2. Academic Validation
  3. Lactylation of mTOR enhances autophagy in skeletal muscle during exercise

Lactylation of mTOR enhances autophagy in skeletal muscle during exercise

  • Cell Chem Biol. 2025 Nov 20;32(11):1367-1380.e5. doi: 10.1016/j.chembiol.2025.10.007.
Yan Li 1,  Lamei Xue 2,  Feijie Wang 3,  Yu Wang 2,  Yujie Sun 2,  Zhoumin Niu 4,  Shengnan Liu 4,  Ying Yan 4,  Siyi Shen 4,  Kuiliang Zhang 2,  Chenzhipeng Nie 2,  Mingcong Fan 2,  Mei Ma 4,  Yuting Wu 4,  Binrui Yang 3,  Jun Du 3,  Ben Zhou 4,  Duo Zhang 5,  Billy K C Chow 6,  Li Zhang 7,  Haifeng Qian 2,  Liang Chen 3,  Hao Ying 8,  Li Wang 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Food Science and Resource, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China. Electronic address: [email protected].
  • 2 State Key Laboratory of Food Science and Resource, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China.
  • 3 Healthy Aging Research Center, Nutrilite Health Institute, Amway (Shanghai) Innovation & Science Co., Ltd., Shanghai 201203, China.
  • 4 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 5 Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, USA.
  • 6 School of Biological Sciences, University of Hong Kong, Hong Kong, China.
  • 7 Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
  • 8 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Food Science and Resource, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China. Electronic address: [email protected].
PMID: 41223856 DOI: 10.1016/j.chembiol.2025.10.007
Abstract

Emerging evidence suggests that Autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle Autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of Autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte Lactate Dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired Autophagy. Our mechanistic study demonstrates that lactate enhances Autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle Autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle Autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.

Keywords

autophagy; exercise; lactylation; mTOR; skeletal muscle.

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