Constitutively Active mTORC1 Signaling Modifies the Skeletal Muscle Metabolome and Lipidome Response to Exercise.

Abstract

A chronic increase in mTORC1 signaling is implicated in reduced longevity, altered metabolism, and mitochondrial dysfunction. Abnormal mTORC1 signaling may also be involved in the etiology of sarcopenia. To better understand the role of mTORC1 signaling in the regulation of muscle metabolism we developed an inducible muscle specific DEPDC5 knockout model which results in constitutively active mTORC1 signaling. We hypothesized that constitutively active mTORC1 signaling in skeletal muscle would alter the metabolomic and lipidomic response to an acute bout of exercise. Wild-type (WT) and DEPDC5 muscle specific knockout (KO) mice were studied at rest and following a 1 hr bout of treadmill exercise. Acute exercise induced an increased reliance on glycolytic and PPP metabolites in the muscle of mice with hyperactive mTORC1. Lipidomic analysis showed an increase in triacylglycerols (TGs) in KO mice. While exercise had a pronounced effect on muscle metabolism, the genotype effect was larger, indicating that constitutively active mTORC1 signaling exerts a dominant influence on metabolic and lipidomic regulation. We conclude that increased mTORC1 signaling shifts muscle metabolism toward greater reliance on non-oxidative energy sources in response to exercise. Understanding the mechanisms responsible for these effects may lead to the development of strategies for restoring proper mTORC1 signaling in conditions such as aging and sarcopenia.