Exercise training decreases lactylation and prevents myocardial ischemia–reperfusion injury by inhibiting YTHDF2
Xu, Gui E.; Yu, Pujiao; Hu, Yuxue; Wan, Wensi; Shen, Keting; Cui, Xinxin; Wang, Jiaqi; Wang, Tianhui; Cui, Caiyue; Chatterjee, Emeli; Li, Guoping; Cretoiu, Dragos; Sluijter, Joost P.G.; Xu, Jiahong; Wang, Lijun; Xiao, Junjie
(2024) Basic Research in Cardiology, volume 119, issue 4, pp. 651 - 671
(Article)
Abstract
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
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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.
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Keywords: Exercise, Lactylation, Myocardial ischemia–reperfusion injury, Physiological cardiac hypertrophy, YTHDF2, Physiology, Cardiology and Cardiovascular Medicine, Physiology (medical)
ISSN: 0300-8428
Publisher: D. Steinkopff-Verlag
Note: Publisher Copyright: © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2024.
(Peer reviewed)