A recent study from the lab of Blake Rasmussen, PhD, and published in the Journal of Applied Physiology provides new insights into how heightened mTORC1 activity in muscle influences the body’s response to endurance exercise. The researchers found that while exercise improved mitochondrial activity and altered muscle lipid metabolism, excessive mTORC1 signaling limited gains in physical performance, highlighting an important factor that may affect exercise adaptations during aging.
Dr. Rasmussen is Professor and Chair of the Department of Cellular & Integrative Physiology and an investigator at the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Hyperactive muscle mTORC1 attenuates functional adaptations to endurance training despite alterations in mitochondrial and lipid profiles
Hanna Kalenta, Erik D Marchant, Sean P Kilroe, Rosario Maroto, Jacquelyn T May, Vladislav Bugay, Trevor B Romsdahl, Jennifer J Linares, Mandy R Hinojosa, Zhao Lai, William K Russell, Blake B Rasmussen
J Appl Physiol (1985). 2026 May 1;140(5):1338-1354. doi: 10.1152/japplphysiol.00730.2025. Epub 2026 Apr 14.
Abstract:
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 wk of exercise training, DEPDC5 mKO mice had increased mitochondrial activity and tibialis anterior (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.
NEW & NOTEWORTHY Endurance exercise training in mice with hyperactive muscle mechanistic target of rapamycin complex I (mTORC1) was associated with increase in mitochondrial activity and TA muscle mass despite lack of changes in physical function. These findings could be attributed to altered autophagy-related signaling and a reduction in the phosphorylation of ribosomal protein S6, downstream target of mTORC1, after exercise training in DEPDC5 mKO mice. Reduction in phosphatidylcholines (PCs) and triglycerides (TGs) may suggest an increase in lipid fuel use and alterations in lipid membrane composition due to an increase in mitochondrial activity.
Keywords: exercise; mTORC1; metabolism; mitochondria; muscle.