Nitric oxide synthase in skeletal muscle fibers: a signaling component of the dystrophin-glycoprotein complex

The present review deals with the anatomical distribution, physiological im portance, and pathological implications of the neuronal-type nitric oxide s ynthase (nNOS) in skeletal muscle. Throughout the body, nNOS is located ben eath the sarcolemma of skeletal muscle fibers. In rodents, nNOS is enriched in type IIb muscle fibers, but is more homogenously distributed among type II and type I fibers in humans and subhuman primates. It is accumulated on the postsynaptic membrane at the neuromuscular junction. An increased conc entration of nNOS is noted at the sarcolemma of muscle spindle fibers, in p articular nuclear bag fibers, which belong to type I fibers. The associatio n of nNOS with the sarcolemma is mediated by the dystrophin-glycoprotein co mplex. Specifically, nNOS is linked to alpha 1-syntrophin through PDZ domai n interactions. Possibly, it also directly binds to dystrophin. The activit y and expression of nNOS are regulated by both myogenic and neurogenic fact ors. Besides acetylcholine, glutamate has also been shown to stimulate nNOS , probably acting through N-methyl-D-aspartate receptors, which are colocal ized with nNOS at the junctional sarcolemma. Functional studies have implic ated nitric oxide as a modulator of skeletal muscle contractility, mitochon drial respiration, carbohydrate metabolism, and neuromuscular transmission. A clinically relevant aspect of nNOS is its absence from the skeletal musc le sarcolemma of patients with Duchenne muscular dystrophy (DMD). A concept is presented which suggests that, as a consequence of the disruption of th e dystrophin-glyoprotein complex in DMD, nNOS fails to become attached to t he sarcolemma and is subject to downregulation in the cytosol.