Hyperactive Muscle mTORC1 Attenuates Functional Adaptations to Endurance Training Despite Alterations in Mitochondrial and Lipid Profiles

Mechanistic target of rapamycin complex I (mTORC1) is a key regulator of cell growth and metabolism, and its activity increases with aging. Hyperactivation of mTORC1 is associated with the pathology of sarcopenia and mitochondrial dysfunction. Exercise training has been shown to improve muscle quality and function in people with sarcopenia. However, it is unknown if hyperactive mTORC1 will alter exercise training-induced adaptations. In this study, we examined the effect of endurance training on muscle function and metabolism in a mouse model of hyperactive mTORC1 (DEP Domain-Containing Protein 5 muscle-specific knockout (DEPDC5 mKO)). After 8 weeks of exercise training, DEPDC5 mKO mice had increased mitochondrial activity and TA muscle mass, despite no change in physical function. Furthermore, DEPDC5 mKO mice had a trend for reduction in the phosphorylation of the mTORC1 downstream target, ribosomal protein S6, which may have contributed to the lack of functional adaptations. In addition, there was a reduction in triglycerides (TGs) and phosphatidylcholines (PCs) in DEPDC5 mKO mice, suggesting an increase in lipid fuel use and alterations in lipid membrane composition due to an increase in mitochondrial activity. We conclude that hyperactive mTORC1 in muscle may attenuate functional adaptations to endurance exercise training, despite increasing mitochondrial respiration and alterations in lipid metabolism.