Exercise training decreases lactylation and prevents myocardial ischemia–reperfusion injury by inhibiting YTHDF2

• DOI: 10.1007/s00395-024-01044-2
• Publication Date: 2024-04-02T08:01:47Z
• Authors: Gui-e Xu; Pujiao Yu; Yuxue Hu; Wensi Wan; Keting Shen; Xinxin Cui; Jiaqi Wang; Tianhui Wang; Caiyue Cui; Emeli Chatterjee; Guoping Li; Dragos Cretoiu; Joost P. G. Sluijter; Jiahong Xu; Lijun Wang; Junjie Xiao
• Keywords: Male; 0303 health sciences; Physiology; Myocardial ischemia–reperfusion injury; Physiological cardiac hypertrophy; RNA-Binding Proteins; Myocardial Reperfusion Injury; Apoptosis; Lactylation; Rats; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; YTHDF2; Physiology (medical); Physical Conditioning, Animal; Animals; Myocytes, Cardiac; Cardiology and Cardiovascular Medicine; Exercise; Protein Processing, Post-Translational

Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N6-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m6A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m6A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.