Project description:The Hippo signalling pathway effector Yap positively regulates adult skeletal muscle mass. However, the biological processes that are modulated by Yap in skeletal muscle remain elusive. Using an integrated transcriptomics and proteomics approach, we define the transcriptional programme regulated by Yap in adult skeletal muscle and demonstrate that Yap is a regulator of metabolic substrate utilisation. Inhibition of Yap in mammalian skeletal muscle results in increased, but incomplete, oxidation of fatty acids and features of lipotoxicity. In line with these findings, we demonstrate that Yap abundance is reduced in the skeletal musculature of obese db/db mice, and in muscle biopsies from obese, insulin-resistant humans where YAP levels positively correlate with whole-body metabolic flexibility. Increasing Yap abundance in the striated muscle of db/db mice attenuated the accumulation of fat mass and development of hepatic steatosis. Our findings demonstrate a vital role for Yap in skeletal muscle as a mediator of metabolic substrate utilisation. Modulating Yap activity in skeletal muscle warrants consideration as part of comprehensive approaches to treat metabolic disease.
Project description:The Hippo signalling pathway effector Yap positively regulates adult skeletal muscle mass. However, the biological processes that are modulated by Yap in skeletal muscle remain elusive. Using an integrated transcriptomics and proteomics approach, we define the transcriptional programme regulated by Yap in adult skeletal muscle and demonstrate that Yap is a regulator of metabolic substrate utilisation. Inhibition of Yap in mammalian skeletal muscle results in increased, but incomplete, oxidation of fatty acids and features of lipotoxicity. In line with these findings, we demonstrate that Yap abundance is reduced in the skeletal musculature of obese db/db mice, and in muscle biopsies from obese, insulin-resistant humans where YAP levels positively correlate with whole-body metabolic flexibility. Increasing Yap abundance in the striated muscle of db/db mice attenuated the accumulation of fat mass and development of hepatic steatosis. Our findings demonstrate a vital role for Yap in skeletal muscle as a mediator of metabolic substrate utilisation. Modulating Yap activity in skeletal muscle warrants consideration as part of comprehensive approaches to treat metabolic disease.
