Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

Summary The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β‐ AR ), and adenylyl cyclase ( AC ) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC 5 disruption, that is, knock out ( KO ) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC 5 KO . The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac‐ and skeletal muscle‐specific AC 5 KO 's, where exercise performance was no longer improved by the cardiac‐specific AC 5 KO , but was by the skeletal muscle‐specific AC 5 KO , and there was no difference in cardiac output during exercise in AC 5 KO vs. WT . Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT 1, FoxO3a, MEK , and the anti‐oxidant, Mn SOD were upregulated in AC 5 KO mice. The improved exercise in the AC 5 KO was blocked with either a SIRT 1 inhibitor, MEK inhibitor, or by mating the AC 5 KO with Mn SOD hetero KO mice, confirming the role of SIRT 1, MEK , and oxidative stress mechanisms. The Caenorhabditis elegans worm AC 5 ortholog, acy‐3 by RNA i, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC 5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.