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

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

doi:10.1007/s00395-024-01044-2

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

Basic Res Cardiol. 2024 Apr 2. doi: 10.1007/s00395-024-01044-2. Online ahead of print.

Authors

Gui-E Xu^#^{1

2}, Pujiao Yu^#³, Yuxue Hu^#^{1

2}, Wensi Wan^#^{1

2}, Keting Shen^{1

2}, Xinxin Cui^{1

2}, Jiaqi Wang^{1

2}, Tianhui Wang^{1

2}, Caiyue Cui², Emeli Chatterjee⁴, Guoping Li⁴, Dragos Cretoiu^{5

6}, Joost P G Sluijter^{7

8}, Jiahong Xu⁹, Lijun Wang^{10

11}, Junjie Xiao^{12

13}

Affiliations

¹ Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Life Science, Shanghai University, Nantong, 226011, China.
² Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China.
³ Department of Cardiology, Shanghai Gongli Hospital, Shanghai, 200135, China.
⁴ Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁵ Department of Medical Genetics, Carol Davila University of Medicine and Pharmacy, 020031, Bucharest, Romania.
⁶ Materno-Fetal Assistance Excellence Unit, Alessandrescu-Rusescu National Institute for Mother and Child Health, 011062, Bucharest, Romania.
⁷ Department of Cardiology, Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3508GA, Utrecht, The Netherlands.
⁸ UMC Utrecht Regenerative Medicine Center, Circulatory Health Research Center, University Medical Center Utrecht, Utrecht University, Utrecht, 3508GA, The Netherlands.
⁹ Department of Cardiology, Shanghai Gongli Hospital, Shanghai, 200135, China. xujiahong@tongji.edu.cn.
¹⁰ Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Life Science, Shanghai University, Nantong, 226011, China. lijunwang@shu.edu.cn.
¹¹ Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China. lijunwang@shu.edu.cn.
¹² Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Life Science, Shanghai University, Nantong, 226011, China. junjiexiao@shu.edu.cn.
¹³ Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai, 200444, China. junjiexiao@shu.edu.cn.

^# Contributed equally.

PMID: 38563985
DOI: 10.1007/s00395-024-01044-2

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.

Keywords: Exercise; Lactylation; Myocardial ischemia–reperfusion injury; Physiological cardiac hypertrophy; YTHDF2.

Abstract

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