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02.04.2024 | Original Contribution

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

verfasst von: 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

Erschienen in: Basic Research in Cardiology

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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 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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Titel: Exercise training decreases lactylation and prevents myocardial ischemia–reperfusion injury by inhibiting YTHDF2
verfasst von: 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
Publikationsdatum: 02.04.2024
Verlag: Springer Berlin Heidelberg
Erschienen in: Basic Research in Cardiology
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-024-01044-2

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