Ganong’s Review of Medical Physiology, 24th Edition

CHAPTER 5 Excitable Tissue: Muscle


After studying this chapter, you should be able to:

image Differentiate the major classes of muscle in the body.

image Describe the molecular and electrical makeup of muscle cell excitation–contraction coupling.

image Define elements of the sarcomere that underlie striated muscle contraction.

image Differentiate the role(s) for Ca2+ in skeletal, cardiac, and smooth muscle contraction.

image Appreciate muscle cell diversity and function.


Muscle cells, like neurons, can be excited chemically, electrically, and mechanically to produce an action potential that is transmitted along their cell membranes. Unlike neurons, they respond to stimuli by activating a contractile mechanism. The contractile protein myosin and the cytoskeletal protein actin are abundant in muscle, where they are the primary structural components that bring about contraction.

Muscle is generally divided into three types: skeletal, cardiac, and smooth, although smooth muscle is not a homogeneous single category. Skeletal muscle makes up the great mass of the somatic musculature. It has well-developed cross-striations, does not normally contract in the absence of nervous stimulation, lacks anatomic and functional connections between individual muscle fibers, and is generally under voluntary control. Cardiac muscle also has cross-striations, but it is functionally syncytial and, although it can be modulated via the autonomic nervous system, it can contract rhythmically in the absence of external innervation owing to the presence in the myocardium of pacemaker cells that discharge spontaneously (see Chapter 29). Smooth muscle lacks cross-striations and can be further subdivided into two broad types: unitary (or visceral) smooth muscle and multiunit smooth muscle. The type found in most hollow viscera is functionally syncytial and contains pacemakers that discharge irregularly. The multiunit type found in the eye and in some other locations is not spontaneously active and resembles skeletal muscle in graded contractile ability.



Skeletal muscle is made up of individual muscle fibers that are the “building blocks” of the muscular system in the same sense that the neurons are the building blocks of the nervous system. Most skeletal muscles begin and end in tendons, and the muscle fibers are arranged in parallel between the tendinous ends, so that the force of contraction of the units is additive. Each muscle fiber is a single cell that is multinucleated, long, cylindrical, and surrounded by a cell membrane, the sarcolemma (Figure 5–1). There are no syncytial bridges between cells. The muscle fibers are made up of myofibrils, which are divisible into individual filaments. These myofilaments contain several proteins that together make up the contractile machinery of the skeletal muscle.


FIGURE 5–1 Mammalian skeletal muscle. A single muscle fiber surrounded by its sarcolemma has been cut away to show individual myofibrils. The cut surface of the myofibrils shows the arrays of thick and thin filaments. The sarcoplasmic reticulum with its transverse (T) tubules and terminal cisterns surrounds each myofibril. The T tubules invaginate from the sarcolemma and contact the myofibrils twice in every sarcomere. Mitochondria are found between the myofibrils and a basal lamina surrounds the sarcolemma.

The contractile mechanism in skeletal muscle largely depends on the proteins myosin-II, actin, tropomyosin, and troponin. Troponin is made up of three subunits: troponin I, troponin T, and troponin C. Other important proteins in muscle are involved in maintaining the proteins that participate in contraction in appropriate structural relation to one another and to the extracellular matrix.


Differences in the refractive indexes of the various parts of the muscle fiber are responsible for the characteristic cross-striations seen in skeletal muscle when viewed under the microscope. The parts of the cross-striations are frequently identified by letters (Figure 5–2). The light I band is divided by the dark Z line, and the dark A band has the lighter H band in its center. A transverse M line is seen in the middle of the H band, and this line plus the narrow light areas on either side of it are sometimes called the pseudo-H zone. The area between two adjacent Z lines is called a sarcomere. The orderly arrangement of actin, myosin, and related proteins that produces this pattern is shown in Figure 5–3. The thick filaments, which are about twice the diameter of the thin filaments, are made up of myosin; the thin filaments are made up of actin, tropomyosin, and troponin. The thick filaments are lined up to form the A bands, whereas the array of thin filaments extends out of the A band and into the less dense staining I bands. The lighter H bands in the center of the A bands are the regions where, when the muscle is relaxed, the thin filaments do not overlap the thick filaments. The Z lines allow for anchoring of the thin filaments. If a transverse section through the A band is examined under the electron microscope, each thick filament is seen to be surrounded by six thin filaments in a regular hexagonal pattern.


FIGURE 5–2 Electronmicrograph of human gastrocnemius muscle. The various bands and lines are identified at the top (× 13,500). (Courtesy of Walker SM, Schrodt GR.)


FIGURE 5–3 A) Arrangement of thin (actin) and thick (myosin) filaments in skeletal muscle (compare to Figure 5–2). B) Sliding of actin on myosin during contraction so that Z lines move closer together. C) Detail of relation of myosin to actin in an individual sarcomere, the functional unit of the muscle. D) Diagrammatic representation of the arrangement of actin, tropomyosin, and troponin of the thin filaments in relation to a myosin thick filament. The globular heads of myosin interact with the thin filaments to create the contraction. Note that myosin thick filaments reverse polarity at the M line in the middle of the sarcomere, allowing for contraction. (C and D are modified with permision from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

The form of myosin found in muscle is myosin-II, with two globular heads and a long tail. The heads of the myosin molecules form cross-bridges with actin. Myosin contains heavy chains and light chains, and its heads are made up of the light chains and the amino terminal portions of the heavy chains. These heads contain an actin-binding site and a catalytic site that hydrolyzes ATP. The myosin molecules are arranged symmetrically on either side of the center of the sarcomere, and it is this arrangement that creates the light areas in the pseudo-H zone. The M line is the site of the reversal of polarity of the myosin molecules in each of the thick filaments. At these points, there are slender cross-connections that hold the thick filaments in proper array. Each thick filament contains several hundred myosin molecules.

The thin filaments are polymers made up of two chains of actin that form a long double helix. Tropomyosin molecules are long filaments located in the groove between the two chains in the actin (Figure 5–3). Each thin filament contains 300–400 actin molecules and 40–60 tropomyosin molecules. Troponin molecules are small globular units located at intervals along the tropomyosin molecules. Each of the three troponin subunits has a unique function: Troponin T binds the troponin components to tropomyosin; troponin I inhibits the interaction of myosin with actin; and troponin C contains the binding sites for the Ca2+ that helps to initiate contraction.

Some additional structural proteins that are important in skeletal muscle function include actinin, titin, and desmin. Actinin binds actin to the Z lines. Titin, the largest known protein (with a molecular mass near 3,000,000 Da), connects the Z lines to the M lines and provides scaffolding for the sarcomere. It contains two kinds of folded domains that provide muscle with its elasticity. At first when the muscle is stretched there is relatively little resistance as the domains unfold, but with further stretch there is a rapid increase in resistance that protects the structure of the sarcomere. Desmin adds structure to the Z lines in part by binding the Z lines to the plasma membrane. Some muscle disorders associated these structural components are described in Clinical Box 5–1. It should be noted that although these proteins are important in muscle structure/function, by no means do they represent an exhaustive list.


The muscle fibrils are surrounded by structures made up of membranes that appear in electronmicrographs as vesicles and tubules. These structures form the sarcotubular system, which is made up of a T system and a sarcoplasmic reticulum. The T system of transverse tubules, which is continuous with the sarcolemma of the muscle fiber, forms a grid perforated by the individual muscle fibrils (Figure 5–1). The space between the two layers of the T system is an extension of the extracellular space. The sarcoplasmic reticulum, which forms an irregular curtain around each of the fibrils, has enlarged terminal cisterns in close contact with the T system at the junctions between the A and I bands. At these points of contact, the arrangement of the central T system with a cistern of the sarcoplasmic reticulum on either side has led to the use of the term triads to describe the system. The T system, which is continuous with the sarcolemma, provides a path for the rapid transmission of the action potential from the cell membrane to all the fibrils in the muscle. The sarcoplasmic reticulum is an important store of Ca2+ and also participates in muscle metabolism.


The large dystrophin protein (molecular mass 427,000 Da) forms a rod that connects the thin actin filaments to the transmembrane protein β-dystroglycan in the sarcolemma by smaller proteins in the cytoplasm, syntrophins. β-dystroglycan is connected to merosin (merosin refers to laminins that contain the α2 subunit in their trimeric makeup) in the extracellular matrix by α-dystroglycan (Figure 5–4). The dystroglycans are in turn associated with a complex of four transmembrane glycoproteins: α-, β-, γ-, and δ-sarcoglycan. This dystrophin–glycoprotein complex adds strength to the muscle by providing a scaffolding for the fibrils and connecting them to the extracellular environment. Disruption of these important structural features can result in several different muscular dystrophies (see Clinical Box 5–1).


FIGURE 5–4 The dystrophin–glycoprotein complex. Dystrophin connects F-actin to the two members of the dystroglycan (DG) complex, α and β-dystroglycan, and these in turn connect to the merosin subunit of laminin 211 in the extracellular matrix. The sarcoglycan complex of four glycoproteins, α-, β-, γ-, and γ-sarcoglycan, sarcospan, and syntropins are all associated with the dystroglycan complex. There are muscle disorders associated with loss, abnormalities, or both of the sarcoglycans and merosin. (This diagram was adapted from diagrams by Justin Fallon and Kevin Campbell.)


Structural and Metabolic Disorders in Muscle Disease

The term muscular dystrophy is applied to diseases that cause progressive weakness of skeletal muscle. About 50 such diseases have been described, some of which include cardiac as well as skeletal muscle. They range from mild to severe and some are eventually fatal. They have multiple causes, but mutations in the genes for the various components of the dystrophin–glycoprotein complex are a prominent cause. The dystrophin gene is one of the largest in the body, and mutations can occur at many different sites in it. Duchenne muscular dystrophy is a serious form of dystrophy in which the dystrophin protein is absent from muscle. It is X-linked and usually fatal by the age of 30. In a milder form of the disease, Becker muscular dystrophy, dystrophin is present but altered or reduced in amount. Limb-girdle muscular dystrophies of various types are associated with mutations of the genes coding for the sarcoglycans or other components of the dystrophin–glycoprotein complex.

Due to its enormous size and structural role in the sarcomere, titin is a prominent target for mutations that give rise to muscle disease. Mutations that encode for shorter titin structure have been associated with dilated cardiomyopathy, while other mutations have been associated with hypertrophic cardiomyopathy. The skeletal muscle-associated tibialis muscular dystrophy is a genetic muscle disease of titin that is predicted to destabilize the folded state of the protein. Interestingly, many of the titin mutations identified thus far are in regions of titin that are expressed in all striated muscles, yet, not all muscles are affected in the same way. Such muscle type–specific phenotypes underscore the need to study titin’s multiple functions in different muscles, under both normal and pathological conditions.

Desmin-related myopathies are a very rare heterogeneous group of muscle disorders that typically result in cellular aggregates of desmin. Common symptoms of these diseases are failing and wasting in the distal muscles of the lower limbs that can later be identified in other body areas. Studies in desmin knockout mice have revealed defects in skeletal, smooth, and cardiac muscle, notably in the diaphragm and heart.

Metabolic Myopathies

Mutations in genes that code for enzymes involved in the metabolism of carbohydrates, fats, and proteins to CO2 and H2O in muscle and the production of ATP can cause metabolic myopathies (eg, McArdle syndrome). Metabolic myopathies all have in common exercise intolerance and the possibility of muscle breakdown due to accumulation of toxic metabolites.


Although acute muscle pain and soreness can be treated with anti-inflammatory drugs and rest, the genetic dysfunctions described above are not as easily addressed. The overall goals are to slow muscle function/structure loss and, when possible relieve symptoms associated with the disease. Extensive monitoring, physical therapy and appropriate drugs including corticosteroids can aid to slow disease progression. Assistive devices and surgery are not uncommon as the diseases progress.



The electrical events in skeletal muscle and the ionic fluxes that underlie them share distinct similarities to those in nerve, with quantitative differences in timing and magnitude. The resting membrane potential of skeletal muscle is about –90 mV. The action potential lasts 2–4 ms and is conducted along the muscle fiber at about 5 m/s. The absolute refractory period is 1–3 ms long, and the after-polarizations, with their related changes in threshold to electrical stimulation, are relatively prolonged. The initiation of impulses at the myoneural junction is discussed in the next chapter.


The distribution of ions across the muscle fiber membrane is similar to that across the nerve cell membrane. Approximate values for the various ions and their equilibrium potentials are shown in Table 5–1. As in nerves, depolarization is largely a manifestation of Na+ influx, and repolarization is largely a manifestation of K+ efflux.


TABLE 5–1 Steady-state distribution of ions in the intracellular and extracellular compartments of mammalian skeletal muscle, and the equilibrium potentials for these ions.


It is important to distinguish between the electrical and mechanical events in skeletal muscle. Although one response does not normally occur without the other, their physiologic bases and characteristics are different. Muscle fiber membrane depolarization normally starts at the motor end plate, the specialized structure under the motor nerve ending. The action potential is transmitted along the muscle fiber and initiates the contractile response.


A single action potential causes a brief contraction followed by relaxation. This response is called a muscle twitch. In Figure 5–5, the action potential and the twitch are plotted on the same time scale. The twitch starts about 2 ms after the start of depolarization of the membrane, before repolarization is complete. The duration of the twitch varies with the type of muscle being tested. “Fast” muscle fibers, primarily those concerned with fine, rapid, precise movement, have twitch durations as short as 7.5 ms. “Slow” muscle fibers, principally those involved in strong, gross, sustained movements, have twitch durations up to 100 ms.


FIGURE 5–5 The electrical and mechanical responses of a mammalian skeletal muscle fiber to a single maximal stimulus. The electrical response (mV potential change) and the mechanical response (T, tension in arbitrary units) are plotted on the same abscissa (time). The mechanical response is relatively long-lived compared to the electrical response that initiates contraction.


The process by which the contraction of muscle is brought about is a sliding of the thin filaments over the thick filaments. Note that this shortening is not due to changes in the actual lengths of the thick and thin filaments, rather, by their increased overlap within the muscle cell. The width of the A bands is constant, whereas the Z lines move closer together when the muscle contracts and farther apart when it relaxes (Figure 5–3).

The sliding during muscle contraction occurs when the myosin heads bind firmly to actin, bend at the junction of the head with the neck, and then detach. This “power stroke” depends on the simultaneous hydrolysis of ATP. Myosin-II molecules are dimers that have two heads, but only one attaches to actin at any given time. The probable sequence of events of the power stroke is outlined in Figure 5–6. In resting muscle, troponin I is bound to actin and tropomyosin and covers the sites where myosin heads interact with actin. Also at rest, the myosin head contains tightly bound ADP. Following an action potential, cytosolic Ca2+ is increased and free Ca2+ binds to troponin C. This binding results in a weakening of the troponin I interaction with actin and exposes the actin binding site for myosin to allow for formation of myosin/actin cross-bridges. Upon formation of the cross-bridge, ADP is released, causing a conformational change in the myosin head that moves the thin filament relative to the thick filament, comprising the cross-bridge “power stroke.” ATP quickly binds to the free site on the myosin, which leads to a detachment of the myosin head from the thin filament. ATP is hydrolyzed and inorganic phosphate (Pi) released, causing a “re-cocking” of the myosin head and completing the cycle. As long as Ca2+ remains elevated and sufficient ATP is available, this cycle repeats. Many myosin heads cycle at or near the same time, and they cycle repeatedly, producing gross muscle contraction. Each power stroke shortens the sarcomere about 10 nm. Each thick filament has about 500 myosin heads, and each head cycles about five times per second during a rapid contraction.



FIGURE 5–6 Power stroke of myosin in skeletal muscle. A) At rest, myosin heads are bound to adenosine diphosphate and are said to be in a “cocked” position in relation to the thin filament, which does not have Ca2+ bound to the troponin–tropomyosin complex. B) Ca2+ bound to the troponin–tropomyosin complex induces a conformational change in the thin filament that allows for myosin heads to cross-bridge with thin filament actin. C) Myosin heads rotate, move the attached actin and shorten the muscle fiber, forming the power stroke. D) At the end of the power stroke, ATP binds to a now exposed site, and causes a detachment from the actin filament. E) ATP is hydrolyzed into ADP and inorganic phosphate (Pi) and this chemical energy is used to “re-cock” the myosin head. (Based on Huxley AF, Simmons RM: Proposed mechanism of force generation in striated muscle. Nature Oct 22;233(5321):533–538, 1971 and Squire JM: Molecular mechanisms in muscular contraction. Trends Neurosci 6:409–413, 1093.)

The process by which depolarization of the muscle fiber initiates contraction is called excitation–contraction coupling. The action potential is transmitted to all the fibrils in the fiber via the T system (Figure 5–7). It triggers the release of Ca2+ from the terminal cisterns, the lateral sacs of the sarcoplasmic reticulum next to the T system. Depolarization of the T tubule membrane activates the sarcoplasmic reticulum via dihydropyridine receptors (DHPR),named for the drug dihydropyridine, which blocks them (Figure 5–8). DHPR are voltage-gated Ca2+ channels in the T tubule membrane. In cardiac muscle, influx of Ca2+ via these channels triggers the release of Ca2+ stored in the sarcoplasmic reticulum (calcium-induced calcium release) by activating the ryanodine receptor (RyR). The RyR is named after the plant alkaloid ryanodine that was used in its discovery. The RyR is a ligand-gated Ca2+ channel with Ca2+ as its natural ligand. In skeletal muscle, Ca2+ entry from the extracellular fluid (ECF) by this route is not required for Ca2+ release. Instead, the DHPR that serves as the voltage sensor unlocks release of Ca2+ from the nearby sarcoplasmic reticulum via physical interaction with the RyR. The released Ca2+ is quickly amplified through calcium-induced calcium release. Ca2+ is reduced in the muscle cell by the sarcoplasmic or endoplasmic reticulum Ca2+ ATPase (SERCA). The SERCA pump uses energy from ATP hydrolysis to remove Ca2+ from the cytosol back into the terminal cisterns, where it is stored until released by the next action potential. Once the Ca2+ concentration outside the reticulum has been lowered sufficiently, chemical interaction between myosin and actin ceases and the muscle relaxes. Note that ATP provides the energy for both contraction (at the myosin head) and relaxation (via SERCA). If transport of Ca2+ into the reticulum is inhibited, relaxation does not occur even though there are no more action potentials; the resulting sustained contraction is called a contracture. Alterations in the excitable response in muscle underscore many different pathologies (Clinical Box 5–2).


FIGURE 5–7 Flow of information that leads to muscle contraction.


FIGURE 5–8 Relation of the T tubule (TT) to the sarcoplasmic reticulum in Ca2+ transport. In skeletal muscle, the voltage-gated dihydropyridine receptor in the T tubule triggers Ca2+ release from the sarcoplasmic reticulum (SR) via the ryanodine receptor (RyR). Upon sensing a voltage change, there is a physical interaction between the sarcolemmal-bound DHPR and the SR-bound RyR. This interaction gates the RyR and allows for Ca2+ release from the SR.


Muscle Channelopathies

Channelopathies are diseases that have as their underlying feature mutations or dysregulation of ion channels. Such diseases are frequently associated with excitable cells, including muscle. In the various forms of clinical myotonia,muscle relaxation is prolonged after voluntary contraction. The molecular bases of myotonias are due to dysfunction of channels that shape the action potential. Myotonia dystrophy is caused by an autosomal dominant mutation that leads to over-expression of a K+ channel (although the mutation is not at the K+ channel). A variety of myotonias are associated with mutations in Na+ channels (eg, hyperkalemic periodic paralysis, paramyotonia congenita, or Na+channel congenita) or Cl channels (eg, dominant or recessive myotonia congenita). Myasthenia, defined as abnormal muscle weakness or disease, can also be related to loss of ion channel function in the muscle. In congenital myasthenia, the patient has an inheritable disorder of one of a group of ion channels necessary for the transmission of neuronal signaling to muscle response. Mutations in Ca2+ channels that allow for neuronal transmitter release or in the acetylcholine receptor nonspecific cation channels, important in recognition of neuronal transmitters, have both been shown to cause congenital myasthenia. Alterations of channel functions can also occur via autoimmune disease, such as that observed in myasthenia gravis. In this disease, antibodies to the nicotinic acetylcholine receptor can reduce its functional presence at the muscle membrane by up to 80%, and thus limit muscle response to neuronal transmitter release.

Channelopathies can also occur in the Ca2+ release channels in muscle (ryanodine receptors) that amplify the Ca2+ response within the cell. Such mutations can cause malignant hyperthermia. Patients with this conditions display normal muscle function under normal conditions. However, certain anesthetic agents, or in rare cases exposure to high environmental heat or strenuous exercise, can trigger abnormal release of Ca2+ from the sarcoplasmic reticulum in the muscle cell, resulting in sustained muscle contraction and heat production. In severe cases, fatality can occur.


Although the symptoms associated with each individual channelopathy may be similar, treatments for the individual diseases include a wide variety of drugs that are targeted to the individual ion channel (or proteins associated with ion channel) defect. Appropriate drug therapy helps to improve symptoms and maintain acceptable muscle function. Further interventions related to individual diseases are to avoid muscle movements that exacerbate the disease.


Muscular contraction involves shortening of the contractile elements, but because muscles have elastic and viscous elements in series with the contractile mechanism, it is possible for contraction to occur without an appreciable decrease in the length of the whole muscle (Figure 5–9). Such a contraction is called isometric (“same measure” or length). Contraction against a constant load with a decrease in muscle length is isotonic (“same tension”). Note that because work is the product of force times distance, isotonic contractions do work, whereas isometric contractions do not. In other situations, muscle can do negative work while lengthening against a constant weight.


FIGURE 5–9 A) Muscle preparation arranged for recording isotonic contractions. B) Preparation arranged for recording isometric contractions. In A, the muscle is fastened to a writing lever that swings on a pivot. In B, it is attached to an electronic transducer that measures the force generated without permitting the muscle to shorten.


The electrical response of a muscle fiber to repeated stimulation is like that of nerve. The fiber is electrically refractory only during the rising phase and part of the falling phase of the spike potential. At this time, the contraction initiated by the first stimulus is just beginning. However, because the contractile mechanism does not have a refractory period, repeated stimulation before relaxation has occurred produces additional activation of the contractile elements and a response that is added to the contraction already present. This phenomenon is known as summation of contractions. The tension developed during summation is considerably greater than that during the single muscle twitch. With rapidly repeated stimulation, activation of the contractile mechanism occurs repeatedly before any relaxation has occurred, and the individual responses fuse into one continuous contraction. Such a response is called a tetanus (tetanic contraction). It is a complete tetanus when no relaxation occurs between stimuli and an incomplete tetanus when periods of incomplete relaxation take place between the summated stimuli. During a complete tetanus, the tension developed is about four times that developed by the individual twitch contractions. The development of an incomplete and a complete tetanus in response to stimuli of increasing frequency is shown in Figure 5–10.


FIGURE 5–10 Tetanus. Isometric tension of a single muscle fiber during continuously increasing and decreasing stimulation frequency. Dots at the top are at intervals of 0.2 s. Note the development of incomplete and then complete tetanus as stimulation is increased, and the return of incomplete tetanus, then full response, as stimulation frequency is decreased.

The stimulation frequency at which summation of contractions occurs is determined by the twitch duration of the particular muscle being studied. For example, if the twitch duration is 10 ms, frequencies less than 1/10 ms (100/s) cause discrete responses interrupted by complete relaxation, and frequencies greater than 100/s cause summation.


Both the tension that a muscle develops when stimulated to contract isometrically (the total tension) and the passive tension exerted by the unstimulated muscle vary with the length of the muscle fiber. This relationship can be studied in a whole skeletal muscle preparation such as that shown in Figure 5–9. The length of the muscle can be varied by changing the distance between its two attachments. At each length, the passive tension is measured, the muscle is then stimulated electrically, and the total tension is measured. The difference between the two values at any length is the amount of tension actually generated by the contractile process, the active tension. The records obtained by plotting passive tension and total tension against muscle length are shown in Figure 5–11. Similar curves are obtained when single muscle fibers are studied. The length of the muscle at which the active tension is maximal is usually called its resting length. The term comes originally from experiments demonstrating that the length of many of the muscles in the body at rest is the length at which they develop maximal tension.


FIGURE 5–11 Length–tension relationship for the human triceps muscle. The passive tension curve measures the tension exerted by this skeletal muscle at each length when it is not stimulated. The total tension curve represents the tension developed when the muscle contracts isometrically in response to a maximal stimulus. The active tension is the difference between the two.

The observed length–tension relation in skeletal muscle can be explained by the sliding filament mechanism of muscle contraction. When the muscle fiber contracts isometrically, the tension developed is proportional to the number of cross-bridges between the actin and the myosin molecules. When muscle is stretched, the overlap between actin and myosin is reduced and the number of cross-linkages is therefore reduced. Conversely, when the muscle is appreciably shorter than resting length, the distance the thin filaments can move is reduced.

The velocity of muscle contraction varies inversely with the load on the muscle. At a given load, the velocity is maximal at the resting length and declines if the muscle is shorter or longer than this length.


Although skeletal muscle fibers resemble one another in a general way, skeletal muscle is a heterogeneous tissue made up of fibers that vary in myosin ATPase activity, contractile speed, and other properties. Muscles are frequently classified into two types, “slow” and “fast.” These muscles can contain a mixture of three fiber types: type I (or SO for slow-oxidative); type IIA (FOG for fast-oxidative-glycolytic); or type IIB (FG for fast glycolytic). Some of the properties associated with type I, type IIA, and type IIB fibers are summarized in Table 5–2. Although these classification schemes are valid for muscles across many mammalian species, there are significant variations of fibers within and between muscles. For example, type I fibers in a given muscle can be larger than type IIA fibers from a different muscle in the same animal. Many of the differences in the fibers that make up muscles stem from differences in the proteins within them. Most of these are encoded by multigene families. Ten different isoforms of the myosin heavy chains (MHCs) have been characterized. Each of the two types of light chains also have isoforms. It appears that there is only one form of actin, but multiple isoforms of tropomyosin and all three components of troponin.


TABLE 5–2 Classification of fiber types in skeletal muscles.


Muscle contraction requires energy, and muscle has been called “a machine for converting chemical energy into mechanical work.” The immediate source of this energy is ATP, and this is formed by the metabolism of carbohydrates and lipids.


ATP is resynthesized from ADP by the addition of a phosphate group. Some of the energy for this endothermic reaction is supplied by the breakdown of glucose to CO2 and H2O, but there also exists in muscle another energy-rich phosphate compound that can supply this energy for short periods. This compound is phosphorylcreatine, which is hydrolyzed to creatine and phosphate groups with the release of considerable energy (Figure 5–12). At rest, some ATP in the mitochondria transfers its phosphate to creatine, so that a phosphorylcreatine store is built up. During exercise, the phosphorylcreatine is hydrolyzed at the junction between the myosin heads and actin, forming ATP from ADP and thus permitting contraction to continue.


FIGURE 5–12 Creatine, phosphorylcreatine, and creatinine cycling in muscle. During periods of high activity, cycling of phosphorylcreatine allows for quick release of ATP to sustain muscle activity.


At rest and during light exercise, muscles utilize lipids in the form of free fatty acids as their energy source. As the intensity of exercise increases, lipids alone cannot supply energy fast enough and so use of carbohydrate becomes the predominant component in the muscle fuel mixture. Thus, during exercise, much of the energy for phosphorylcreatine and ATP resynthesis comes from the breakdown of glucose to CO2 and H2O. Glucose in the bloodstream enters cells, where it is degraded through a series of chemical reactions to pyruvate. Another source of intracellular glucose, and consequently of pyruvate, is glycogen, the carbohydrate polymer that is especially abundant in liver and skeletal muscle. When adequate O2 is present, pyruvate enters the citric acid cycle and is metabolized—through this cycle and the so-called respiratory enzyme pathway—to CO2 and H2O. This process is called aerobic glycolysis.The metabolism of glucose or glycogen to CO2 and H2O forms large quantities of ATP from ADP. If O2 supplies are insufficient, the pyruvate formed from glucose does not enter the tricarboxylic acid cycle but is reduced to lactate. This process of anaerobic glycolysis is associated with the net production of much smaller quantities of energy-rich phosphate bonds, but it does not require the presence of O2. A brief overview of the various reactions involved in supplying energy to skeletal muscle is shown in Figure 5–13.


FIGURE 5–13 ATP turnover in muscle cells. Energy released by hydrolysis of 1 mol of ATP and reactions responsible for resynthesis of ATP. The amount of ATP formed per mole of free fatty acid (FFA) oxidized is large but varies with the size of the FFA. For example, complete oxidation of 1 mol of palmitic acid generates 140 mol of ATP.


During exercise, the muscle blood vessels dilate and blood flow is increased so that the available O2 supply is increased. Up to a point, the increase in O2 consumption is proportional to the energy expended, and all the energy needs are met by aerobic processes. However, when muscular exertion is very great, aerobic resynthesis of energy stores cannot keep pace with their utilization. Under these conditions, phosphorylcreatine is still used to resynthesize ATP. In addition, some ATP synthesis is accomplished by using the energy released by the anaerobic breakdown of glucose to lactate. Use of the anaerobic pathway is self-limiting because in spite of rapid diffusion of lactate into the bloodstream, enough accumulates in the muscles to eventually exceed the capacity of the tissue buffers and produce an enzyme-inhibiting decline in pH. However, for short periods, the presence of an anaerobic pathway for glucose breakdown permits muscular exertion of a far greater magnitude than would be possible without it. For example, in a 100-m dash that takes 10 s, 85% of the energy consumed is derived anaerobically; in a 2-mile race that takes 10 min, 20% of the energy is derived anaerobically; and in a long-distance race that takes 60 min, only 5% of the energy comes from anaerobic metabolism.

After a period of exertion is over, extra O2 is consumed to remove the excess lactate, replenish the ATP and phosphorylcreatine stores, and replace the small amounts of O2 that were released by myoglobin. Without replenishment of ATP, muscles enter a state of rigor (Clinical Box 5–3). The amount of extra O2 consumed is proportional to the extent to which the energy demands during exertion exceeded the capacity for the aerobic synthesis of energy stores, that is, the extent to which an oxygen debt was incurred. The O2 debt is measured experimentally by determining O2 consumption after exercise until a constant, basal consumption is reached and subtracting the basal consumption from the total. The amount of this debt may be six times the basal O2 consumption, which indicates that the subject is capable of six times the exertion that would have been possible without it.


Muscle Rigor

When muscle fibers are completely depleted of ATP and phosphorylcreatine, they develop a state of rigidity called rigor. When this occurs after death, the condition is called rigor mortis. In rigor, almost all of the myosin heads attach to actin but in an abnormal, fixed, and resistant way. The muscles effectively are locked into place and become quite stiff to the touch.


Thermodynamically, the energy supplied to a muscle must equal its energy output. The energy output appears in work done by the muscle, in energy-rich phosphate bonds formed for later use, and in heat. The overall mechanical efficiency of skeletal muscle (work done/total energy expenditure) ranges up to 50% while lifting a weight during isotonic contraction and is essentially 0% during isometric contraction. Energy storage in phosphate bonds is a small factor. Consequently, heat production is considerable. The heat produced in muscle can be measured accurately with suitable thermocouples.

Resting heat, the heat given off at rest, is the external manifestation of basal metabolic processes. The heat produced in excess of resting heat during contraction is called the initial heat. This is made up of activation heat, the heat that muscle produces whenever it is contracting, and shortening heat, which is proportional in amount to the distance the muscle shortens. Shortening heat is apparently due to some change in the structure of the muscle during shortening.

Following contraction, heat production in excess of resting heat continues for as long as 30 min. This recovery heat is the heat liberated by the metabolic processes that restore the muscle to its precontraction state. The recovery heat of muscle is approximately equal to the initial heat; that is, the heat produced during recovery is equal to the heat produced during contraction.

If a muscle that has contracted isotonically is restored to its previous length, extra heat in addition to recovery heat is produced (relaxation heat). External work must be done on the muscle to return it to its previous length, and relaxation heat is mainly a manifestation of this work.



Innervation of muscle fibers is critical to muscle function (Clinical Box 5–4). Because the axons of the spinal motor neurons supplying skeletal muscle each branch to innervate several muscle fibers, the smallest possible amount of muscle that can contract in response to the excitation of a single motor neuron is not one muscle fiber but all the fibers supplied by the neuron. Each single motor neuron and the muscle fibers it innervates constitute a motor unit.The number of muscle fibers in a motor unit varies. In muscles such as those of the hand and those concerned with motion of the eye (ie, muscles concerned with fine, graded, precise movement), each motor unit innervates very few (on the order of three to six) muscle fibers. On the other hand, values of 600 muscle fibers per motor unit can occur in human leg muscles. The group of muscle fibers that contribute to a motor unit can be intermixed within a muscle. That is, although they contract as a unit, they are not necessarily “neighboring” fibers within the muscle.


Denervation of Muscle

In the intact animal healthy skeletal muscle does not contract except in response to stimulation of its motor nerve supply. Destruction of this nerve supply causes muscle atrophy. It also leads to abnormal excitability of the muscle and increases its sensitivity to circulating acetylcholine (denervation hypersensitivity; see Chapter 6). Fine, irregular contraction of individual fibers (fibrillations) appears. This is the classic picture of a lower motor neuron lesion. If the motor nerve regenerates, the fibrillations disappear. Usually, the contractions are not visible grossly, and they should not be confused with fasciculations, which are jerky, visible contractions of groups of muscle fibers that occur as a result of pathologic discharge of spinal motor neurons.

Each spinal motor neuron innervates only one kind of muscle fiber, so that all the muscle fibers in a motor unit are of the same type. On the basis of the type of muscle fiber they innervate, and thus on the basis of the duration of their twitch contraction, motor units are divided into S (slow), FR (fast, resistant to fatigue), and FF (fast, fatigable) units. Interestingly, there is also a gradation of innervation of these fibers, with S fibers tending to have a low innervation ratio (ie, small units) and FF fibers tending to have a high innervation ratio (ie, large units). The recruitment of motor units during muscle contraction is not random; rather it follows a general scheme, the size principle.In general, a specific muscle action is developed first by the recruitment of S muscle units that contract relatively slowly to produce controlled contraction. Next, FR muscle units are recruited, resulting in more powerful response over a shorter period of time. Lastly, FF muscle units are recruited for the most demanding tasks. For example, in muscles of the leg, the small, slow units are first recruited for standing. As walking motion is initiated, their recruitment of FR units increases. As this motion turns to running or jumping, the FF units are recruited. Of course, there is overlap in recruitment, but, in general, this principle holds true.

The differences between types of muscle units are not inherent but are determined by, among other things, their activity. When the nerve to a slow muscle is cut and the nerve to a fast muscle is spliced to the cut end, the fast nerve grows and innervates the previously slow muscle. However, the muscle becomes fast and corresponding changes take place in its muscle protein isoforms and myosin ATPase activity. This change is due to changes in the pattern of activity of the muscle; in stimulation experiments, changes in the expression of MHC genes and consequently of MHC isoforms can be produced by changes in the pattern of electrical activity used to stimulate the muscle. More commonly, muscle fibers can be altered by a change in activity initiated through exercise (or lack thereof). Increased activity can lead to muscle cell hypertrophy, which allows for increase in contractile strength. Type IIA and IIB fibers are most susceptible to these changes. Alternatively, inactivity can lead to muscle cell atrophy and a loss of contractile strength. Type I fibers—that is, the ones used most often—are most susceptible to these changes.


Activation of motor units can be studied by electromyography, the process of recording the electrical activity of muscle. This may be done in unanaesthetized humans by using small metal disks on the skin overlying the muscle as the pick-up electrodes or by using needle or fine wire electrodes inserted into the muscle. The record obtained with such electrodes is the electromyogram (EMG). With needle or fine wire electrodes, it is usually possible to pick up the activity of single muscle fibers. The measured EMG depicts the potential difference between the two electrodes, which is altered by the activation of muscles in between the electrodes. A typical EMG is shown in Figure 5–14.


FIGURE 5–14 Relative joint angle and electromyographic tracings from human extensor pollicis longus and flexor pollicis longus during alternate flexion and extension of the distal joint of the thumb. The extensor pollicis longus and flexor pollicis longus extend and flex the distal joint of the thumb, respectively. The distal thumb joint angle (top) is superimposed over the extensor pollicis longus (middle) and flexor pollicus longus (bottom) EMGs. Note the alternate activation and rest patterns as one muscle is used for extension and the other for flexion. (Courtesy of Andrew J. Fuglevand.)

It has been shown by electromyography that little if any spontaneous activity occurs in the skeletal muscles of normal individuals at rest. With minimal voluntary activity a few motor units discharge, and with increasing voluntary effort, more and more are brought into play to monitor the recruitment of motor units. Gradation of muscle response is therefore in part a function of the number of motor units activated. In addition, the frequency of discharge in the individual nerve fibers plays a role, the tension developed during a tetanic contraction being greater than that during individual twitches. The length of the muscle is also a factor. Finally, the motor units fire asynchronously, that is, out of phase with one another. This asynchronous firing causes the individual muscle fiber responses to merge into a smooth contraction of the whole muscle. In summary, EMGs can be used to quickly (and roughly) monitor abnormal electrical activity associated with muscle responses.


Human skeletal muscle can exert 3–4 kg of tension per square centimeter of cross-sectional area. This figure is about the same as that obtained in a variety of experimental animals and seems to be constant for mammalian species. Because many of the muscles in humans have a relatively large cross-sectional area, the tension they can develop is quite large. The gastrocnemius, for example, not only supports the weight of the whole body during climbing but resists a force several times this great when the foot hits the ground during running or jumping. An even more striking example is the gluteus maximus, which can exert a tension of 1200 kg. The total tension that could be developed if all muscles in the body of an adult man pulled together is approximately 22,000 kg (nearly 25 tons).


Body movements are generally organized in such a way that they take maximal advantage of the physiologic principles outlined above. For example, the attachments of the muscles in the body are such that many of them are normally at or near their resting length when they start to contract. In muscles that extend over more than one joint, movement at one joint may compensate for movement at another in such a way that relatively little shortening of the muscle occurs during contraction. Nearly isometric contractions of this type permit development of maximal tension per contraction. The hamstring muscles extend from the pelvis over the hip joint and the knee joint to the tibia and fibula. Hamstring contraction produces flexion of the leg on the thigh. If the thigh is flexed on the pelvis at the same time, the lengthening of the hamstrings across the hip joint tends to compensate for the shortening across the knee joint. In the course of various activities, the body moves in a way that takes advantage of this. Such factors as momentum and balance are integrated into body movement in ways that make possible maximal motion with minimal muscular exertion. One net effect is that the stress put on tendons and bones rarely exceeds 50% of their failure strength, protecting them from damage.

In walking, each limb passes rhythmically through a support or stance phase when the foot is on the ground and a swing phase when the foot is off the ground. The support phases of the two legs overlap, so that two periods of double support occur during each cycle. There is a brief burst of activity in the leg flexors at the start of each step, and then the leg is swung forward with little more active muscular contraction. Therefore, the muscles are active for only a fraction of each step, and walking for long periods causes relatively little fatigue.

A young adult walking at a comfortable pace moves at a velocity of about 80 m/min and generates a power output of 150–175 W per step. A group of young adults asked to walk at their most comfortable rate selected a velocity close to 80 m/min, and it was found that they had selected the velocity at which their energy output was minimal. Walking more rapidly or more slowly took more energy.


The striations in cardiac muscle are similar to those in skeletal muscle, and Z lines are present. Large numbers of elongated mitochondria are in close contact with the muscle fibrils. The muscle fibers branch and interdigitate, but each is a complete unit surrounded by a cell membrane. Where the end of one muscle fiber abuts on another, the membranes of both fibers parallel each other through an extensive series of folds. These areas, which always occur at Z lines, are called intercalated disks (Figure 5–15). They provide a strong union between fibers, maintaining cell-to-cell cohesion, so that the pull of one contractile cell can be transmitted along its axis to the next. Along the sides of the muscle fibers next to the disks, the cell membranes of adjacent fibers fuse for considerable distances, forming gap junctions. These junctions provide low-resistance bridges for the spread of excitation from one fiber to another. They permit cardiac muscle to function as if it were a syncytium, even though no protoplasmic bridges are present between cells. The T system in cardiac muscle is located at the Z lines rather than at the A–I junction, where it is located in mammalian skeletal muscle.


FIGURE 5–15 Cardiac muscle. A) Electronmicrograph of cardiac muscle. Note the similarity of the A-I regions seen in the skeletal muscle EM of Figure 3–2. The fuzzy thick lines are intercalated disks and function similarly to the Z-lines but occur at cell membranes (× 12,000). (Reproduced with permission from Bloom W, Fawcett DW: A Textbook of Histology, 10th ed. Saunders, 1975.) B) Artist interpretation of cardiac muscle as seen under the light microscope (top) and the electron microscope (bottom). Again, note the similarity to skeletal muscle structure. N, nucleus. (Reproduced with permission from Braunwald E, Ross J, Sonnenblick EH: Mechanisms of contraction of the normal and failing heart. N Engl J Med 1967;277:794.)



The resting membrane potential of individual mammalian cardiac muscle cells is about –80 mV. Stimulation produces a propagated action potential that is responsible for initiating contraction. Although action potentials vary among the cardiomyocytes in different regions of the heart (discussed in Chapter 29), the action potential of a typical ventricular cardiomyocyte can be used as an example (Figure 5–16). Depolarization proceeds rapidly and an overshoot of the zero potential is present, as in skeletal muscle and nerve, but this is followed by a plateau before the membrane potential returns to the baseline. In mammalian hearts, depolarization lasts about 2 ms, but the plateau phase and repolarization last 200 ms or more. Repolarization is therefore not complete until the contraction is half over.


FIGURE 5–16 Comparison of action potentials and contractile response of a mammalian cardiac muscle fiber in a typical ventricular cell. In the top trace, the intracellular recording of the action potential shows the quick depolarization and extended recovery. In the bottom trace, the mechanical response is matched to the extracellular and intracellular electrical activities. Note that in the absolute refractory period (ARP), the cardiac myocyte cannot be excited, whereas in the relative refractory period (RRP) minimal excitation can occur.

As in other excitable tissues, changes in the external K+ concentration affect the resting membrane potential of cardiac muscle, whereas changes in the external Na+ concentration affect the magnitude of the action potential. The initial rapid depolarization and the overshoot (phase 0) are due to opening of voltage-gated Na+ channels similar to that occurring in nerve and skeletal muscle (Figure 5–17). The initial rapid repolarization (phase 1) is due to closure of Na+ channels and opening of one type of K+ channel. The subsequent prolonged plateau (phase 2) is due to a slower but prolonged opening of voltage-gated Ca2+ channels. Final repolarization (phase 3) to the resting membrane potential (phase 4) is due to closure of the Ca2+ channels and a slow, delayed increase of K+ efflux through various types of K+ channels. Cardiac myocytes contain at least two types of Ca2+ channels (T- and L-types), but the Ca2+current is mostly due to opening of the slower L-type Ca2+ channels. Mutations or dysfunction in any of these channels lead to serious pathologies of the heart (eg, Clinical Box 5–5).


FIGURE 5–17 Dissection of the cardiac action potential. Top: The action potential of a cardiac muscle fiber can be broken down into several phases: 0, depolarization; 1, initial rapid repolarization; 2, plateau phase; 3, late rapid repolarization; 4, baseline. Bottom: Diagrammatic summary of Na+, Ca2+, and cumulative K+ currents during the action potential. As is convention, inward currents are downward, and outward currents are upward.


Long QT Syndrome

Long QT syndrome (LQTS) is defined as a prolongation of the QT interval observed on an electrocardiogram. LQTS can lead to irregular heartbeats and subsequent fainting, seizure, cardiac arrest, or even death. Although certain medications can lead to LQTS, it is more frequently associated with genetic mutations in a variety of cardiac-expressed ion channels. Mutations in cardiac-expressed voltage gated K+ channel genes (KCNQ1 or KCNH2) account for most of the mutation-based cases of LQTS (∼90%). Mutations in cardiac-expressed voltage-gated Na+ channels (eg, SCN5A) or cardiac-expressed Ca2+ channels (eg, CACNA1C) have also been associated with the disease. The fact that mutations in diverse channels all can result in the prolongation of the QT interval and subsequent pathology underlies the intricate interplay of these channels in shaping the heart’s electrical response.


Patients with long QT syndrome (LQTS) should avoid drugs that prolong the QT interval or reduce their serum K+ or Mg2+ levels; any K+ or Mg2+ deficiencies should be corrected. Drug interventions in asymptomatic patients remain somewhat controversial, although patients with congenital defects that lead to LQTS are considered candidates for intervention independent of symptoms. In general, β-blockers have been used for LQTS to reduce the risk of cardiac arrhythmias. More specific and effective treatments can be introduced once the underlying cause of LQTS is identified.



The contractile response of cardiac muscle begins just after the start of depolarization and lasts about 1.5 times as long as the action potential (Figure 5–16). The role of Ca2+ in excitation–contraction coupling is similar to its role in skeletal muscle (see above). However, it is the influx of extracellular Ca2+ through the voltage-sensitive DHPR in the T system that triggers calcium-induced calcium release through the RyR at the sarcoplasmic reticulum. Because there is a net influx of Ca2+ during activation, there is also a more prominent role for plasma membrane Ca2+ ATPases and the Na+/Ca2+ exchanger in recovery of intracellular Ca2+ concentrations. Specific effects of drugs that indirectly alter Ca2+ concentrations are discussed in Clinical Box 5–6.


Glycolysidic Drugs & Cardiac Contractions

Oubain and other digitalis glycosides are commonly used to treat failing hearts. These drugs have the effect of increasing the strength of cardiac contractions. Although there is discussion as to full mechanisms, a working hypothesis is based on the ability of these drugs to inhibit the Na, K ATPase in cell membranes of the cardiomyocytes. The block of the Na, K ATPase in cardiomyocytes would result in an increased intracellular Na+ concentration. Such an increase would result in a decreased Na+ influx and hence Ca2+ efflux via the Na+-Ca2+ exchange antiport during the Ca2+ recovery period. The resulting increase in intracellular Ca2+ concentration in turn increases the strength of contraction of the cardiac muscle. With this mechanism in mind, these drugs can also be quite toxic. Overinhibition of the Na, K ATPase would result in a depolarized cell that could slow conduction, or even spontaneously activate. Alternatively, an overly increased Ca2+ concentration could also have ill effects on cardiomyocyte physiology.

During phases 0 to 2 and about half of phase 3 (until the membrane potential reaches approximately –50 mV during repolarization), cardiac muscle cannot be excited again; that is, it is in its absolute refractory period. It remains relatively refractory until phase 4. Therefore, tetanus of the type seen in skeletal muscle cannot occur. Of course, tetanization of cardiac muscle for any length of time would have lethal consequences, and in this sense, the fact that cardiac muscle cannot be tetanized is a safety feature.


Cardiac muscle is generally slow and has relatively low ATPase activity. Its fibers are dependent on oxidative metabolism and hence on a continuous supply of O2. The human heart contains both the α and the β isoforms of the myosin heavy chain (α MHC and β MHC). β MHC has lower myosin ATPase activity than α MHC. Both are present in the atria, with the α isoform predominating, whereas the β isoform predominates in the ventricle. The spatial differences in expression contribute to the well-coordinated contraction of the heart.


The relation between initial fiber length and total tension in cardiac muscle is similar to that in skeletal muscle; there is a resting length at which the tension developed on stimulation is maximal. In the body, the initial length of the fibers is determined by the degree of diastolic filling of the heart, and the pressure developed in the ventricle is proportional to the volume of the ventricle at the end of the filling phase (Starling’s law of the heart). The developed tension (Figure 5–18) increases as the diastolic volume increases until it reaches a maximum, then tends to decrease. However, unlike skeletal muscle, the decrease in developed tension at high degrees of stretch is not due to a decrease in the number of cross-bridges between actin and myosin, because even severely dilated hearts are not stretched to this degree. The decrease is instead due to beginning disruption of the myocardial fibers.


FIGURE 5–18 Length–tension relationship for cardiac muscle. Comparison of the systolic intraventricular pressure (top trace) and diastolic intraventricular pressure (bottom trace) display the developed tension in the cardiomyocyte. Values shown are for canine heart.

The force of contraction of cardiac muscle can be also increased by catecholamines, and this increase occurs without a change in muscle length. This positive ionotropic effect of catecholamines is mediated via innervated β1-adrenergic receptors, cyclic AMP, and their effects on Ca2+ homeostasis. The heart also contains noninnervated β2-adrenergic receptors, which also act via cyclic AMP, but their ionotropic effect is smaller and is maximal in the atria. Cyclic AMP activates protein kinase A, and this leads to phosphorylation of the voltage-dependent Ca2+ channels, causing them to spend more time in the open state. Cyclic AMP also increases the active transport of Ca2+ to the sarcoplasmic reticulum, thus accelerating relaxation and consequently shortening systole. This is important when the cardiac rate is increased because it permits adequate diastolic filling (see Chapter 30).


Mammalian hearts have an abundant blood supply, numerous mitochondria, and a high content of myoglobin, a muscle pigment that can function as an O2 storage mechanism. Normally, less than 1% of the total energy liberated is provided by anaerobic metabolism. During hypoxia, this figure may increase to nearly 10%; but under totally anaerobic conditions, the energy liberated is inadequate to sustain ventricular contractions. Under basal conditions, 35% of the caloric needs of the human heart are provided by carbohydrate, 5% by ketones and amino acids, and 60% by fat. However, the proportions of substrates utilized vary greatly with the nutritional state. After ingestion of large amounts of glucose, more lactate and pyruvate are used; during prolonged starvation, more fat is used. Circulating free fatty acids normally account for almost 50% of the lipid utilized. In untreated diabetics, the carbohydrate utilization of cardiac muscle is reduced and that of fat is increased.


Smooth muscle is distinguished anatomically from skeletal and cardiac muscle because it lacks visible cross-striations. Actin and myosin-II are present, and they slide on each other to produce contraction. However, they are not arranged in regular arrays, as in skeletal and cardiac muscle, and so the striations are absent. Instead of Z lines, there are dense bodies in the cytoplasm and attached to the cell membrane, and these are bound by α-actinin to actin filaments. Smooth muscle also contains tropomyosin, but troponin appears to be absent. The isoforms of actin and myosin differ from those in skeletal muscle. A sarcoplasmic reticulum is present, but it is less extensive than those observed in skeletal or cardiac muscle. In general, smooth muscles contain few mitochondria and depend, to a large extent, on glycolysis for their metabolic needs.


There is considerable variation in the structure and function of smooth muscle in different parts of the body. In general, smooth muscle can be divided into unitary (or visceralsmooth muscle and multiunit smooth muscle. Unitary smooth muscle occurs in large sheets, has many low-resistance gap junctional connections between individual muscle cells, and functions in a syncytial fashion. Unitary smooth muscle is found primarily in the walls of hollow viscera. The musculature of the intestine, the uterus, and the ureters are examples. Multiunit smooth muscle is made up of individual units with few (or no) gap junctional bridges. It is found in structures such as the iris of the eye, in which fine, graded contractions occur. It is not under voluntary control, but it has many functional similarities to skeletal muscle. Each multiunit smooth muscle cell has en passant endings of nerve fibers, but in unitary smooth muscle there are en passant junctions on fewer cells, with excitation spreading to other cells by gap junctions. In addition, these cells respond to hormones and other circulating substances. Blood vessels have both unitary and multiunit smooth muscle in their walls.


Unitary smooth muscle is characterized by the instability of its membrane potential and by the fact that it shows continuous, irregular contractions that are independent of its nerve supply. This maintained state of partial contraction is called tonus, or tone. The membrane potential has no true “resting” value, being relatively low when the tissue is active and higher when it is inhibited, but in periods of relative quiescence values for resting potential are on the order of –20 to –65 mV. Smooth muscle cells can display divergent electrical activity (eg, Figure 5–19). There are slow sine wave-like fluctuations a few millivolts in magnitude and spikes that sometimes overshoot the zero potential line and sometimes do not. In many tissues, the spikes have a duration of about 50 ms, whereas in some tissues the action potentials have a prolonged plateau during repolarization, like the action potentials in cardiac muscle. As in the other muscle types, there are significant contributions of K+, Na+, and Ca2+ channels and Na, K ATPase to this electrical activity. However, discussion of contributions to individual smooth muscle types is beyond the scope of this text.


FIGURE 5–19 Electrical activity of individual smooth muscle cells in the guinea pig taenia coli. Left: Pacemaker-like activity with spikes firing at each peak. Right: Sinusoidal fluctuation of membrane potential with firing on the rising phase of each wave. In other fibers, spikes can occur on the falling phase of sinusoidal fluctuations and there can be mixtures of sinusoidal and pacemaker potentials in the same fiber.

Because of the continuous activity, it is difficult to study the relation between the electrical and mechanical events in unitary smooth muscle, but in some relatively inactive preparations, a single spike can be generated. In such preparations, the excitation–contraction coupling in unitary smooth muscle can occur with as much as a 500 ms delay. Thus, it is a very slow process compared with that in skeletal and cardiac muscle, in which the time from initial depolarization to initiation of contraction is less than 10 ms. Unlike unitary smooth muscle, multiunit smooth muscle is nonsyncytial and contractions do not spread widely through it. Because of this, the contractions of multiunit smooth muscle are more discrete, fine, and localized than those of unitary smooth muscle.


As in skeletal and cardiac muscle, Ca2+ plays a prominent role in the initiation of contraction of smooth muscle. However, the source of Ca2+ increase can be quite different in unitary smooth muscle. Depending on the activating stimulus, Ca2+ increase can be due to influx through voltage- or ligand-gated plasma membrane channels, efflux from intracellular stores through the RyR, efflux from intracellular stores through the inositol trisphosphate receptor (IP3R) Ca2+ channel, or via a combination of these channels. In addition, the lack of troponin in smooth muscle prevents Ca2+ activation via troponin binding. Rather, myosin in smooth muscle must be phosphorylated for activation of the myosin ATPase. Phosphorylation and dephosphorylation of myosin also occur in skeletal muscle, but phosphorylation is not necessary for activation of the ATPase. In smooth muscle, Ca2+ binds to calmodulin, and the resulting complex activates calmodulin-dependent myosin light chain kinase. This enzyme catalyzes the phosphorylation of the myosin light chain on serine at position 19, increasing its ATPase activity.

Myosin is dephosphorylated by myosin light chain phosphatase in the cell. However, dephosphorylation of myosin light chain kinase does not necessarily lead to relaxation of the smooth muscle. Various mechanisms are involved. One appears to be a latch bridge mechanism by which myosin cross-bridges remain attached to actin for some time after the cytoplasmic Ca2+ concentration falls. This produces sustained contraction with little expenditure of energy, which is especially important in vascular smooth muscle. Relaxation of the muscle presumably occurs when the Ca2+-calmodulin complex finally dissociates or when some other mechanism comes into play. The events leading to contraction and relaxation of unitary smooth muscle are summarized in Figure 5–20. The events in multiunit smooth muscle are generally similar.


FIGURE 5–20 Sequence of events in contraction and relaxation of smooth muscle. Flow chart illustrates many of the molecular changes that occur from the initiation of contraction to its relaxation. Note the distinct differences from skeletal and cardiac muscle excitation.

Unitary smooth muscle is unique in that, unlike other types of muscle, it contracts when stretched in the absence of any extrinsic innervation. Stretch is followed by a decline in membrane potential, an increase in the frequency of spikes, and a general increase in tone.

If epinephrine or norepinephrine is added to a preparation of intestinal smooth muscle arranged for recording of intracellular potentials in vitro, the membrane potential usually becomes larger, the spikes decrease in frequency, and the muscle relaxes (Figure 5–21). Norepinephrine is the chemical mediator released at noradrenergic nerve endings, and stimulation of the noradrenergic nerves to the preparation produces inhibitory potentials. Acetylcholine has an effect opposite to that of norepinephrine on the membrane potential and contractile activity of intestinal smooth muscle. If acetylcholine is added to the fluid bathing a smooth muscle preparation in vitro, the membrane potential decreases and the spikes become more frequent. The muscle becomes more active, with an increase in tonic tension and the number of rhythmic contractions. The effect is mediated by phospholipase C, which produces IP3 and allows for Ca2+ release through IP3 receptors. In the intact animal, stimulation of cholinergic nerves causes release of acetylcholine, excitatory potentials, and increased intestinal contractions.


FIGURE 5–21 Effects of various agents on the membrane potential of intestinal smooth muscle. Drugs and hormones can alter firing of smooth muscle action potentials by raising (top trace) or lowering (bottom trace) resting membrane potential.

Like unitary smooth muscle, multiunit smooth muscle is very sensitive to circulating chemical substances and is normally activated by chemical mediators (acetylcholine and norepinephrine) released at the endings of its motor nerves. Norepinephrine in particular tends to persist in the muscle and to cause repeated firing of the muscle after a single stimulus rather than a single action potential. Therefore, the contractile response produced is usually an irregular tetanus rather than a single twitch. When a single twitch response is obtained, it resembles the twitch contraction of skeletal muscle except that its duration is 10 times as long.


In addition to cellular mechanisms that increase contraction of smooth muscle, there are cellular mechanisms that lead to its relaxation (Clinical Box 5–7). This is especially important in smooth muscle that surrounds the blood vessels to increase blood flow. It was long known that endothelial cells that line the inside of blood cells could release a substance that relaxed smooth muscle (endothelial derived relaxing factor, EDRF). EDRF was later identified as the gaseous second messenger molecule, nitric oxide (NO). NO produced in endothelial cells is free to diffuse into the smooth muscle for its effects. Once in muscle, NO directly activates a soluble guanylate cyclase to produce another second messenger molecule, cyclic guanosine monophosphate (cGMP). This molecule can activate cGMP-specific protein kinases that can affect ion channels, Ca2+ homeostasis, or phosphatases, or all of those mentioned, leading to smooth muscle relaxation (see Chapters 7 and 32).


Common Drugs That Act on Smooth Muscle

Overexcitation of smooth muscle in the airways, such as that observed during an asthma attack, can lead to bronchoconstriction. Inhalers that deliver drugs to the conducting airway are commonly used to offset this smooth muscle bronchoconstriction, as well as other symptoms in the asthmatic airways. The rapid effects of drugs in inhalers are related to smooth muscle relaxation. Rapid response inhaler drugs (eg, ventolin, albuterol, sambuterol) frequently target β-adrenergic receptors in the airway smooth muscle to elicit a relaxation. Although these β-adrenergic receptor agonists targeting the smooth muscle do not treat all symptoms associated with asthma (eg, inflammation and increased mucus), they act rapidly and frequently allow for sufficient opening of the conducting airway to restore airflow, and thus allow for other treatments to reduce airway obstruction.

Smooth muscle is also a target for drugs developed to increase blood flow. As discussed in the text, NO is a natural signaling molecule that relaxes smooth muscle by raising cGMP. This signaling pathway is naturally down-regulated by the action of phosphodiesterase (PDE), which transforms cGMP into a nonsignaling form, GMP. The drugs sildenafil, tadalafil, and vardenafil are all specific inhibitors of PDE V, an isoform found mainly in the smooth muscle in the corpus cavernosum of the penis (see Chapters 25 and 32). Thus, oral administration of these drugs can block the action of PDE V, increasing blood flow in a very limited region in the body and offsetting erectile dysfunction.


The effects of acetylcholine and norepinephrine on unitary smooth muscle serve to emphasize two of its important properties: (1) its spontaneous activity in the absence of nervous stimulation and (2) its sensitivity to chemical agents released from nerves locally or brought to it in the circulation. In mammals, unitary muscle usually has a dual nerve supply from the two divisions of the autonomic nervous system. The function of the nerve supply is not to initiate activity in the muscle but rather to modify it. Stimulation of one division of the autonomic nervous system usually increases smooth muscle activity, whereas stimulation of the other decreases it. In some organs, noradrenergic stimulation increases and cholinergic stimulation decreases smooth muscle activity; in others, the reverse is true.


Smooth muscle displays a unique economy when compared to skeletal muscle. Despite approximately 20% of the myosin content and a 100-fold difference in ATP use when compared with skeletal muscle, they can generate similar force per cross-sectional area. One of the tradeoffs of obtaining force under these conditions is the noticeably slower contractions when compared to skeletal muscle. There are several known reasons for these noticeable changes, including unique isoforms of myosin and contractile-related proteins expressed in smooth muscle and their distinct regulation (discussed above). The unique architecture of the smooth cell and its coordinated units also likely contribute to these changes.

Another special characteristic of smooth muscle is the variability of the tension it exerts at any given length. If a unitary smooth muscle is stretched, it first exerts increased tension. However, if the muscle is held at the greater length after stretching, the tension gradually decreases. Sometimes the tension falls to or below the level exerted before the muscle was stretched. It is consequently impossible to correlate length and developed tension accurately, and no resting length can be assigned. In some ways, therefore, smooth muscle behaves more like a viscous mass than a rigidly structured tissue, and it is this property that is referred to as the plasticity of smooth muscle.

The consequences of plasticity can be demonstrated in humans. For example, the tension exerted by the smooth muscle walls of the bladder can be measured at different degrees of distention as fluid is infused into the bladder via a catheter. Initially, tension increases relatively little as volume is increased because of the plasticity of the bladder wall. However, a point is eventually reached at which the bladder contracts forcefully (see Chapter 37).


image There are three main types of muscle cells: skeletal, cardiac, and smooth.

image Skeletal muscle is a true syncytium under voluntary control. Skeletal muscles receive electrical stimuli from neurons to elicit contraction: “excitation–contraction coupling.” Action potentials in muscle cells are developed largely through coordination of Na+, K+, and Ca2+ channels. Contraction in skeletal muscle cells is coordinated through Ca2+ regulation of the actomyosin system that gives the muscle its classic striated pattern under the microscope.

image There are several different types of skeletal muscle fibers (I, IIA, IIB) that have distinct properties in terms of protein makeup and force generation. Skeletal muscle fibers are arranged into motor units of like fibers within a muscle. Skeletal motor units are recruited in a specific pattern as the need for more force is increased.

image Cardiac muscle is a collection of individual cells (cardiomyocytes) that are linked as a syncytium by gap junctional communication. Cardiac muscle cells also undergo excitation–contraction coupling. Pacemaker cells in the heart can initiate propagated action potentials. Cardiac muscle cells also have a striated, actomyosin system that underlies contraction.

image Smooth muscle exists as individual cells and are frequently under control of the autonomic nervous system.

image There are two broad categories of smooth muscle cells: unitary and multiunit. Unitary smooth muscle contraction is synchronized by gap junctional communication to coordinate contraction among many cells. Multiunit smooth muscle contraction is coordinated by motor units, functionally similar to skeletal muscle.

image Smooth muscle cells contract through an actomyosin system, but do not have well-organized striations. Unlike skeletal and cardiac muscle, Ca2+ regulation of contraction is primarily through phosphorylation–dephosphorylation reactions.


For all questions, select the single best answer unless otherwise directed.

1. The action potential of skeletal muscle

A. has a prolonged plateau phase.

B. spreads inward to all parts of the muscle via the T tubules.

C. causes the immediate uptake of Ca2+ into the lateral sacs of the sarcoplasmic reticulum.

D. is longer than the action potential of cardiac muscle.

E. is not essential for contraction.

2. The functions of tropomyosin in skeletal muscle include

A. sliding on actin to produce shortening.

B. releasing Ca2+ after initiation of contraction.

C. binding to myosin during contraction.

D. acting as a “relaxing protein” at rest by covering up the sites where myosin binds to actin.

E. generating ATP, which it passes to the contractile mechanism.

3. The cross-bridges of the sarcomere in skeletal muscle are made up of

A. actin.

B. myosin.

C. troponin.

D. tropomyosin.

E. myelin.

4. The contractile response in skeletal muscle

A. starts after the action potential is over.

B. does not last as long as the action potential.

C. produces more tension when the muscle contracts isometrically than when the muscle contracts isotonically.

D. produces more work when the muscle contracts isometrically than when the muscle contracts isotonically.

E. decreases in magnitude with repeated stimulation.

5. Gap junctions

A. are absent in cardiac muscle.

B. are present but of little functional importance in cardiac muscle.

C. are present and provide the pathway for rapid spread of excitation from one cardiac muscle fiber to another.

D. are absent in smooth muscle.

E. connect the sarcotubular system to individual skeletal muscle cells.


Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, 5th ed. Garland Science, 2007.

Fung YC: Biomechanics, 2nd ed. Springer, 1993.

Hille B: Ionic Channels of Excitable Membranes, 3rd ed. Sinaver Associates, 2001.

Horowitz A: Mechanisms of smooth muscle contraction. Physiol Rev 1996;76:967.

Kandel ER, Schwartz JH, Jessell TM (editors): Principles of Neural Science, 4th ed. McGraw-Hill, 2000.

Katz AM: Phyysiology of the Heart, 4th ed. Raven Press, 2006.

Sperelakis N (editor): Cell Physiology Sourcebook, 3rd ed. Academic Press, 2001.