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