Anya Kalenta, a final year PhD student, has published her first first-author publication. In this study, they investigated how an acute bout of treadmill running alters the skeletal muscle metabolome and lipidome in mice with hyperactive mTORC1 signaling. Anya is a PhD student in the lab of Blake Rasmussen, PhD at the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Constitutively active mTORC1 signaling modifies the skeletal muscle metabolome and lipidome response to exercise
Hanna Kalenta, Sean P Kilroe, Trevor B Romsdahl, Erik D Marchant, Rosario Maroto, Jennifer J Linares, William K Russell, Blake B Rasmussen
J Appl Physiol (1985). 2025 May 1;138(5):1173-1186. doi: 10.1152/japplphysiol.00987.2024. Epub 2025 Apr 11.
Abstract:
A chronic increase in the Mammalian Target of Rapamycin Complex 1 (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 knockout model of DEP domain-containing 5 protein (DEPDC5 mKO), 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 h bout of treadmill exercise. Acute exercise induced an increased reliance on glycolytic and pentose phosphate pathway (PPP) metabolites in the muscle of mice with hyperactive mTORC1. Lipidomic analysis showed an increase in triglycerides (TGs) in KO mice. Although 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 nonoxidative 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. NEW & NOTEWORTHY This study demonstrates that hyperactive mTORC1 alters the muscle metabolomic and lipidomic response to exercise, with genotype having a larger effect than exercise. Knockout mice exhibited an increase in reliance on glycolysis and pentose phosphate pathway and an increase in triglyceride turnover. Wild-type mice primarily showed an increase in utilization of TCA cycle and lipid metabolism intermediates.
Keywords: exercise; lipidomics; mTORC1; metabolomics; muscle.