Loss of nNOS Signaling Exacerbates Dystrophic Pathology, but not Skeletal Muscle Fatigue in the mdx Mouse Model of Duchenne Muscular Dystrophy

Debilitating fatigue is common in muscle wasting diseases such as Duchenne Muscular Dystrophy (DMD). NO produced by nNOSμ and nNOSβ is a critical regulator of skeletal muscle fatigue. Levels of NOSμ are depleted in the skeletal muscles of DMD patients and may contribute to their fatigue. Increased nitric oxide (NO) levels in the mdx mouse (a model for DMD) significantly reduced dystrophic pathology; however, it is unclear whether the anti‐dystrophic effects of exogenous NO are due to activation of downstream targets of nNOSμ or nNOSβ or both. To address nNOS function in mdx muscle, mdx mice were engineered to lack residual nNOSμ and all nNOSβ nNOS‐deficient mdx muscles were smaller in size and showed evidence of increased inflammation. Tibialis anterior (TA) muscles from nNOS‐deficient mdx mice exhibited reduced maximal tetanic and specific force capacity. Unexpectedly, nNOS‐deficient mdx muscle exhibited increased susceptibility to injury by eccentric contractions. Also surprisingly, absence of both nNOS isozymes from mdx muscle did not affect muscle fatigue. In conclusion, the absence of fatigue in nNOS‐deficient mdx muscle suggests the existence of mechanisms that compensate for absent nNOS signaling. This novel compensatory mechanism may contribute to the mild phenotype of the mdx mouse compared to its DMD homologue. These data support the hypothesis that nNOS, particularly nNOSβ, modulates clinically relevant features of dystrophin‐deficient muscle. Funding sources: PPMD, MDA, NIH.