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

Author:

Zhang Zongwang1,Zheng Lixia1,Chen Yang1,Chen Yuanyuan1,Hou Junjie2,Xiao Chenglu2,Zhu Xiaojun1,Zhao Shi-Min3,Xiong Jing-Wei12ORCID

Affiliation:

1. Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Academy for Advanced Interdisciplinary Studies, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University

2. School of Basic Medical Sciences and The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University

3. Obstetrics and Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University

Abstract

AARS2, an alanyl-tRNA synthase, is essential for protein translation, but its function in mouse hearts is not fully addressed. Here, we found that cardiomyocyte-specific deletion of mouse AARS2 exhibited evident cardiomyopathy with impaired cardiac function, notable cardiac fibrosis and cardiomyocyte apoptosis. Cardiomyocyte-specific AARS2 overexpression in mice improved cardiac function and reduced cardiac fibrosis after myocardial infarction (MI), without affecting cardiomyocyte proliferation and coronary angiogenesis. Mechanistically, AARS2 overexpression suppressed cardiomyocyte apoptosis and mitochondrial reactive oxide species production, and changed cellular metabolism from oxidative phosphorylation toward glycolysis in cardiomyocytes, thus leading to cardiomyocyte survival from ischemia and hypoxia stress. Ribo-Seq revealed that AARS2 overexpression increased pyruvate kinase M2 (PKM2) protein translation and the ratio of PKM2 dimers to tetramers that promote glycolysis. Additionally, PKM2 activator TEPP-46 reversed cardiomyocyte apoptosis and cardiac fibrosis caused by AARS2 deficiency. Thus, this study demonstrates that AARS2 plays an essential role in protecting cardiomyocytes from ischemic pressure via fine-tuning PKM2-mediated energy metabolism, and presents a novel cardiac protective AARS2-PKM2 signaling during the pathogenesis of MI.

Publisher

eLife Sciences Publications, Ltd

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