Neuronal nitric oxide synthase (nNOS) splice variant function: Insights into nitric oxide signaling from skeletal...

Defects in neuronal nitric oxide synthase (nNOS) splice variant localization and signaling in skeletal muscle are a firmly established pathogenic characteristic of many neuromuscular diseases, including Duchenne and Becker muscular dystrophy (DMD and BMD, respectively). Therefore, substantial efforts have been made to understand and therapeutically target skeletal muscle nNOS isoform signaling. The purpose of this review is to summarize recent salient advances in understanding of the regulation, targeting, and function of nNOSμ and nNOSβ splice variants in normal and dystrophic skeletal muscle, primarily using findings from mouse models. The first focus of this review is how the differential targeting of nNOS splice variants creates spatially and functionally distinct nitric oxide (NO) signaling compartments at the sarcolemma, Golgi complex, and cytoplasm. Particular attention is given to the functions of sarcolemmal nNOSμ and limitations of current nNOS knockout models. The second major focus is to review current understanding of cGMP-mediated nNOS signaling in skeletal muscle and its emergence as a therapeutic target in DMD and BMD. Accordingly, we address the preclinical and clinical successes and setbacks with the testing of phosphodiesterase 5 inhibitors to redress nNOS signaling defects in DMD and BMD. In summary, this review of nNOS function in normal and dystrophic muscle aims to advance understanding how the messenger NO is harnessed for cellular signaling from a skeletal muscle perspective.