A Novel nNOS Signaling Pathway Regulates Skeletal Muscle Size, Strength and Fatigue Resistance

Abstract

Nitric oxide (NO) is a highly versatile signaling molecule which participates in a broad array of pathways in the cardiovascular, immune and nervous systems. We present further evidence for this physiological diversity by identifying a novel nNOS signaling pathway in skeletal muscle. NO is synthesized by neuronal nitric oxide synthase mu isoenzyme (nNOSμ) in skeletal muscle. nNOSμ is found associated with the dystrophin‐associated glycoprotein complex and in a soluble pool. During investigation of the soluble nNOS pool, we identified a splice variant of nNOS called nNOSβ localized to the Golgi complex. Soluble guanylyl cyclase and protein kinase G also localized to the Golgi suggesting that a classical NO–cGMP signaling pathway functioned at the Golgi complex. Loss of nNOSβ activity resulted in reduced muscle mass with muscles exhibiting lower force‐generating capacity, even after correcting for decreased muscle size. Furthermore, the absence of nNOS decreased the ability of muscle to resist exercise‐induced fatigue. In summary, we have identified a novel nNOS‐signaling pathway that regulates skeletal muscle size and strength and provided the first evidence that differential targeting of nNOS isozymes facilitates the creation of spatially and functionally distinct nNOS signaling pathways by localized synthesis of an otherwise directionless free radical gas. Furthermore, these results make nNOSβ of potential relevance to myopathies and dystrophies where preventing the loss of muscle bulk and strength is of clinical importance.