The basic function of all types of muscle is to generate force or movement. Electrical or chemical stimuli are transduced into a mechanical response. The three anatomic types of muscle are skeletal, cardiac, and smooth. Both skeletal and cardiac muscle are classified microscopically as striated muscle. Skeletal muscle is also referred to as voluntary because it remains relaxed in the absence of nerve stimulation. Cardiac and smooth muscle can function without nerve input and are referred to as involuntary.
Skeletal muscle does not contract until stimulated by action potentials arriving from a motor neuron (Figure 1-10A). The synapse between a motor neuron and a skeletal muscle cell is called a neuromuscular junction or end plate (see Figure 1-10B). Every skeletal muscle cell (fiber) has only one neuromuscular junction, near its midpoint. An individual neuromuscular junction consists of a small, branched patch of bulb-shaped nerve endings, called terminal boutons. Motor neurons branch to activate a group of muscle fibers, known collectively as a motor unit. Muscles that are subject to fine control (e.g., muscles of the hand) have many small motor units.
Innervation of skeletal muscle. A. Motor units include a motor neuron and the group of muscle fibers that are innervated by its branches. B. The neuromuscular junction. Acetylcholine release from motor neuron terminals stimulates nicotinic receptors in the muscle membrane, producing an excitatory postsynaptic potential. C. End-plate potentials. Acetylcholine in a single presynaptic vesicle (quantum) evokes a miniature end-plate potential. Action potential in a motor neuron triggers the release of many quanta, and miniature end-plate potentials summate to exceed the threshold for action potential in the muscle fiber.
Motor neurons release acetylcholine as their neurotransmitter. Acetylcholine is synthesized in the cytoplasm of presynaptic terminals from acetyl coenzyme A and choline, via the enzyme choline acetyltransferase, and is stored in vesicles within the nerve terminal. The amount of acetylcholine within a single presynaptic vesicle is called a quantum.
The postsynaptic muscle cell membrane immediately opposite the presynaptic terminals has a high density of nicotinic acetylcholine receptors. Nicotinic receptors are ionotropic receptors that function as nonselective Na+ and K+ channels. When opened, nicotinic receptors cause skeletal muscle membrane potential to depolarize because the combined equilibrium potential for Na+ and K+ (Ecation) is approximately 0 mV. Each quantum of acetylcholine produces a small depolarization of the muscle membrane, called a miniature end-plate potential (see Figure 1-10C). Depolarizations from many quanta summate to produce a full end-plate potential in the muscle membrane, which is an example of an excitatory postsynaptic potential. A single motor nerve impulse normally produces an end-plate potential that exceeds the threshold for action potential generation in the muscle cell membrane.
Acetylcholine within the synaptic cleft is rapidly broken down to choline and acetic acid by the enzyme acetylcholinesterase, which is anchored to the muscle cell basement membrane. Choline is taken up by presynaptic nerve terminals and is reused for acetylcholine synthesis. Table 1-5 summarizes the effects of several toxins and drugs that interfere with the neuromuscular junction.
Table 1-5Drugs and Toxins That Affect Neuromuscular Transmission ||Download (.pdf) Table 1-5Drugs and Toxins That Affect Neuromuscular Transmission
|Agent(s) ||Action ||Effect |
|Botulinum toxin ||Enters motor nerve terminal, irreversibly inhibits acetylcholine release ||Failure of acetylcholine release; flaccid paralysis of muscle |
|α-Latrotoxin ||Enters motor nerve terminal, promotes massive release of acetylcholine ||Initial surge of acetylcholine release followed by irreversible depletion of acetylcholine; contractions followed by flaccid paralysis |
|ω-Conotoxin ||Binds irreversibly to Ca2+ channels in motor nerve terminal membrane ||Reduced Ca2+ entry to nerve terminal, reduced acetylcholine release; flaccid paralysis |
|d-Tubocurarine, pancuronium ||Reversible competitive antagonists at nicotinic acetylcholine receptors ||Prevents acetylcholine action; flaccid paralysis |
|α-Bungarotoxin ||Irreversible antagonist at nicotinic acetylcholine receptors ||Prevents acetylcholine action; flaccid paralysis |
|Neostigmine ||Inhibits acetylcholinesterase in synaptic cleft ||Prolongs action of acetylcholine at the end plate |
|Hemicholinium ||Choline reuptake blocker in motor neuron terminal ||Depletes acetylcholine in nerve terminals; muscle weakness or flaccid paralysis |
Myasthenia gravis is an autoimmune disease in which antibodies are directed against nicotinic acetylcholine receptors, reducing the number at the end plate. Acetylcholine release is normal, but the postsynaptic membrane is less responsive and results in muscle weakness. Treatment of myasthenia gravis is with agents such as neostigmine, which inhibit acetylcholinesterase in the cleft, thereby prolonging the action of acetylcholine at the neuromuscular junction.
The generation of action potentials in the skeletal muscle cell membrane (sarcolemma) triggers a sequence of events that result in force development by the muscle. The unique ability of muscle to generate force when stimulated results from the presence of motor proteins inside muscle cells.
Skeletal muscles consist of muscle columns, each of which consists of a bundle of muscle cells (also called fibers or myocytes) (Figure 1-11A). Muscle cells are multinucleate and are bounded by the sarcolemma. Each myocyte contains several cylindrical myofibrils, which display a distinctive pattern of light and dark bands under the light microscope. This striated appearance arises from the orderly arrangement of structural and contractile proteins. Each repeating motif in the striated pattern is called a sarcomere, which is the fundamental contractile unit of skeletal muscle. Each sarcomere has the following elements (see Figure 1-11B):
A Z disk bounds the sarcomere at each end.
Thin filaments, composed of actin, tropomyosin, and troponins, project from each Z disk toward the center of the sarcomere.
Thick filaments, composed of myosin, are present in the center of the sarcomere and are overlapped by thin filaments.
Sarcomeres line up end-to-end within a single myofibril. The darker areas that can be seen microscopically are denoted as A bands and correspond to the location of thick filaments. Lighter areas at the ends of sarcomeres are denoted as I bands and correspond to thin filaments where no overlap with thick filaments occurs.
A. Structure of skeletal muscle: muscle cells (fibers) contain a group of myofilaments, each composed of sarcomeres aligned end-to-end. B. The sarcomere. A regular array of filament proteins between adjacent Z disks comprises a sarcomere. Thin actin filaments extend from Z disks toward a central M line, partially overlapping thick myosin filaments. Under a microscope, the region of thick filaments (A band) appears darker than adjacent areas with only thin filaments (I band), producing the striated appearance of skeletal muscle. Striations in adjacent myofibrils are also aligned. C. Molecular components of thin and thick filaments. Thin filaments are composed of actin, with the associated proteins tropomyosin and troponins; thick filaments are composed of myosin. ATP, adenosine triphosphate.
Molecular Components of Sarcomeres
The orderly array of thin and thick myofilaments produces the characteristic striations of skeletal muscle. Thin filaments have three major components (see Figure 1-11C):
The backbone of a thin filament is a double-stranded helix of actin.
The helical groove on the actin filament is occupied by tropomyosin. Skeletal muscle contraction is regulated via a protein complex that consists of tropomyosin plus attached troponin subunits.
Troponin is a heterotrimer consisting of troponins T, C, and I; troponin T anchors the trimer to tropomyosin; troponin C binds Ca2+, which allows muscle contraction to occur; and troponin I inhibits interaction between actin and myosin if the intracellular Ca2+ concentration is low.
Thick filaments are composed of myosin molecules, which are the molecular motors responsible for the generation of force. Myosin molecules are composed of the following major parts:
The myosin head contains the actin-binding site plus elements necessary for ATP binding and hydrolysis. The heads are cross-bridges that bind to actin during muscle contraction.
Myosin heads are connected to the tail of the molecule via a hinge. The hinge allows the movement of cross-bridges, which is the basis of force generation.
The giant protein titin is important for maintaining sarcomere structure and runs from the Z disk to the M line at the center of the sarcomere. In the region of the I band, titin is extensible and is largely responsible for the passive tension that is measured when a relaxed muscle is stretched (see Muscle Mechanics).
The mechanism of active force generation in all muscle types is based on thin filaments being pulled over thick filaments (Figure 1-12). In a relaxed skeletal muscle, contraction is inhibited by the tropomyosin-troponin complexes, which obscure the active site on actin and prevent cross-bridge binding (Figure 1-12, panel 2). When the muscle is stimulated, the intracellular Ca2+ concentration increases and Ca2+ binds to troponin C. The resulting conformational change exposes active sites on actin (Figure 1-12, panel 3). A cycle of events now occurs in which myosin cross-bridges bind to actin, perform a powerstroke, detach, become cocked again, and then reattach (Figure 1-12, panel 4). The cycle repeats in the continued presence of sufficient Ca2+ and ATP. As a result, thin filaments from each end of the sarcomere move toward the center by sliding over thick filaments, causing neighboring Z disks to approach each other. In the example shown in Figure 1-12, muscle shortening has occurred and the sarcomere length is reduced (compare panels 1 and 5).
Sliding filament theory of muscle contraction. Ca2+ binding to troponin C causes actin active sites to be exposed (compare panels 2 and 3). In the presence of adenosine triphosphate (ATP), myosin repeats a cycle of binding to actin, performance of a power stroke, detaching, becoming cocked, and reattaching further along the actin molecule (panel 4). Actin filaments are drawn over myosin. In this example, muscle shortening occurs (compare panels 1 and 5). ADP, adenosine diphosphate.
When death occurs, ATP production by mitochondria stops and rigor mortis (stiffening of the muscles) sets in. ATP is necessary for the myosin heads to detach from the actin filaments after a powerstroke occurs. Once ATP production ceases, the cross-bridges are locked in place, which results in stiff muscles. Rigor mortis is a sign of death.
In all types of muscle, the key event causing contraction is increased intracellular Ca2+ concentration. In skeletal muscle, the source of Ca2+ for contraction is the sarcoplasmic reticulum (SR). Muscle contraction only occurs after an increase in cytosolic Ca2+, which follows the generation of a muscle action potential (Figure 1-13). The only physiologic stimulus for skeletal muscle action potentials is the end-plate potential, developed in response to motor nerve impulses.
E–C coupling sequence in skeletal muscle. Force development depends on increased intracellular Ca2+, which is preceded by the muscle action potential.
The contractile apparatus of each sarcomere is surrounded by the SR, providing a short diffusion distance for Ca2+ to its site of action. The membrane system of the SR is completely enclosed within the cell and is comprised of longitudinal tubules, which surround the contractile apparatus and terminate in lateral sacs (terminal cisternae). Lateral sacs are closely associated with invaginations of the muscle cell plasma membrane called T tubules. The T tubules extend deep into the cell to form blind-ended tubes containing ECF. The lateral sacs from two neighboring sarcomeres converge on a T tubule to form a structure known as a triad (Figure 1-14A). Triads are located at the junction of the A band and the I band of every sarcomere.
A. Muscle triads. Each T tubule is associated with a lateral sac from each of two neighboring sarcomeres to form a triad. B. The excitation-contraction coupling mechanism in skeletal muscle. The close association of membranes in the triad allows muscle action potentials to open the sarcoplasmic reticulum Ca2+ release channels, through activation of voltage sensors in T tubules.
Action potentials in T tubules induce Ca2+ release from the lateral sacs. The Ca2+ release mechanism involves voltage sensors in the T-tubule membrane (L-type Ca2+ channels), which are linked to Ca2+ release channels (ryanodine receptors) in the SR (see Figure 1-14B). The voltage sensors respond to depolarization in the T tubule with conformational changes that result in the opening of the Ca2+ release channels of the SR. The intracellular [Ca2+] increases from about 10−8 M at rest to about 10−5 M during a muscle contraction. To return a muscle to the relaxed state, Ca2+ uptake occurs in the longitudinal tubules via Ca2+-ATPases of the SR. Following Ca2+ reuptake, most stored Ca2+ is found in the lateral sacs, where it is weakly bound to the protein calsequestrin.
The force of skeletal muscle contraction is controlled by altering the firing pattern of motor nerves to the muscle. The effect of increasing action potential frequency to a muscle is known as temporal summation (Figure 1-15). At low stimulation frequency, the muscle briefly generates force and then relaxes. At high stimulation frequency, the muscle does not have time to relax between stimuli. Contractions fuse into a plateau of active force called a tetanic contraction; the steady high force level is called the tetanic force. Force does not increase if the stimulation frequency is further increased because cross-bridge attachment is already maximal; at this point, the muscle is said to be tetanized.
Temporal summation. Increased frequency of muscle stimulation (indicated by downward arrows) causes increased force of contraction. At low frequency stimulation, Ca2+ reuptake is complete and the muscle relaxes completely between stimuli. With high frequency stimulation, intracellular Ca2+ concentration remains high; the contraction force reaches a plateau (tetanus) when all the troponin C sites are filled with Ca2+.
If a greater force of muscle contraction is needed, the number of active motor neurons increases. Recruitment of motor units is called spatial summation and is organized according to the “size principle.” Small motor neurons, which reach only a few muscle fibers, are more excitable than large motor neurons and are recruited first. A weak contraction is produced initially because only a few muscle fibers comprise the motor unit of small motor neurons. Large motor neurons are less excitable and require a stronger stimulus from the central nervous system. When large motor neurons are recruited, a large number of muscle fibers are stimulated to produce a strong contraction.
Tetanus toxin, which is produced by the bacterium Clostridium tetani, can result in tetany throughout all the skeletal muscles of the body. The bacterium lives in the soil, and once it contaminates a dirty wound, the tetanus toxin is released. The toxin travels to the spinal cord where it blocks inhibitory nerves, allowing the excitatory motor neurons to fire rapidly. Rapidly firing motor neurons summate to produce tetany, a potentially fatal condition!
Skeletal Muscle Diversity
There are two types of muscle fibers: slow twitch (type I) and fast twitch (type II) (Table 1-6). Expression of different isoforms of myosin and other proteins accounts for different shortening speeds of fast and slow twitch fibers. Muscles have different proportions of slow and fast twitch fibers, which are classified according to their function. For example, postural muscles contain a higher proportion of slow twitch fibers because they must maintain tone and resist fatigue. Extraocular muscles are required to make fast, brief movements of the eye and therefore contain a high proportion of fast twitch fibers. There are genetic differences in the general proportions of muscle fiber types that are expressed among individuals, which accounts in part for the tendency for a person to be either a better sprinter (more fast twitch fibers) or have higher endurance (more slow twitch fibers).
Table 1-6Comparison of Slow Twitch and Fast Twitch Muscle Fibers ||Download (.pdf) Table 1-6Comparison of Slow Twitch and Fast Twitch Muscle Fibers
|Characteristic ||Slow Twitch (Type I) ||Fast Twitch (Type II) |
|Color ||Red (myoglobin) ||White (low myoglobin) |
|Metabolism ||Oxidative ||Glycolytic |
|Mitochondria ||Abundant ||Few |
|Glycogen content ||Low ||High |
|Fatigability ||Low ||High |
The sliding filament mechanism provides the potential for a muscle to develop force; the characteristics of the resulting contraction depend on a combination of intrinsic muscle properties and the external constraints placed on the muscle. There are two general modes of muscle contraction:
An isometric, or fixed-length contraction, occurs if both ends of a muscle are fixed. In this case, the muscle is able to develop tension but it cannot shorten.
An isotonic, or fixed-load contraction, occurs if a muscle is able to shorten to carry a given load.
Muscle length is an important determinant of the force of contraction. The length-tension (length-force) relation is studied under isometric conditions. A resting muscle behaves like a rubber band, requiring force to stretch it to different lengths. The preload is the amount of force applied to a resting muscle before stimulation, creating passive tension (Figure 1-16A, blue curve). When the muscle is stimulated, active tension is added to the passive tension. The amount of active tension produced is the difference between passive tension and total tension (Figure 1-16A, red curve).
The length-tension relationship in skeletal muscle. A. Passive tension (preload) is the force required to set the resting length (blue curve). Total tension (red curve) includes active (developed) tension in addition to passive tension. Maximum active tension is developed from an optimal resting muscle length; short and long resting lengths both reduce developed tension. B. Optimal resting muscle length corresponds with optimal overlap of thick and thin filaments in sarcomeres.
There is an optimal range of resting muscle length (preload) that produces maximal contraction. At very short or very long muscle lengths, active force development declines, producing the characteristic length-tension relationship of striated muscle. The plateau of the length-tension relation (Figure 1-16B, point y) reflects optimal overlap of thin and thick filaments within sarcomeres, providing maximum myosin cross-bridge binding. On the ascending limb (Figure 1-16B, between points x and y), the muscle is too short, resulting in double overlap of thin filaments and attachment of fewer cross-bridges. On the descending limb of the curve (Figure 1-16B, points y and z), the muscle is too long, resulting in inadequate overlap of thin and thick filaments. An additional mechanism contributing to the length-tension relationship in cardiac muscle is the increased Ca2+-sensitivity of troponin C as muscle length increases.
Skeletal muscles operate at the plateau of their length-tension relation because preload is set at the optimal level by bony attachments at each end of the muscle. By contrast, preload is not fixed in cardiac muscle but varies according to the amount of venous return. Preload is a key determinant of the force of cardiac muscle contraction (see Chapter 4).
In a healthy heart, an increased preload will stretch the cardiac myocytes, resulting in a more forceful and speedy contraction. However, in a diseased heart (e.g., left ventricular hypertrophy), cardiac muscle can become stiff, impairing its ability to stretch. Increasing preload in this setting will mainly increase the pressures in the heart without the benefit of improving contractile force or speed.
Muscle performance can be studied under isotonic conditions to produce a force-velocity relation. The resting muscle length is set by adding a given preload, and the initial velocity of shortening is then measured as the muscle is stimulated to lift a range of additional weights. The weight a muscle must lift upon stimulation after resting length has been established is called afterload. The speed of shortening decreases as the total load increases (Figure 1-17A). Extrapolating this curve to a theoretical zero load indicates the maximum possible speed of shortening (Vmax),.which reflects the rate of myosin ATPase activity. If preload is increased, there is an increased speed of shortening for any given total load, but without any change in Vmax (see Figure 1-17B).
The force-velocity relationship in skeletal muscle. A. Shortening velocity decreases with increasing total load. The theoretical maximum shortening velocity, Vmax, indicates intrinsic myosin ATPase activity. B. Effect of preload on shortening velocity. Increased preload increases the velocity of muscle shortening in a loaded muscle but does not change Vmax.
In cardiac muscle, increased force and speed of contraction can be produced without changing preload. This is called increased contractility and can be identified by an increase in Vmax (see Chapter 4).