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.

运动可以改善心脏功能和新陈代谢。尽管长期运动会导致循环和微环境代谢变化，但运动对蛋白质翻译后乳酰化修饰的影响及其功能相关性尚不清楚。在这里，我们报道乳酸可以通过提高蛋白质乳酰化水平和提高细胞内 N⁶-甲基腺苷 RNA 结合蛋白 YTHDF2 来调节心肌细胞变化。YTHDF2 的内在无序区域而不是 RNA m⁶A 结合活性是必不可少的，因为它通过上调 Ras GTP 酶激活蛋白结合蛋白 1 （G3BP1） 影响心肌细胞大小变化和氧葡萄糖剥夺/再氧合 （OGD/R） 刺激的细胞凋亡。运动诱导的生理性心脏肥大需要下调 YTHDF2。此外，心肌 YTHDF2 抑制减轻了缺血/再灌注诱导的急性损伤和病理重塑。我们在这里的结果将乳酸和乳酰化修饰与 RNA m⁶A 读取器 YTHDF2 联系起来，并强调了心肌细胞对运动反应的这种创新的转录后内在调节机制的生理重要性。减少乳酰化或抑制 YTHDF2/G3BP1 可能是一种很有前途的心脏病治疗策略。