Lactylation of mTOR enhances autophagy in skeletal muscle during exercise

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.