Physiology - An Illustrated Review
3. Muscle Cell Physiology
3.1 Skeletal Muscle
Skeletal muscle is composed of long, cylindrical, multinucleated cells called muscle fibers. Each fiber contains a bundle of myofibrils. Myofibrils contain myofilaments, overlapping thick and thin filaments. The filament arrays are arranged into sarcomeres, the functional unit of skeletal muscle cells. Sarcomere units, delimited by Z lines, are linked linearly.
Because the sarcomeres within the myofibrils are in register, the fibers of skeletal muscle have a striated appearance (Fig. 3.1).
Fig. 3.1 Ultrastructure of striated muscle fibers.
Skeletal muscle is composed of bundles of muscle fibers. Each muscle fiber is composed of myofibrils.
Thin Filaments. Thin filaments are made of actin, with the regulatory proteins tropomyosin and troponin positioned along the surface.
Thick Filaments. Thick filaments are made of myosin molecules assembled together with globular heads exposed.
– Titin is a giant protein that keeps the myosin filaments accurately lined up within the sarcomere.
– Cross-bridges are myosin heads that bind to actin filaments.
Z disks are at either end of a given sarcomere and anchor the thin filaments. The I band is the region near the Z line where there are thin filaments only, without overlap of thick filaments. The A band is the middle part of the sarcomere containing thick filaments. Thin filaments overlap into the A band. The H zone is the area in the center of the A band where the thin filaments do not reach, and there are thick filaments only. The M line is in the center of the H zone (Figs. 3.2, 3.3).
Sarcoplasmic Reticulum. The sarcoplasmic reticulum (SR) is a modified endoplasmic reticulum found only in muscle cells. It consists of a flattened, irregular, saclike system that drapes around the myofibrils. Its membrane contains an active transport Ca2+ pump that is responsible for removing Ca2+ from the cytoplasm and its accumulation within the SR.
Fig. 3.2 Sarcomere structure.
Sarcomeres are bounded by Z disks. The I band contains only thin actin filaments. The A band contains thick filaments and is where the actin and myosin filaments overlap. The H zone solely contains myosin filaments, which thicken toward the middle of the sarcomere to form the M line. Actin is a globular protein molecule. Four hundred such molecules join to form F actin, a beaded polymer chain. Two of the twisted protein filaments combine to form an actin filament. Tropomyosin molecules joined end to end lie adjacent to the actin filaments, and a troponin molecule is attached every 40 nm or so. The sarcomere also has another system of filaments formed by the filamentous protein titin. Titin is anchored to the M and Z plates. Each myosin filament consists of bundles of myosin molecules (see Fig. 3.3).
Fig. 3.3 Myosin II molecule.
Each myosin molecule has two globular heads connected by flexible necks. Each of the heads has a motor domain with a nucleotide binding pocket (for adenosine triphosphate [ATP], or adenosine diphosphate [ADP],+ inorganic phosphate [Pi]) and an actin-binding site. The light protein chains are located on this heavy molecule; one is regulatory, the other, so-called essential. Conformational changes in the head–neck segment allow the myosin head to “tilt” when interacting with actin.
Transverse Tubules. Transverse tubules are deep invaginations of the sarcolemma (the plasma membrane of the muscle fiber) that penetrate into the muscle fiber and allow the m uscle action potential to be directed from the surface into the interior of the muscle fiber.
The sarcoplasmic reticulum adjacent to the transverse tubules is expanded to form terminal cisternae. A transverse tubule and its two adjacent terminal cisternae are linked into a triad.
Muscular dystrophy is a term used to describe a group of inherited muscle diseases. Each individual type of muscular dystrophy has its own genetic defect. The most common type of muscular dystrophy is due to a genetic defect that causes a mutation in dystrophin, part of a protein complex that conveys force from the Z disks to connective tissue on the surface of the fiber. Dystrophin mutations result in degeneration of muscle fibers with increasing muscle weakness. As the disease progresses, there are muscular contractures with loss of mobility of joints. There is no cure for this group of diseases, but drugs are sometimes used to provide symptomatic relief or to slow its progression. Drugs that help with contractures include phenytoin, carbamazepine, and dantrolene. Prednisone, cyclosporin, and azathioprine may also be used to protect muscle cells from damage. Physical therapy is the mainstay of treatment for muscular dystrophy to try to preserve mobility. Surgery may be used for the relief of contractures.
Skeletal muscle is innervated by the somatic nervous system.
A motoneuron action potential, by release of acetylcholine at the neuromuscular junction, triggers a muscle action potential that is conducted along the sarcolemma and passes down the transverse tubules. The electrical impulse affects a voltage-sensing protein in the transverse tubule membrane (dihydropyridine receptor), which is linked to a Ca2+ release channel (ryanodine receptor) in the terminal cisterna membrane. Ca2+ is released through these channels into the cytoplasm to induce muscle contraction.
Action of Regulatory Proteins
Cross-bridge binding to thin filaments is controlled by the regulatory proteins troponin and the rodlike tropomyosin. Troponin is made up of three subunits that play specific roles:—Troponin T keeps tropomyosin in the groove of actin.
– Troponin I inhibits the interaction of between the myosin cross-bridges and the actin thin filaments.
– Troponin C binds to Ca2+shifting the position of tropomyosin to expose the binding sites on actin for the myosin cross-bridges.
Cross-Bridge Cycle (Fig. 3.4)
In the resting (relaxed) state, adenosine monophosphate (ADP) and inorganic phosphate (Pi) are bound to the myosin cross-bridge, which is energized, but the cross-bridge cannot attach to actin as the binding sites are blocked by tropomyosin.
– In step 1, due to arrival of an action potential, cytosolic Ca2+rises and Ca2+binds troponin, which shifts tropomyosin, exposing the binding sites on actin and allowing cross-bridge attachment.
– In step 2, Pi and then ADP are released from the cross-bridge, causing the cross-bridge to tilt (the power stroke) and the actin thin filament to slide along the myosin thick filament.
– In step 3, adenosine triphosphate (ATP) attaches to cross-bridge, which results in detachment of the cross-bridge from the actin thin filament.
– In step 4, the bound ATP is hydrolyzed to ADP and Pi, energizing the cross-bridge, and beginning the cycle again.
The cycle repeats if the cytosolic Ca2+ concentration remains high and Ca2+continues to bind to troponin. It ends if reuptake of Ca2+into the sarcoplasmic reticulum (via Ca2+-ATPase) reduces the cytosolic Ca2+ concentration sufficiently so that Ca2+is no longer bound to troponin, causing tropomyosin to shift and once again block the binding sites on actin.
Sliding Filament Mechanism
The rowing action of the myosin cross-bridges in each cycle cause the thin filaments to slide past the thick filaments toward the center of the sarcomere. Sarcomere shortening is manifested in reduction in the distance between Z lines, as well as reductions in the widths of the I band and the H zone. There is no change in the length of the A band.
Twitches and Tetani
The contraction of a muscle fiber following a single action potential is called a twitch.
Rapidly applied stimuli produce tetani (singular tetanus). Sustained contractions representing summation of individual twitches. The resulting tension (force) produced by the muscle is greater than that for a single twitch. The higher concentration of Ca2+ remaining in the cytoplasm during tetanic stimulation is responsible for the increased muscle tension (Fig. 3.5).
Fig. 3.4 Cross-bridge cycle.
Isometric, Isotonic, and Eccentric Contractions
– In isometric contraction, external muscle length is held constant.
– In isotonic contraction, the muscle length shortens.
– In eccentric contraction, the muscle exerts a pulling force but is actually getting longer because the external attachments exert more force than is developed within the muscle (Fig. 3.6).
Fig. 3.5 Tetani.
When individual twitches are elicited by rapidly repeating stimuli, the muscle does not relax between stimuli and continuously contracts. This is referred to as a tetanus. Muscle force is significantly greater in a tetanus than in a twitch because more cross-bridges are activated.
Fig. 3.6 Isometric muscle tension relative to sarcomere length.
The length (L) and force (F), or tension, of a muscle are closely related. Because the active force is determined by the magnitude of all potential actin–myosin interactions, it varies with sarcomere length. Skeletal muscle can develop maximum (isometric) force (F0) at its maximum resting length (LMAX). When the sarcomeres shorten (L < LMAX), part of the thin filaments overlap, allowing only forces smaller than F0 to develop. When L is 70% of LMAX, the thick filaments make contact with the Z disks, and F becomes even smaller. In addition, at nonphysiological extensions (L > LMAX), a muscle can develop only restricted force because the number of potentially available actin–myosin bridges is reduced.
The Length–Tension Relationship
The tension developed during isometric contractions at various muscle lengths demonstrates the mechanical properties of muscle tissue and of the sliding filament mechanism.
Passive tension is the force of the elastic elements of a muscle without involvement of the sliding filament apparatus. This is obtained from measurements made on resting, unstimulated muscle. This force is similar to that observed in other elastic structures, such as rubber bands.
Active tension is the force produced by the interaction between myosin and actin at various lengths. This unique curve demonstrates that there is a muscle length at which the sliding filaments will produce their maximum force output. The explanation for the existence of an optimum length is that this sarcomere length produces the maximum amount of overlap between actin and myosin and the largest number of active cross-bridges.
Total tension is the sum of passive and active tension (Fig. 3.7).
The Force–Velocity Relationship
During isotonic contraction, when a muscle lifts a load, the weight of the load affects the speed of shortening. Muscle contracts more slowly with a heavy load because cross-bridges cycle more slowly. When the cycling speed is slower, greater force is generated by the sustained attachment of the cross-bridges.
Types of Skeletal Muscle
The two main types of skeletal muscle are type I and type II.
Type I. Type I (red muscle) is employed for slow, sustained contractions as occurs in postural muscles. It can contract for long periods (minutes to hours) without fatigue.
Fig. 3.7 Length–tension curve for skeletal muscle.
The total force, or tension, exerted by a muscle is the sum of the active and passive (resting) forces. Active tension is at its maximum when actin and myosin filaments completely overlap. Skeletal muscle normally functions in the plateau region of its length–tension curve. When extended to 130% or more of the LMAX, which is beyond the physiological range, the resting tension becomes the major part of the total muscle tension.
The isoform of myosin in this type of muscle has a slower rate of reaction with ATP. Red muscle has more mitochondria, a greater capillary supply, and a high myoglobin content, resulting in a reliance on oxidative metabolism.
Type II. Type II (white muscle) is used for rapid and/or strong muscle action. It fatigues rapidly (seconds).
Myosin reacts more rapidly in this type of muscle. It has fewer mitochondria and a lower capillary density and is suited for anaerobic glycolysis.
3.2 Cardiac Muscle
Cardiac muscle is striated and organized into sarcomeres like skeletal muscle, except that each myocyte is a single cell with a single nucleus. Like smooth muscle, cardiac muscle cells are connected by gap junctions and function in a coordinated fashion as a unit (functional syncytium). Elongated mitochondria located close to myofibrils minimize the distance for diffusion of ATP in cardiac muscle.
Cardiac tissue shows automaticity (spontaneous activity) and rhythmicity (the ability to beat). This is due to the pacemaker activity at the sinoatrial (SA) node, which excites nearby muscle cells. The contractile myocytes that make up the chamber walls are not automatic.
Cardiac muscle is innervated by the autonomic nervous system.
The contractile proteins and the molecular mechanism of contraction in cardiac muscle are identical to that of skeletal muscle. Cardiac muscle cannot be tetanized: the long duration of cardiac action potentials prevents reexcitation by high-frequency stimulation. The physiology of cardiac muscle is discussed in more detail in Chapter 8 (Fig. 3.8).
Fig. 3.8 Length–tension curve for cardiac muscle.
The passive extension force, tension, of cardiac muscle is greater than that of skeletal muscle due to lower extensibility of noncontractile components. Cardiac muscle tends to operate in the ascending limb (below LMAX) of its length–tension curve without a plateau. Hence, the ventricle responds to increased diastolic filling loads by increasing its force development (Frank–Starling mechanism). In cardiac muscle, extension also affects troponin’s sensitivity to Ca2+, resulting in a steeper curve.
3.3 Smooth Muscle
Smooth muscle differs from skeletal and cardiac muscle in several ways:
– Smooth muscle cells are much smaller.
– Smooth muscle lacks striations, and its filaments are not arranged in sarcomeres. Instead, actin and myosin are linked to dense bodies that are located on the sarcolemma and in the cytoplasm of the smooth muscle cell.
– The sarcoplasmic reticulum is not as extensive in smooth muscle as in striated muscle. Although they lack transverse tubules, the sarcolemma shows numerous invaginations, which allow influx of Ca2+ during an action potential.
Smooth muscle, like cardiac muscle, is innervated by the autonomic nervous system. Some smooth muscles also have stretch-gated channels, and so stretch can also initiate contraction.
Ca2+ plays a different role in regulating cross-bridge binding in smooth muscle than in skeletal muscle, as smooth muscle lacks the Ca2+ binding protein troponin. In smooth muscle, myosin cross-bridges cannot bind actin thin filaments unless activated by phosphorylation. Ca2+ regulates this process. When cytosolic Ca2+ rises in response to a stimulus, Ca2+ binds to calmodulin. This complex then binds to and activates the enzyme myosin light chain kinase, which phosphorylates the myosin light chain protein, forcing the myosin cross-bridge toward the actin thin filament and allowing for binding and muscle contraction (Fig. 3.9).
Cross-bridge cycling is the same process as in skeletal muscle. Cross-bridges go through repeated cycles as long as they are phosphorylated. Myosin is dephosphorylated by the enzyme myosin light chain phosphatase, which leads to detachment of the cross-bridge and muscle relaxation.
In smooth muscle there is an additional mechanism (latch bridge mechanism) for cross-bridge attachment that results in a long duration, contracted state that does not require ATP (Fig. 3.9).
Types of Smooth Muscle
Unitary smooth muscle. Unitary smooth muscle is found in the walls of the hollow viscera of the body, such as the gastrointestinal (GI) tract, uterus, and blood vessels. Communication via gap junctions permits electrical potential changes to be communicated from cell to cell, allowing for coordinated contraction in which the muscle sheet acts as one unit.
Multiunit smooth muscle. Multiunit smooth muscle is less common than single unit. It is found in the iris and vas deferens.
Multiunit smooth muscle cells do not have gap junctions; thus, each smooth muscle cell operates independently of its neighbors. Each cell receives its own neural input, permitting finer control (Fig. 3.10).
Fig. 3.9 Regulation of cross-bridge cycle in smooth muscle.
Fig. 3.10 Single- and multiunit smooth muscle fibers.
(A) Single-unit fibers have many gap junctions, permitting coordinated contraction. (B) In multiunit fibers smooth muscle cells are individually stimulated.
Table 3.1 compares skeletal, cardiac, and smooth muscle.