GSE124902
Yap regulates lipid metabolism in skeletal muscle, and is perturbed by metabolic stress
The Hippo signalling pathway effector protein Yap positively regulates adult skeletal muscle mass and limits muscle atrophy in settings of neuromuscular perturbation. However, the mechanisms that lead to changes in muscle mass following alterations in Yap activity remain unclear. Here, we show in the limb musculature of adult mice, that Yap inhibition alters the expression of genes associated with metabolic capacity, with sustained inhibition of Yap resulting in incomplete metabolism of fatty acids. In the context of metabolic disease, we demonstrate that Yap levels are lower in both the glycolytic skeletal musculature of Lepr db/db mice and in the muscles of insulin-resistant humans. Restoring Yap levels in the striated muscles of Lepr db/db mice was associated with an increase in skeletal muscle oxidative potential and resulted in a reduction in adiposity and hepatic steatosis. Our findings provide the first evidence of a metabolic role for the Hippo pathway effector Yap in post-mitotic skeletal muscle cells and suggest that modulating Yap activity may be an approach to promote skeletal muscle lipid metabolism. Overall design: We treated the contralateral tibialis anterior (TA) muscles of 8 week old male C57BL/6 mice with AAV6:Yap-shRNA or AAV6:LacZ-shRNA vectors and performed RNA-sequencing after 7 days.  Control TA muscle was paired with the treated TA muscle in n=3 animals.