Various forms of muscular dystrophy involve defects in the dystrophin-glycoprotein complex. However, there are some types of muscular dystrophy that are associated with different mechanisms. For example, a defect in sarcolemmal repair, which is caused by the loss or mutation of the protein dysferlin, underlies limb-girdle muscular dystrophy 2B, leading to muscle wasting in the pelvic region. Other forms of muscular dystrophy, such as limb-girdle muscular dystrophy 2J and tibial muscular dystrophy, have been linked to defects in the protein titin (known as titinopathies). Additionally, mutations in the protease calpain 3, resulting in the loss of protease activity, have been implicated in certain types of muscular dystrophy, like limb-girdle muscular dystrophy 2A, possibly due to apoptosis.

Fig. 12.6 illustrates the organization of the thick filament. Myosin is a large protein consisting of six different polypeptides. It includes a pair of large heavy chains and two pairs of light chains. The heavy chains are wound together in an α-helical configuration, forming a long rod-like segment. The N-terminal portions of each heavy chain create a large globular head, which extends towards the actin thin filament and is responsible for actin binding. Myosin possesses ATPase activity located in the globular head, allowing it to hydrolyze ATP. Two pairs of light chains are associated with the globular head. The essential light chains are critical for myosin's ATPase activity, while the regulatory light chains can be phosphorylated by Ca++/calmodulin-dependent myosin light chain protein kinase, influencing myosin's interaction with actin.

Myosin filaments form through a tail-to-tail association of myosin molecules, resulting in a bipolar arrangement of the thick filament. The thick filament extends on both sides of the central bare zone through a head-to-tail association of myosin molecules, maintaining its bipolar organization centered on the M line. This bipolar arrangement is crucial for the contraction process, as it brings the Z lines closer together, shortening the sarcomere length. The mechanisms governing the highly organized structure of the myosin thick filament are not fully understood. However, it is believed that the cytoskeletal protein titin plays a role in the formation of a scaffold that organizes and aligns the thick filament within the sarcomere. Other proteins, such as myomesin and C protein, found in the thick filaments may also participate in the bipolar organization or packing of the thick filament.

The central nervous system controls skeletal muscle activity. Each skeletal muscle is innervated by an α motor neuron, with the cell bodies of these neurons located in the ventral horn of the spinal cord (Fig. 12.7). The motor axons exit through the ventral roots and reach the muscle via mixed peripheral nerves. Within the muscle, the motor nerves branch out, with each branch innervating a single muscle fiber. The neuromuscular junction, which forms a specialized cholinergic synapse, and the neuromuscular transmission process that generates an action potential in the muscle fiber are explained in further detail.
Althoughdefectsinthedystrophin-glycoproteincomplexareinvolvedinmanyformsofmusculardystrophy,someformsofmusculardystrophythatinvolveothermechanismshavebeenidentified.Specifically,adefectinsarcolemmarepair(attributedtoloss/mutationoftheproteindysferlin)appearstounderlieatleastoneformofmusculardystrophy(limb-girdle muscular dystrophy 2B, associatedwithmusclewastinginthepelvicregion).Defectsintheproteintitin(titinopathies)havebeenimplicatedinotherformsofmusculardystrophy(e.g.,limb-girdle muscular dystrophy 2J andtibial muscular dystrophy).Mutationsintheproteasecalpain 3 (resultinginlossofproteaseactivity)havealsobeenimplicatedinsometypesofmusculardystrophy(e.g.,limb-girdlemusculardystrophy2A),apparentlysecondarytoapoptosis.
Organization of the thick filament is shown in
Fig. 12.6 . Myosin is a large protein (≈480 kDa) that consists of six different polypeptides with one pair of large heavy chains (≈200 kDa) and two pairs of light chains (≈20 kDa). The heavy chains are wound together in an α-helical configuration to form a long rod-like segment, and the N-terminal portions of each heavy chain form a large globular head. The head region extends away from the thick filament toward the actin thin filament and is the portion of the molecule that can bind to actin. Myosin is also able to hydrolyze ATP, and ATPase activity is located in the globular head as well. Two pairs of light chains are associated with the globular head. One of these pairs of light chains, termed essential light chains, is crucial for the ATPase activity of myosin. The other pair of light chains, called regulatory light chains, can be phosphorylated by Ca++/calmodulin-dependent myosin light chain protein kinase, which can influence the interaction of myosin with actin (see the section “
Skeletal Muscle Types”).
Thus myosin ATPase activity occurs in the globular head of myosin and requires the presence of light chains (namely, the “essential” light chains).
Myosin filaments form by a tail-to-tail association of myosin molecules, which results in a bipolar arrangement of the thick filament. The thick filament then extends on either side of the central bare zone by a head-to-tail association of myosin molecules, thus maintaining the filament’s bipolar organization centered on the M line. Such a bipolar arrangement is critical for drawing the Z lines together (i.e., shortening the length of the sarcomere) during contraction. The mechanisms controlling this highly organized structure of the myosin thick filament are not clear, although the cytoskeletal protein titin is thought to participate in the formation of a scaffold for organization and alignment of the thick filament in the sarcomere. Additional proteins found in the thick filaments (e.g., myomesin and C protein) may also participate in the bipolar organization or packing of the thick filament (or both).
Control of Skeletal Muscle Activity
Skeletal muscle is controlled by the central nervous system. Specifically, each skeletal muscle is innervated by an α motor neuron. The cell bodies of α motor neurons are located in the ventral horn of the spinal cord (
Fig. 12.7 ). The motor axons exit via the ventral roots and reach the muscle through mixed peripheral nerves. The motor nerves branch in the muscle, and each branch innervates a single muscle fiber. The specialized cholinergic synapse that forms the neuromuscular junction and the neuromuscular transmission process that generates an action potential in the muscle fiber are described in