Medical Physiology, 3rd Edition

Diversity among Muscles

As we have seen, each muscle type (skeletal, cardiac, and smooth) is distinguishable on the basis of its unique histological features, EC coupling mechanisms, and regulation of contractile function. However, even within each of the three categories, muscle in different locations must serve markedly different purposes, with different demands for strength, speed, and fatigability. This diversity is possible because of differences in the expression of specific isoforms of various contractile and regulatory proteins (see Table 9-1).

Skeletal muscle is composed of slow-twitch and fast-twitch fibers

Some skeletal muscles must be resistant to fatigue and be able to maintain tension for relatively long periods, although they need not contract rapidly. Examples are muscles that maintain body posture, such as the soleus muscle of the lower part of the leg. In contrast, some muscles need to contract rapidly, yet infrequently. Examples are the extraocular muscles, which must contract rapidly to redirect the eye as an object of visual interest moves about.

Individual muscle fibers are classified as slow twitch (type I) or fast twitch (type II), depending on their rate of force development. These fiber types are also distinguished by their histological appearance and their ability to resist fatigue.

Slow-twitch fibers (Table 9-2) are generally thinner and have a denser capillary network surrounding them. These type I fibers also appear red because of a large amount of the oxygen-binding protein myoglobin (see pp. 648–649) within the cytoplasm. This rich capillary network together with myoglobin facilitates oxygen transport to the slow-twitch fibers, which mostly rely on oxidative metabolism for energy. The metabolic machinery of the slow-twitch fiber also favors oxidative metabolism because it has low glycogen content and glycolytic-enzyme activity but a rich mitochondrial and oxidative-enzyme content. Oxidative metabolism is slow but efficient, which makes these fibers resistant to fatigue.


Properties of Fast- and Slow-Twitch Muscle Fibers






Type I

Type IIa

Type IIx/IIb






Red (myoglobin)

Red (myoglobin)

White (low myoglobin)













Fast-twitch fibers differ among themselves with respect to fatigability. Some fast-twitch fibers are fatigue resistant (type IIa); they rely on oxidative metabolism and are quite similar to slow-twitch fibers with respect to myoglobin content (indeed, they are red) and metabolic machinery. One important difference is that fast-twitch oxidative fibers contain abundant glycogen and have a greater number of mitochondria than slow-twitch fibers do. These features ensure adequate ATP generation to compensate for the increased rate of ATP hydrolysis in fast-twitch fibers.

Other fast-twitch fibers are not capable of sufficient oxidative metabolism to sustain contraction. Because these fibers must rely on the energy that is stored within glycogen (and phosphocreatine), they are more easily fatigable. Fatigable fast-twitch fibers (type IIx/IIb) have fewer mitochondria and lower concentrations of myoglobin and oxidative enzymes. Because of their low myoglobin content, type IIb muscle fibers appear white. They are, however, richer in glycolytic-enzyme activity than other fiber types are.

In reality, slow- and fast-twitch fibers represent the extremes of a continuum of muscle fiber characteristics. Moreover, each whole muscle is composed of fibers of each twitch type, with one twitch type predominating. The differences between fiber types derive in large part from differences in isoform expression of the various contractile and regulatory proteins (see Table 9-1).

Differences in the rate of contraction, for example, may be directly correlated with the maximal rate of myosin ATPase activity. The human genome database lists 15 MYH genes that encode myosin heavy chains (MHCs). Expression of these genes and their splice variants differs among muscle types and with stage of development. Skeletal muscle expresses at least six MYH genes (MYH1 to MYH4, MYH8, MYH13). For the most part, a muscle fiber type expresses a single MHC type, the ATPase activity of which appears to correspond to the rate of contraction in that fiber type. Whereas most fibers express one MHC type, some fibers express a combination of two different types. These hybrid cells have rates of contraction that are intermediate between the two pure fiber types.

Differences in the rates and strength of contraction may also reflect differences in expression of types of myosin light chains or other components of the EC coupling, such as the SR Ca pump (i.e., the SERCA), calsequestrin, Ca2+-release channels, and troponin C (see Table 9-1). Furthermore, some regulatory proteins, such as phospholamban, are expressed in certain muscle types (i.e., slow-twitch skeletal, cardiac, smooth) and not the others.

One particularly interesting feature of muscle differentiation is that fiber-type determination is not static. Through exercise training or changes in patterns of neuronal stimulation, alterations in contractile and regulatory protein isoform expression may occur. For example, it is possible for a greater proportion of fast-twitch fibers to develop in a specific muscle with repetitive training. It is even possible to induce cardiac-specific isoforms in skeletal muscle, given appropriate stimulation patterns.

The properties of cardiac cells vary with location in the heart

Just as skeletal muscle consists of multiple fiber types, so too does heart muscle. The electrophysiological and mechanical properties of cardiac muscle vary with their location (i.e., atria versus conducting system versus ventricles). Moreover, even among cells within one anatomical location, functional differences may exist between muscle cells near the surface of the heart (epicardial cells) and those lining the interior of the same chambers (endocardial cells). As in skeletal muscle, many of these differences reflect differences in isoform expression of the various contractile and regulatory proteins. Although some of the protein isoforms expressed in cardiac tissue are identical to those expressed in skeletal muscle, many of the proteins have cardiac-specific isoforms (see Table 9-1). The MHC in heart, for example, exists in two isoforms, α and β, which may be expressed alone or in combination.

The properties of smooth-muscle cells differ markedly among tissues and may adapt with time

When one considers that smooth muscle has a broad range of functions, including regulating the diameter of blood vessels, propelling food through the gastrointestinal tract, regulating the diameter of airways, and delivering a newborn infant from the uterus, it is not surprising that smooth muscle is a particularly diverse type of muscle. In addition to being distinguished as unitary or multiunit muscle (see p. 243), smooth muscle in different organs diverges with respect to nerve and hormonal control, electrical activity, and characteristics of contraction.

Even among smooth-muscle cells within the same sort of tissue, important functional differences may exist. For example, vascular smooth-muscle cells within the walls of two arterioles that perfuse different organs may vary in their contractile response to various stimuli. Differences may even exist between vascular smooth-muscle cells at two different points along one arterial pathway.

The phenotype of smooth muscle within a given organ may change with shifting demands. The uterus, for example, is composed of smooth muscle—the myometrium (see Fig. 56-2)—that undergoes remarkable transformation during gestation as it prepares for parturition. In addition to hypertrophy, greater coupling develops between smooth-muscle cells via the increased formation of gap junctions. The cells also undergo changes in their expression of contractile protein isoforms. Changes in the expression of ion channels and hormone receptors facilitate rhythmic electrical activity. This activity is coordinated across the myometrium by propagation of action potentials and increases in [Ca2+]i via the gap junctions. These rhythmic, coordinated contractions develop spontaneously, but they are strongly influenced by the hormone oxytocin, levels of which increase just before and during labor and just after parturition.

These differences in smooth-muscle function among various tissues or even over the lifetime of a single cell probably reflect differences in protein composition. Indeed, in comparison to striated muscle, smooth-muscle cells express a wider variety of isoforms of contractile and regulatory proteins (see Table 9-1). This variety is a result of both multiple genes and variability among mRNA products of a gene (see pp. 96–97). This richness in diversity is likely to have important consequences for smooth-muscle cell function.

Smooth-muscle cells express a wide variety of neurotransmitter and hormone receptors

Perhaps one of the most impressive sources of diversity among smooth-muscle cells relates to differences in response to neurotransmitters, environmental factors, and circulating hormones. Smooth-muscle cells differ widely with respect to the types of cell-surface receptors that mediate the effects of these various mediators. In general, smooth-muscle cells each express a variety of such receptors, and receptor stimulation may lead to either contraction or relaxation. Many substances act via different receptor subtypes in different cells, and these receptor subtypes may act via different mechanisms. For example, whereas some neurotransmitter/hormone receptors may be ligand-gated ion channels (e.g., ATP-activated P2X receptor Ca2+ channel), other receptors are G protein–coupled receptors (e.g., adrenergic β2, muscarinic M2) that either act directly on targets or act via intracellular second messengers (e.g., cAMP, cGMP, or IP3 and DAG).

The list of neurotransmitters (see Table 20-7), hormones (see Table 20-8), and environmental factors (see Table 20-9) regulating the function of vascular smooth-muscle cells alone is vast. Identical stimuli, however, may result in remarkably different physiological responses by smooth muscle in different locations. For example, systemic arterial smooth-muscle cells relax when the oxygen concentration around them decreases, whereas pulmonary arterial smooth muscle contracts when local oxygen concentration decreases (see p. 687).

A summary comparison among muscle types is presented in Table 9-3.


Comparison of Properties among Muscle Types





Mechanism of excitation

Neuromuscular transmission (release of ACh, activating nicotinic ACh receptor)

Pacemaker depolarization, spread electrotonically via gap junctions

Synaptic transmission
Agonist-activated receptors
Electrical coupling
Pacemaker potentials

Electrical activity of muscle cell

Action potential spikes

Action potential plateaus

Action potential spikes, plateaus
Graded membrane potential changes
Slow waves

Ca2+ sensor

Troponin C

Troponin C


EC coupling

L-type Ca2+ channel (Cav1.1, DHP receptor) in T-tubule membrane mechanically activates Ca2+-release channel (RYR1) in SR membrane

Ca2+ entry via L-type Ca2+ channel (Cav1.2, DHP receptor) triggers Ca2+-induced Ca2+ release (sparks) via RYR2 in SR membrane

Ca2+ entry via voltage-gated Ca2+ channel, Cav1.2
Ca2+- or IP3-mediated Ca2+ release (sparks) via RYR3 or IP3R1, IP3R2, IP3R3 in SR membrane
Ca2+ entry through SOCs via Orai and TRP channels

Terminator of contraction

Breakdown of ACh by acetylcholinesterase
SR Ca2+ uptake

Action potential repolarization
SR Ca2+ uptake

SR Ca2+ uptake

Twitch duration

20–200 ms

200–400 ms

200 ms—sustained

Regulation of force

Frequency and multifiber summation

Regulation of calcium entry

Balance between MLCK phosphorylation and dephosphorylation
Latch state


Oxidative, glycolytic