axons lose their myelin sheath at the neuromuscular junction. None of the other structures exhibit histologic features of a motor end plate.

*The answer is B.* Muscles that control precise and delicate movements (e.g., extraocular muscles and intrinsic hand muscles) are richly innervated. In these muscles, a single nerve fiber usually innervates a single muscle fiber. By contrast, muscles that produce large and coarse movements (e.g., back and limb muscles) are typically innervated by nerve fibers with hundreds of terminal branches (twigs). In these muscles, axon twigs (not individual axons) form synapses with myofibers. Thus, a motor unit is best described as a single nerve axon and the muscle fiber or fibers that it innervates. None of the other choices describe histologic features of a motor unit.

*The answer is B.* Myasthenia gravis is a type II hypersensitivity disorder caused by autoantibodies that bind to the acetylcholine receptor. These antibodies interfere with the transmission of neural impulses at the neuromuscular junction, causing muscle weakness and easy fatigability. External ocular and eyelid muscles are most often affected, but the disease is often progressive and may cause death, owing to respiratory muscle paralysis.

*The answer is A.* Skeletal muscle develops from myoblasts that migrate throughout the embryo. During migration, myoblasts receive biochemical signals and cues from the surrounding connective tissue. In the head region of the embryo, connective tissue is primarily of neural crest origin. In the limbs, the connective tissue is derived from lateral plate parietal (somatic) mesoderm. The cellular and molecular mechanisms that pattern the size, shape, and attachments of muscles are largely unknown. None of the other cells or tissues are known to regulate the patterning of skeletal muscles during embryonic development.

*The answer is C.* Muscle spindles are encapsulated sensory receptors that are situated among muscle fascicles. They are proprioceptors that continuously monitor changes in muscle fiber length during body movement. As shown in the image, muscle spindles consist of a connective tissue capsule that surrounds a few small muscle fibers. These small fibers are said to be "intrafusal," whereas the surrounding large muscle fibers are said to be "extrafusal." Unlike extrafusal fibers, intrafusal fibers are not striated. Sensory nerve fibers penetrate the capsule and synapse with individual intrafusal fibers. Muscle spindles constantly monitor muscle stretching and relay this information to the spinal cord for processing. Muscle spindles generate essential reflexes that maintain posture and coordinate the actions of opposing muscle groups during body movement.

*The answer is B.* Unlike skeletal muscle, where muscle fibers are multinucleated cells, cardiac muscle fibers are composed of multiple cells that make tight end-to-end connections. Cardiac muscle cells may split and unite, giving cardiac muscle a typical "branching" morphology. Cardiac and skeletal muscles both exhibit cross-striations—their thick and thin contractile filaments exhibit the same organization (choices C, D, E). The nuclei of cardiac and skeletal muscle are, however, distinctly different. The nuclei of skeletal muscle cells are located at the periphery of the fiber, whereas the nucleus of a cardiac myocyte is located in the center of the cell (shown in the image). This difference in nuclear location provides a useful means for distinguishing cardiac from skeletal muscle. Cardiac and skeletal muscle fibers are both invested with connective tissue that conveys nerves and capillaries (choice A).

*The answer is C.* Intercalated disks are a distinctive histologic feature of cardiac muscle. In routine H&E histologic preparations, intercalated disks appear as darker-stained lines that cross the muscle fibers. They represent highly specialized regions of cell-cell adhesion. They are composed of junctional complexes that form strong molecular bridges between cardiac myocytes. When examined by scanning electron microscopy, intercalated disks appear as steplike disks with transverse and lateral regions. In the transverse region, fascia adherens (the equivalent of zonula adherens in epithelial cells) and desmosomes mediate cell adhesion. Gap junctions and desmosomes are found in the lateral region of the intercalated disk. The other structures (lines and bands) are present in cardiac myocytes, but they do not contribute to the morphology of intercalated disks, and they would not be visible at this magnification.

*The answer is C.* Gap junctions are molecular pores that permit ions and other small molecules to pass between adjacent cells. Gap junctions are found in the lateral regions of the intercalated disks in cardiac muscle. They permit electrochemical signals to move between cardiac myocytes (ionic coupling). Gap junction communication enables cardiac muscle cells to form an electrochemical syncytium that helps maintain a normal heart rhythm.

*The answer is E.* Smooth muscle is an involuntary and nonstriated muscle that is widely distributed in the body. For example, smooth muscle is found in the gastrointestinal tract, blood vessels, urinary bladder, uterus, male/female reproductive tracts, and iris of the eye. In longitudinal sections, smooth muscle fibers appear as elongated fusiform cells with central nuclei and uniformly eosinophilic cytoplasm (illustrated in the image). Depending on location, the length of smooth muscle fibers varies from 20 μm (media of small blood vessel) to 500 μm (myometrium of pregnant uterus). Smooth muscle fibers are typically arranged into bundles or sheets. None of the other tissues exhibit the distinctive histologic features of smooth muscle.

*The answer is E.* In addition to their contractile properties, smooth muscle cells demonstrate the characteristic features of secretory cells. For example, endomysium, a thin layer of connective tissue, and the basal lamina that surrounds smooth muscle fibers are produced and deposited by smooth muscle cells. Reticular fibers in the endomysium form an intricate network that supports the parenchymal cells and binds them together. In large blood vessels, smooth muscle cells secrete type I collagen and elastic tissue components.

*The answer is D.* Gap junctions facilitates the spread of nitric oxide molecules in the smooth muscle to permit erection because they allow cell-cell communication via adjacent cells.

*The answer is E.* This image shows skeletal muscle, which is a striated muscle with peripheral nuclei. The image is stained with hematocylin and eosin.

*The answer is D.* When electrically stimulated skeletal muscle will generate an action potential which will open the L-Type Ca++ channels that will lead to the opening of the sarcoplasmic reticulum calcium channels mechanically. Ca++ will be released from SR to cytoplasm, Ca++ will bind to troponin C and will result in contraction. In this experiment, the SR is functional therefore all the steps before this point is functional. Electrical stimulation does not need Acetylcholine receptors, therefore, the lack of these receptors cannot explain the lack of contraction. If Na+ channels were dysfunctional there wouldn't be an electrical stimulation that leads to Ca++ release from SR. Calmodulin binds calcium in smooth muscle not in skeletal muscle. Defective troponin C cannot bind Ca++.

*The answer is E.* Under low oxygen, skeletal muscle will generate lesser ATP. ATP is required to detach the myosin head from myosin binding sites on actin.

*The answer is B.* In smooth muscle, chemicals, drugs, hormones, and neurotransmitters can initiate a contraction without an action potential. This is called pharmaco-mechanic coupling.

*The answer is A.* When a striated muscle fiber actively shortens, the only band that remains the same is the A band.

*The answer is D.* In striated muscle, rigor results from a low ATP concentration in the sarcomeres. As a result, the myosin heads remain attached to the actin filaments.

*The answer is A.* In smooth muscle cells, regulation of the myosin cross-bridge cycle requires calcium and calmodulin.

*The answer is D.* A triad is the structure formed by a T tubule with a sarcoplasmic reticulum (SR) known as the terminal cisterna on either side found in the skeletal muscle. They are typically located at the A-I junction. A diad is a structure in the cardiac myocyte located at the sarcomere Z-line. It is composed of a single t-tubule paired with a terminal cisterna of the sarcoplasmic reticulum.

*The answer is E.* Tension development in a single sarcomere is directly proportional to the number of active myosin cross-bridges attached to actin filaments. Overlap between the myosin and actin filaments is optimal at sarcomere lengths of about 2.0 to 2.5 micrometers, which allows maximal contact between myosin heads and actin filaments. At lengths less than 2.0 micrometers, the actin filaments protrude into the H band, where no myosin heads exist. At lengths greater than 2.5 micrometers, the actin filaments are pulled toward the ends of the myosin filaments, again reducing the number of possible cross-bridges.

*The answer is B.* Excitation-contraction coupling in skeletal muscle begins with an excitatory depolarization of the muscle fiber membrane (sarcolemma). This depolarization triggers the all-or-none opening of voltage-sensitive Na+ channels and an action potential that travels deep into the muscle fiber via the T tubule network. At the T tubule-sarcoplasmic reticulum "triad," the depolarization of the T tubule causes a conformational change in the dihydropyridine receptor and subsequently in the ryanodine receptor on the sarcoplasmic reticulum. The latter causes the release of Ca++ into the sarcoplasm and the binding of Ca++ to troponin C (not to calmodulin) on the actin filament.

*The answer is D.* Skeletal muscle contraction is tightly regulated by the concentration of Ca++ in the sarcoplasm. As long as sarcoplasmic Ca++ is sufficiently high, none of the remaining events—removal of acetylcholine from the neuromuscular junction, removal of Ca++ from the presynaptic terminal, closure of the acetylcholine receptor channel, and return of the dihydropyridine receptor to its resting conformation—would have any effect on the contractile state of the muscle.

*The answer is B.* An important characteristic of visceral smooth muscle is its ability to contract in response to stretch. Stretch results in depolarization and potentially the generation of action potentials. These action potentials, coupled with normal slow-wave potentials, stimulate rhythmical contractions. Like skeletal muscle, smooth muscle contraction is both actin and ATP dependent. However, the cross-bridge cycle in smooth muscle is considerably slower than in skeletal muscle, which allows for a higher maximal force of contraction.

*The answer is D.* In smooth muscle, the binding of four Ca++ ions to the protein calmodulin permits the interaction of the Ca++-calmodulin complex with myosin light chain kinase. This interaction activates myosin light chain kinase, resulting in the phosphorylation of the myosin light chains and, ultimately, muscle contraction. In skeletal muscle, the activating Ca++ signal is received by the protein troponin C. Like calmodulin, each molecule of troponin C can bind with up to four Ca++ ions. Binding results in a conformational change in the troponin C protein that dislodges the tropomyosin molecule and exposes the active sites on the actin filament.

*The answer is A.* Muscle fibers involved in fine motor control are generally innervated by small motor neurons with relatively small motor units, including those that innervate single fibers. These neurons fire in response to a smaller depolarizing stimulus compared with motor neurons with larger motor units. As a result, during weak contractions, increases in muscle contraction can occur in small steps, allowing for fine motor control. This concept is called the size principle.

*The answer is B.* The strongest common denominator among smooth, skeletal, and cardiac muscle contraction is their shared dependence on Ca++ for the initiation of contraction. Cardiac and skeletal muscles exhibit several characteristics not shared by smooth muscle. For example, the contractile proteins in both cardiac and skeletal muscles are organized into discrete sarcomeres. Both muscle types also possess some semblance of a T tubule system and are dependent on the generation of action potentials for their contraction. Smooth muscle, in contrast, is relatively less organized, is uniquely regulated by myosin light chain phosphorylation, and can contract in vivo in the absence of action potentials.

*The answer is E.* The neuromuscular junction is equipped with a so-called safety factor that ensures that every nerve impulse that travels to the terminal of a motor neuron results in an action potential in the sarcolemma. Given a normal, healthy muscle, contraction is also ensured. The voltage sensitivity of the Ca++ channels in the presynaptic membrane and the high concentration of extracellular Ca++ ensure an influx of Ca++ sufficient to stimulate the fusion of synaptic vesicles to the presynaptic membrane and the release of acetylcholine. The overabundance of acetylcholine released guarantees a depolarization of the postsynaptic membrane and the firing of an action potential.

*The answer is B.* The physical lengths of the actin and myosin filaments do not change during contraction. Therefore, the A band, which is composed of myosin filaments, does not change either. The distance between Z discs decreases, but the Z discs themselves do not change. Only the I band decreases in length as the muscle contracts.

*The answer is E.* The H zone is the region in the center of the sarcomere composed of the lighter bands on either side of and including the M line. In this region, the myosin filaments are centered on the M line, and there are no overlapping actin filaments. Therefore, a cross-section through this region would reveal only myosin.

*The answer is B.* Muscle contraction is dependent on an elevation of intracellular Ca++ concentration. As the twitch frequency increases, the initiation of a subsequent twitch can occur before the previous twitch has subsided. As a result, the amplitude of the individual twitches is summed. At very high twitch frequencies, the muscle exhibits tetanic contraction. Under these conditions, intracellular Ca++ accumulates and supports sustained maximal contraction.

*The answer is C.* As long as the ryanodine receptor channel on the sarcoplasmic reticulum remains open, Ca++ will continue to flood the sarcoplasm and stimulate contraction. This prolonged contraction results in heat production, muscle rigidity, and lactic acidosis. In contrast, factors that either inhibit Ca++ release or stimulate Ca++ uptake into the sarcoplasmic reticulum, or that prevent either the depolarization of the T tubule membrane or the transduction of the depolarization into Ca++ release, would favor muscle relaxation.

*The answer is B.* Prolonged or repeated maximal contraction results in a concomitant increase in the synthesis of contractile proteins and an increase in muscle mass. This increase in mass, or hypertrophy, is observed at the level of individual muscle fibers.

*The answer is D.* The slower cycling rate of the cross-bridges in smooth muscle means that a higher percentage of possible cross-bridges is active at any point in time. The more active cross-bridges there are, the greater the force that is generated. Although the relatively slow cycling rate means that it takes longer for the myosin head to attach to the actin filament, it also means that the myosin head remains attached longer, prolonging muscle contraction. Because of the slow cross bridge cycling rate, smooth muscle actually requires less energy to maintain a contraction compared with skeletal muscle.

*The answer is E.* The stimulation of either adenylate or guanylate cyclase induces smooth muscle relaxation. The cyclic nucleotides produced by these enzymes stimulate cAMPand cGMP-dependent kinases, respectively. These kinases phosphorylate, among other things, enzymes that remove Ca++ from the cytosol, and in doing so they inhibit contraction. In contrast, either a decrease in K+ permeability or an increase in Na+ permeability results in membrane depolarization and contraction. Likewise, inhibition of the sarcoplasmic reticulum Ca++-ATPase, one of the enzymes activated by cyclic nucleotide-dependent kinases, would also favor muscle contraction. Smooth muscle does not express troponin.

*The answer is D.* Muscle B is characteristic of a slow twitch muscle (Type 1) composed of predominantly slow twitch muscle fibers. These fibers are smaller in size and are innervated by smaller nerve fibers. They typically have a more extensive blood supply, a greater number of mitochondria, and large amounts of myoglobin, all of which support high levels of oxidative phosphorylation.

*The answer is C.* Muscle contraction is triggered by an increase in sarcoplasmic Ca++ concentration. The delay between the termination of the depolarizing pulse and the onset of muscle contraction, also called the "lag," reflects the time necessary for the depolarizing pulse to be translated into an increase in sarcoplasmic Ca++ concentration. This process involves a conformational change in the voltage-sensing, or dihydropyridine receptor, located on the T tubule membrane; the subsequent conformational change in the ryanodine receptor on the sarcoplasmic reticulum; and the release of Ca++ from the sarcoplasmic reticulum.

*The answer is B.* Myasthenia gravis is an autoimmune disease in which antibodies damage postsynaptic nicotinic acetylcholine receptors. This damage prevents the firing of an action potential in the postsynaptic membrane. Tensilon is a readily reversible acetylcholinesterase inhibitor that increases acetylcholine levels in the neuromuscular junction, thereby increasing the strength of muscle contraction.

*The answer is A.* Myasthenia gravis is an autoimmune disease characterized by the presence of anti-acetylcholine receptor antibodies in the plasma. Overexertion can cause junction fatigue, and both a decrease in the density of voltage-sensitive Ca++ channels in the presynaptic membrane and botulinum toxicity can cause muscle weakness. However, these effects are presynaptic and therefore would not be reversed by acetylcholinesterase inhibition. Although the macro-motor units formed during reinnervation following poliomyelitis compromise the patient's fine motor control, they do not affect muscle strength.

*The answer is E.* Neostigmine is an acetylcholinesterase inhibitor. Administration of this drug would increase the amount of acetylcholine (ACh) present in the synapse and its ability to sufficiently depolarize the postsynaptic membrane and trigger an action potential. Botulinum toxin antiserum is effective only against botulinum toxicity. Curare blocks the nicotinic ACh receptor and causes muscle weakness. Atropine is a muscarinic ACh receptor antagonist, and halothane is an anesthetic gas. Neither atropine nor halothane has any effect on the neuromuscular junction.

*The answer is B.* Smooth muscle contraction is regulated by both Ca++ and myosin light chain phosphorylation. When the cytosolic Ca++ concentration decreases following the initiation of contraction, myosin kinase becomes inactivated. However, cross-bridge formation continues, even in the absence of Ca++, until the myosin light chains are dephosphorylated through the action of myosin light chain phosphatase.

*The answer is C.* The normal miniature end-plate potentials indicate sufficient synthesis and packaging of ACh and the presence and normal function of ACh receptor channels. The most likely explanation for this patient's symptoms is a presynaptic deficiency—in this case, an impairment of the voltage-sensitive Ca++ channels responsible for the increase in cytosolic Ca++ that triggers the release of ACh into the synapse. The increase in postsynaptic depolarization observed after exercise is indicative of an accumulation of Ca++ in the presynaptic terminal after multiple action potentials have reached the nerve terminal.

*The answer is B.* Inhibition of the presynaptic voltage-sensitive Ca++ channels is most consistent with the presence of antibodies against this channel. Antibodies against the ACh receptor, a mutation in the ryanodine receptor, and residual ACh in the junction are all indicative of postsynaptic defects. Although it is a presynaptic defect, a deficit of ACh vesicles is unlikely in this scenario, given the normal miniature end-plate potentials recorded in the postsynaptic membrane.

*The answer is B.* Botulinum toxin inhibits muscle contraction presynaptically by decreasing the amount of ACh released into the neuromuscular junction. In contrast, curare acts post-synaptically, blocking the nicotinic ACh receptors and preventing the excitation of the muscle cell membrane. Tetrodotoxin blocks voltage-sensitive Na+ channels, impacting both the initiation and the propagation of action potentials in the motor neuron. Both ACh and neostigmine stimulate muscle contraction.

*The answer is B.* For a muscle to contract spontaneously and rhythmically, there must be an intrinsic rhythmical "pacemaker." Intestinal smooth muscle, for example, exhibits a rhythmical slow-wave potential that transiently depolarizes and repolarizes the muscle membrane. This slow wave does not stimulate contraction itself, but if the amplitude is sufficient, it can trigger one or more action potentials that result in Ca++ influx and contraction. Although they are typical of smooth muscle, neither "slow" voltage-sensitive Ca++ channels nor action potentials with "plateaus" play a necessary role in rhythmical contraction. A high resting cytosolic Ca++ concentration would support a sustained contraction, and hyperpolarization would favor relaxation.

*The answer is D.* Myasthenia gravis is an acquired autoimmune disease causing skeletal muscle fatigue and weakness. The disease is associated with (caused by) IgG antibodies to acetylcholine receptors at post-synaptic membranes of neuromuscular junctions. The major symptom is muscle weakness, which gets worse with activity. Patients often feel well in the morning, but become weaker as the day goes on. The muscle weakness usually causes symptoms of double vision (diplopia) and drooping eyelids (ptosis). The presence of anti acetylcholine antibodies in the plasma is specific for myasthenia gravis and thus rules out the other answer choices. In addition, the normal CT scan of the brain and orbit specifically rules out the possibility of an astrocytoma (choice A), that is, brain tumor, that could compress cranial nerves. Double vision commonly occurs in Graves disease (choice B); however, the thyroid test was normal (which also rules out Hashimoto thyroiditis, choice C). Multiple sclerosis (choice E) is commonly associated with a spastic weakness of the legs, but, again, the presence of anti-acetylcholine antibodies is specific for myasthenia gravis.

*The answer is E.* Smooth muscle is unique in its ability to generate various degrees of tension at a constant concentration of intracellular calcium. This change in calcium sensitivity of smooth muscle can be attributed to differences in the activity of MLCP. Smooth muscle contracts when the myosin light chain is phosphorylated by the actions of myosin light chain kinase (MLCK). MLCP is a phosphatase that can dephosphorylate the myosin light chain, rendering it inactive and therefore attenuating the muscle contraction. Choice A: Both actin and myosin are important components of the smooth muscle contractile apparatus much like that of skeletal muscle and cardiac muscle, but these do not play a role in calcium sensitivity. Choice B: ATP is required for smooth muscle contraction. Decreased ATP levels would be expected to decrease the ability of smooth muscle to contract even in the face of high calcium levels. Choice C: The calcium-calmodulin complex binds with MLCK, which leads to phosphorylation of the myosin light chain. A decrease in the calcium-calmodulin complex should attenuate the contraction of smooth muscle. Choice D: Again, the binding of calcium ions to calmodulin is an initial step in the activation of the smooth muscle contractile apparatus.

*The answer is B.* Acetylcholine (ACh) is stored in vesicles and is released when an action potential in the motor nerve opens Ca2+ channels in the presynaptic terminal. ACh diffuses across the synaptic cleft and opens Na+ and K+ channels in the muscle end plate, depolarizing it (but not producing an action potential). Depolarization of the muscle end plate causes local currents in adjacent muscle membrane, depolarizing the membrane to threshold and producing action potentials.

*The answer is C.* An elevation of intracellular [Ca2+] is common to the mechanism of excitation-contraction coupling in skeletal and smooth muscle. In skeletal muscle, Ca2+ binds to troponin C, initiating the cross-bridge cycle. In smooth muscle, Ca2+ binds to calmodulin. The Ca2+-calmodulin complex activates myosin lightchain kinase, which phosphorylates myosin so that shortening can occur. The striated appearance of the sarcomeres and the presence of troponin are characteristic of skeletal, not smooth, muscle. Spontaneous depolarizations and gap junctions are characteristics of unitary smooth muscle but not skeletal muscle.

*The answer is E.* During repeated stimulation of a muscle fiber, Ca2+ is released from the sarcoplasmic reticulum (SR) more quickly than it can be reaccumulated; therefore, the intracellular [Ca2+] does not return to resting levels as it would after a single twitch. The increased [Ca2+] allows more cross-bridges to form and, therefore, produces increased tension (tetanus). Intracellular Na+ and K+ concentrations do not change during the action potential. Very few Na+ or K+ ions move into or out of the muscle cell, so bulk concentrations are unaffected. Adenosine triphosphate (ATP) levels would, if anything, decrease during tetanus.

*The answer is B.* Myasthenia gravis is characterized by a decreased density of acetylcholine (ACh) receptors at the muscle end plate. An acetylcholinesterase (AChE) inhibitor blocks degradation of ACh in the neuromuscular junction, so levels at the muscle end plate remain high, partially compensating for the deficiency of receptors.

*The answer is B.* The correct sequence is action potential in the muscle membrane; depolarization of the T tubules; release of Ca2+ from the sarcoplasmic reticulum (SR); binding of Ca2+ to troponin C; cross-bridge formation; and splitting of adenosine triphosphate (ATP).

*The answer is A.* In the mechanism of excitation-contraction coupling, excitation always precedes contraction. Excitation refers to the electrical activation of the muscle cell, which begins with an action potential (depolarization) in the sarcolemmal membrane that spreads to the T tubules. Depolarization of the T tubules then leads to the release of Ca2+ from the nearby sarcoplasmic reticulum (SR), followed by an increase in intracellular Ca2+ concentration, binding of Ca2+ to troponin C, and then contraction.