Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. Autophagy is an intracellular “housekeeping” process that clears damaged components and is vital for muscle function and exercise. During exercise, lactate levels in muscle rise rapidly, yet its physiological functions are unclear.

In a study published in Cell Chemical Biology, a team led by Dr. LI Yan and Dr. WANG Li from Jiangnan University and a team led by Dr. YING Hao from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences revealed the physiological action of lactate in regulating mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.

The researchers showed a direct link between lactate elevation and autophagy activation. They found that after acute exercise, lactate levels in skeletal muscle of mice increased rapidly and was prior to the activation of autophagy temporally. They then confirmed that lactate was necessary for maintaining normal autophagy function and exercise capacity in skeletal muscle in skeletal muscle-specific lactate dehydrogenase A knockout mice. Mice lacking lactate showed abnormalities including impaired autophagy, reduced exercise capacity, muscle atrophy, and decreased insulin sensitivity.

To uncover the molecular mechanism, the researchers focused on mTORC1, a key negative regulator of autophagy. They discovered that lactate did not act through traditional signaling pathways but rather directly induced a novel post-translational modification—lactylation—on the mTOR protein itself. Through techniques such as mass spectrometry, the researchers identified a highly conserved lactylation site on the mTOR protein: lysine 921 (K921).

In a mouse model with a mutation at this site (K921R), the researchers found that when the K921 site of mTOR could not be lactylated, exercise failed to effectively inhibit mTORC1 activity, leading to impaired autophagy induction. These mice exhibited muscle dysfunction similar to that observed in lactate-deficient mice, which demonstrated that the lactylation of mTOR at K921 is the critical molecular switch connecting lactate signaling to autophagy activation.

This lactylation modification was found to inhibit mTORC1 activity by promoting the recruitment of negative regulatory proteins TSC1 and the circadian protein PER2 to mTORC1. In addition, this modification was found to be required for the effective inhibition of mTORC1 by AMPK, which was concurrently activated during exercise.

Based on these findings, the researchers proposed the following working hypothesis: Exercise leads to a rapid increase in skeletal muscle lactate; the elevated lactate directly lactylates the K921 site of the mTOR protein; this modification, in concert with AMPK activation, collaboratively inhibits mTORC1 activity; the reduced mTORC1 activity relieves its inhibitory effect on autophagy initiation, activating autophagy to clear damaged organelles and maintain muscle health.

This study identifies the lactylation modification of the mTOR protein and elucidates its physiological function, expanding the understanding of lactate’s role and the benefits of exercise. It lays a theoretical foundation for the development of new strategies aimed at improving muscle health and treating metabolic diseases.