Mice lacking both nNOSmu and nNOSbeta exhibited severe myopathy, structural defects, and marked postexercise weakness compared to those lacking nNOSmu alone.
Does the deletion of nNOS splice variants affect skeletal muscle structure and exercise performance in mice?
The study identifies nNOSbeta as a critical regulator of skeletal muscle structural and functional integrity, demonstrating two functionally distinct nNOS microdomains that regulate exercise performance.
Signaling via the neuronal NOS (nNOS) splice variant nNOSmu is essential for skeletal muscle health and is commonly reduced in neuromuscular disease. nNOSmu 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 nNOSbeta, localized at the Golgi complex in mouse skeletal muscle cells. In contrast to muscles lacking nNOSmu alone, muscles missing both nNOSmu and nNOSbeta were severely myopathic, exhibiting structural defects in the microtubule cytoskeleton, Golgi complex, and mitochondria. Skeletal muscles lacking both nNOSmu and nNOSbeta were smaller in mass, intrinsically weak, highly susceptible to fatigue, and exhibited marked postexercise weakness. Our data indicate that nNOSbeta is a critical regulator of the structural and functional integrity of skeletal muscle and demonstrate the existence of 2 functionally distinct nNOS microdomains in skeletal muscle, created by the differential targeting of nNOSmu to the sarcolemma and nNOSbeta to the Golgi. We have previously shown that sarcolemmal nNOSmu matches the blood supply to the metabolic demands of active muscle. We now demonstrate that nNOSbeta 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.
Percival et al. (Mon,) conducted a other in Neuromuscular disease (mouse model). nNOSbeta and nNOSmu deficiency vs. nNOSmu deficiency alone was evaluated on Structural and functional integrity of skeletal muscle (myopathy, fatigue, weakness). Mice lacking both nNOSmu and nNOSbeta exhibited severe myopathy, structural defects, and marked postexercise weakness compared to those lacking nNOSmu alone.