The research team led by Dr. LI Yan and Dr. WANG Li from the School of Food Science and Technology/State Key Laboratory of Food Science and Resource at Jiangnan University, in collaboration with the research team led by Dr. YING Hao from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, has made a research progress in the field of exercise metabolism, which was published in Cell Chemical Biology on Nov. 11, 2025.

This study revealed that lactate produced by skeletal muscle during exercise can act as a crucial signaling molecule. Through the mechanism of lactylation modification, lactate directly modifies the intracellular mTOR protein, thereby inhibiting the activity of the mTORC1 complex and initiating the autophagy process in skeletal muscle, which is essential for skeletal muscle adaptation to exercise and the maintenance of metabolic health.

Exercise is beneficial for health, but its underlying molecular mechanisms remain to be fully elucidated. 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 not entirely clear.

Through close collaboration, the research team established a direct link between lactate elevation and autophagy activation, laying a new molecular foundation for understanding the benefits of exercise. The study found that in mice, lactate levels in skeletal muscle increased rapidly after acute exercise, preceding the activation of autophagy temporally. By constructing skeletal muscle-specific lactate dehydrogenase A (LDHA) knockout mice, the researchers confirmed that lactate is necessary for maintaining normal autophagy function and exercise capacity in skeletal muscle. Mice lacking lactate exhibited a range of issues, including impaired autophagy, reduced exercise capacity, muscle atrophy, and decreased insulin sensitivity.

To further uncover the molecular underpinnings, the research team turned their attention to mTORC1, a key negative regulator of autophagy. They discovered that lactate does not act through traditional signaling pathways but rather directly induces a novel post-translational modification—lactylation—on the mTOR protein itself. Utilizing techniques such as mass spectrometry, the team precisely identified a highly conserved lactylation site on the mTOR protein: lysine 921 (K921). To validate the function of this site, the researchers generated a mouse model with a mutation at this site (K921R). Intriguingly, 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. This demonstrates that lactylation of mTOR at K921 is the critical molecular switch connecting lactate signaling to autophagy activation. Further mechanistic studies revealed that this lactylation modification inhibits mTORC1 activity by promoting the recruitment of negative regulatory proteins TSC1 and the circadian protein PER2 to mTORC1. Additionally, the study found that this modification is also required for the effective inhibition of mTORC1 by AMPK, which is concurrently activated during exercise.

Based on this research, the team 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 subsequently relieves its inhibitory effect on autophagy initiation, ultimately activating autophagy to clear damaged organelles and maintain muscle health.

Physiological mechanism by which lactate regulates skeletal muscle autophagy through mTOR K921 lactylation modification. (Image provided by Dr. YING Hao’s group)

This study not only identified the lactylation modification of the mTOR protein and elucidated its physiological function for the first time, expanding the understanding of lactate’s role and the benefits of exercise, but more importantly, it revealed a novel signaling axis of “Exercise-Lactate-Autophagy”. This laid a solid theoretical foundation for the future development of new strategies aimed at improving muscle health and treating metabolic diseases by mimicking this mechanism.

Dr. LI Yan and Dr. WANG Li from the State Key Laboratory of Food Science and Resources, Jiangnan University, and Dr. YING Hao from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences are the corresponding authors of the paper.

This work was granted by projects funded by the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.

Paper link: https://doi.org/10.1016/j.chembiol.2025.10.007

Scientific Contact:
Dr. YING Hao
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: yinghao@sinh.ac.cn 

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn