Muscle contraction is due to relative sliding of two sets of filaments identified by light and electron microscopy

Light microscopists have long recognized that the physiological unit of muscle, the cell or fiber, contains repeating structures known as sarcomeres that are separated from each other by dark lines called Z disks. Within each sarcomere, the A and I bands are seen; the A band, lying between two I bands, occupies the center of each sarcomere and is highly birefringent. Within the A band is a central, lighter zone, the H band, and in the center of the H band is the darker M band. The Z disk is at the center of the I band (Fig. 43-1). The difference in birefringence between the A and I bands produces the characteristic striated appearance of voluntary muscle when seen through the light microscope.

Figure 43-1

Schematic representation of the structure of striated muscle. Actin-containing thin filaments originate at Z lines. Note thick myosin-containing filaments that bear cross-bridges. The M disk lies in the center of the H band (see text). (From [46], with (more...)

The repeating optical characteristics of the A and I bands in each sarcomere reflect the regular arrangement of two sets of filaments. The thin filaments have a diameter of ~180 Å, appear to be attached to the Z bands and are found in the I band and part of the A band. The thick filaments have a diameter of ~150 Å, occupy the A band and are connected crosswise by material in the M band. In cross section, the thick filaments are arranged in a hexagonal lattice and the thin filaments occupy the centers of the triangles formed by the thick filaments.

With the identification of two sets of discontinuous filaments in the sarcomere came the recognition that (i) the two kinds of filaments become cross-linked only on excitation and (ii) contraction of muscle does not depend on shortening the length of the filaments but rather on the relative motion of the two sets of filaments, termed the sliding-filament mechanism. Thus, the length of the muscle depends on the length of the sarcomeres and, in turn, variation in sarcomere length is based on variation in the degree of overlap between the thin and thick filaments. High-resolution electron micrographs have shown that cross-bridges emanate from the thick filaments; in active muscle, these structures are responsible both for the links with thin filaments [1] and for generation of the force that produces fiber translocation.

Actin and myosin form the chief components of the thin and thick filaments, respectively

In addition, other proteins are found in the two sets of filaments. Tropomyosin and a complex of three subunits collectively called troponin are present in the thin filaments and play an important role in the regulation of muscle contraction. Although the proteins constituting the M and the Z bands have not been fully characterized, they include α-actinin and desmin as well as the enzyme creatine kinase and a number of other proteins [2]. A continuous elastic network of proteins, such as connectin, surround the actin and myosin filaments, providing muscle with a parallel passive elastic element.

Actin forms the backbone of the thin filaments. The thin filaments of muscle are linear polymers of slightly elongated, bilobar actin subunits, each about 4 × 6 nm, arranged in a helical fashion, with the longer dimension roughly at right angles to the filament axis [1]. Each monomer has a molecular weight of about 42,000 and contains a single nucleotide-binding site. Hydrolysis of ATP to ADP takes place during actin polymerization but is not involved in muscle contraction.

A wide variety of proteins interact with actin in both muscle and nonmotile cells. They may affect the polymerization-depolymerization of actin and are involved in the attachment of actin to other cellular structures, including the Z disks in muscle as well as membranes in both muscle and nonmuscle cells. One protein interacting with actin in the Z disk, α-actinin, is also a component of the rod-like bodies found in nemaline myopathy.

Myosin, the chief constituent of thick filaments, is a multisubunit protein. It is a highly asymmetrical molecule of ~500 kDa with an overall length of ~150 nm (Fig. 43-2) [3]. Its width varies between about 2 and 10 nm. In contrast to actin, myosin consists of several peptide subunits. Each myosin molecule contains two heavy chains of ~200 kDa; these extend through the length of the molecule. Over most of their length, the two chains are intertwined to form a double α-helical rod; at one end they separate, each forming an elongated globular portion. The two globular portions contain the sites responsible for ATP hydrolysis and interaction with actin. In addition to the two heavy chains, each myosin molecule contains four light chains of ~20 kDa. These light chains modulate myosin activity. Some can be covalently modified by kinases in the muscle cell.

Figure 43-2

Schematic representation of the structure of the myosin molecule. The rod portion of the molecule has a coiled α-helical structure. Hinge regions postulated in the mechanism of contraction are at the junctions of heavy chain meromyosin (HMM) S-1 (more...)

Myosin molecules form end-to-end aggregates involving the rod-like segments, which then grow into larger structures, that is, the thick filament [3]. The polarity of the myosin molecules is reversed on either side of the central portion of the filament. The globular ends of the molecules form projections, termed cross-bridges, on the aggregates that interact with actin. Conformational changes within this region, driven by ATP hydrolysis, provide the force that propels the movement of actin fibrils with respect to the myosin filament.

The ATPase activity of myosin itself is stimulated by Ca²⁺ and is low in Mg²⁺-containing media. The precise details of the conformational changes accompanying the hydrolysis of ATP and of the mechanism by which the free energy of ATP is converted into mechanical work are quite complicated [4] and will not be considered further here.

Tropomyosin and troponin regulate the interaction of actin and myosin

Tropomyosin and troponin are proteins located in the thin filaments, and together with Ca²⁺, they regulate the interaction of actin and myosin [5] (Fig. 43-3). Tropomyosin is an α-helical protein consisting of two polypeptide chains; its structure is similar to that of the rod portion of myosin. Troponin is a complex of three proteins. If the tropomyosin—troponin complex is present, actin cannot stimulate the ATPase activity of myosin unless the concentration of free Ca²⁺ exceeds about 10⁻⁶ M, while a system consisting solely of purified actin and myosin does not show Ca²⁺ dependence. Thus, the actin—myosin interaction is controlled by Ca²⁺ in the presence of the regulatory troponin—tropomyosin complex.

Figure 43-3

Model of arrangements of actin, tropomyosin and troponin in the thin filament. Note that troponin itself is a complex of three proteins. Tropomyosin is close to the groove of the actin filaments in relaxed muscle. Note that, according to current views, (more...)