Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle

Signaling via the neuronal NOS (nNOS) splice variant nNOS mu is essential for skeletal muscle health and is commonly reduced in neuromuscular disease. nNOS mu is thought to be the predominant source of NO in skeletal muscle. Here we demonstrate the existence of what we believe to be a novel signaling pathway, mediated by the nNOS splice variant nNOS beta, localized at the Golgi complex in mouse skeletal muscle cells. In contrast to muscles lacking nNOS mu alone, muscles missing both nNOS mu and nNOS beta were severely myopathic, exhibiting structural defects in the microtubule cytoskeleton, Golgi complex, and mitochondria. Skeletal muscles lacking both nNOS mu and nNOS beta were smaller in mass, intrinsically weak, highly susceptible to fatigue, and exhibited marked postexercise weakness. Our data indicate that nNOS beta is a critical regulator of the structural and functional integrity of skeletal muscle and demonstrate the existence of 2 functionally distinct nNOS micro-domains in skeletal muscle, created by the differential targeting of nNOS mu to the sarcolemma and nNOS beta to the Golgi. We have previously shown that sarcolemmal nNOS mu matches the blood supply to the metabolic demands of active muscle. We now demonstrate that nNOS beta simultaneously modulates the ability of skeletal muscle to maintain force production during and after exercise. We conclude therefore that nNOS splice variants are critical regulators of skeletal muscle exercise performance.