AARS2 ameliorates myocardial ischemia via fine-tuning PKM2-mediated metabolism

AARS2, an alanyl-tRNA synthetase critical for protein translation, has an incompletely understood role in cardiac function. In this study, we demonstrate that cardiomyocyte-specific deletion of AARS2 in mice leads to marked cardiomyopathy characterized by impaired cardiac function, extensive fibrosis, and increased cardiomyocyte apoptosis. Conversely, cardiomyocyte-specific overexpression of AARS2 improved cardiac function and reduced fibrosis following myocardial infarction (MI), without affecting cardiomyocyte proliferation or coronary angiogenesis. Mechanistically, AARS2 overexpression reduced cardiomyocyte apoptosis and mitochondrial reactive oxygen TP-1454 species (ROS) production, while shifting cellular metabolism from oxidative phosphorylation toward glycolysis, thereby enhancing cardiomyocyte survival under ischemic and hypoxic stress. Ribosome profiling (Ribo-Seq) revealed that AARS2 overexpression enhances translation of pyruvate kinase M2 (PKM2) and increases the ratio of PKM2 dimers to tetramers, favoring glycolytic activity. Furthermore, treatment with the PKM2 activator TEPP-46 rescued cardiomyocyte apoptosis and cardiac fibrosis resulting from AARS2 deficiency. Collectively, these findings identify AARS2 as a key regulator of cardiomyocyte survival under ischemic stress through modulation of PKM2-dependent metabolic reprogramming, highlighting a novel cardioprotective AARS2–PKM2 signaling axis in the context of MI.