Soluble guanylyl cyclase regulates skeletal muscle fiber type plasticity, fatigue resistance and whole body insulin resistance

摘要: Pathogenic defects in NO-cGMP signaling drive skeletal muscle dysfunction Duchenne muscular dystrophy (DMD). These arise from decreased nNOS and guanylyl cyclase (GC) activity loss of spatial control NO production. Therapeutics such as sildenafil that amplify reduce DMD patients mouse models making GC cGMP attractive therapeutic targets. However, functions are poorly defined hindering therapy development. To remove this barrier, we investigated the muscle. We report α1β1 soluble (sGC) is primary source muscle. sGC expression was greater oxidative muscles suggesting a synthesis capacity muscle-specific differences function. Interestingly, exhibited partial dependence. Analyses subcellular localization revealed pool at cis-Golgi complex cells. α2β1 localized to microvasculature. Muscles lacking functional α1 subunit (α1β1 deficient) reduced fatigue resistance normal hypertrophic growth. Surprisingly, deficiency had no impact on mitochondrial content density may not be tightly regulated by previously thought. modest effect ATP synthesis. Also, triggered type IIA IIX fiber shift. Although shift unlikely significantly enhance fatigability, it insulin metabolism because positively correlates with insensitivity. Indeed, null mice gender-specific whole body sensitivity consistent reports effects but glucose tolerance indicating compensatory changes metabolism. In summary, these findings argue through plays important roles specification suggest target for mitigating DMD. data also disruption contribute understood metabolic patients. By showing reductions promote fatigue, resistance, new insights how decreases development disease, particularly over time. Importantly, results potential resistance.