Loss of nNOS inhibits compensatory muscle hypertrophy and exacerbates inflammation and eccentric contraction-induced damage in mdx mice

Abstract

Approaches targeting nitric oxide (NO) signaling show promise as therapies for Duchenne and Becker muscular dystrophies. However, the mechanisms by which NO benefits dystrophin-deficient muscle remain unclear, but may involve nNOSß, a newly discovered enzymatic source of NO in skeletal muscle. Here we investigate the impact of dystrophin deficiency on nNOSß and use mdxmice engineered to lack nNOSμ and nNOSß to discern how the loss of nNOS impacts dystrophic skeletal muscle pathology. In mdx muscle, nNOSß wasmislocalized and its association with the Golgi complex was reduced. nNOS depletion from mdxmice prevented compensatory skeletal muscle cell hypertrophy, decreased myofiber central nucleation and increased focal macrophage cell infiltration, indicating exacerbated dystrophic muscledamage. Reductions inmuscle integrity in nNOS-null mdx mice were accompanied by decreases in specific force and increased susceptibility to eccentric contraction-induced muscle damage compared with mdx controls. Unexpectedly, muscle fatigue was unaffected by nNOS depletion, revealing a novel latent compensatory mechanism for the loss of nNOS in mdx mice. Together with previous studies, these data suggest that localization of both nNOSμ and nNOSß is disrupted by dystrophin deficiency. They also indicate that nNOS has amore complex role as amodifier of dystrophic pathology and broader therapeutic potential than previously recognized. Importantly, these findings also suggest nNOSß as a new drug target and provide a new conceptual framework for understanding nNOS signaling and the benefits of NO therapies in dystrophinopathies.