Abstract
Regulation of the subcellular localization of nitric oxide synthases is important for conferring specificity to intracrine nitric oxide signaling. We report that two splice variants of nNOS, nNOSμ and nNOSβ, are differentially targeted to the sarcolemma and the Golgi complex in skeletal muscle, respectively. Sarcolemmal nNOSμ and Golgi nNOSβ?exhibit independent and overlapping functions in modulating the muscle phenotype. First, nNOSμ and NOSβ?differentially regulate skeletal muscle mass through sex‐specific mechanisms. Second, nNOSμ‐deficient skeletal muscles display increased susceptibility to contraction‐induced fatigue, independently of structural defects. However, muscles lacking both nNOSμ and nNOSβ display markedly exacerbated fatigue associated with specific force deficits, an aberrant microtubule cytoskeleton, fewer fatigue‐resistant type IIa fibers and greater numbers of fatigable type IIb fibers. Thus, Golgi nNOSβ appears to modulate susceptibility to contraction‐induced fatigue through alterations in muscle structural integrity and shifts in fiber composition. These data suggest that one function of alternative splicing of the NOS1 gene is the creation of isozyme‐specific signaling compartments. We conclude that sarcolemmal nNOSμ and Golgi nNOSβ? are critical regulators of skeletal muscle performance and that the spatial confinement of nNOS isozymes plays an important role in imparting specificity to NO signaling.
Published Version
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