Exercise-Induced miR-210 Promotes Cardiomyocyte Proliferation and Survival and Mediates Exercise-Induced Cardiac Protection against Ischemia/Reperfusion Injury

Yihua Bei; Hongyun Wang; Yang Liu; Zhuhua Su; Xinpeng Li; Yujiao Zhu; Ziyi Zhang; Mingming Yin; Chen Chen; Lin Li; Meng Wei; Xiangmin Meng; Xuchun Liang; Zhenzhen Huang; Richard Yang Cao; Lei Wang; Guoping Li; Dragos Cretoiu; Junjie Xiao

doi:10.34133/research.0327

Exercise-Induced miR-210 Promotes Cardiomyocyte Proliferation and Survival and Mediates Exercise-Induced Cardiac Protection against Ischemia/Reperfusion Injury

Research (Wash D C). 2024 Feb 26:7:0327. doi: 10.34133/research.0327. eCollection 2024.

Authors

Yihua Bei^{1

2

3}, Hongyun Wang^{1

2

3}, Yang Liu⁴, Zhuhua Su^{1

2

3}, Xinpeng Li^{2

3

5}, Yujiao Zhu^{1

2

3}, Ziyi Zhang^{1

2

3}, Mingming Yin^{1

2}, Chen Chen^{1

2}, Lin Li^{1

2}, Meng Wei^{1

2}, Xiangmin Meng¹, Xuchun Liang^{1

2}, Zhenzhen Huang^{1

2}, Richard Yang Cao⁶, Lei Wang⁷, Guoping Li⁸, Dragos Cretoiu^{9

10}, Junjie Xiao^{1

2

3}

Affiliations

¹ Institute of Geriatrics ( Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong) and School of Life Science, Shanghai University, Nantong 226011, China.
² Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), Shanghai University, Shanghai 200444, China.
³ Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine, Shanghai University, Shanghai 200444, China.
⁴ Department of Cardiology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
⁵ School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
⁶ Cardiac Rehabilitation Program, Shanghai Xuhui Central Hospital/Zhongshan-Xuhui Hospital, Fudan University/Shanghai Clinical Research Center, Shanghai 200031, China.
⁷ Department of Rehabilitation Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁸ Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁹ Department of Medical Genetics, Carol Davila University of Medicine and Pharmacy, Bucharest 020031, Romania.
¹⁰ Materno-Fetal Assistance Excellence Unit, Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest 011062, Romania.

Abstract

Exercise can stimulate physiological cardiac growth and provide cardioprotection effect in ischemia/reperfusion (I/R) injury. MiR-210 is regulated in the adaptation process induced by exercise; however, its impact on exercise-induced physiological cardiac growth and its contribution to exercise-driven cardioprotection remain unclear. We investigated the role and mechanism of miR-210 in exercise-induced physiological cardiac growth and explored whether miR-210 contributes to exercise-induced protection in alleviating I/R injury. Here, we first observed that regular swimming exercise can markedly increase miR-210 levels in the heart and blood samples of rats and mice. Circulating miR-210 levels were also elevated after a programmed cardiac rehabilitation in patients that were diagnosed of coronary heart diseases. In 8-week swimming model in wild-type (WT) and miR-210 knockout (KO) rats, we demonstrated that miR-210 was not integral for exercise-induced cardiac hypertrophy but it did influence cardiomyocyte proliferative activity. In neonatal rat cardiomyocytes, miR-210 promoted cell proliferation and suppressed apoptosis while not altering cell size. Additionally, miR-210 promoted cardiomyocyte proliferation and survival in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and AC16 cell line, indicating its functional roles in human cardiomyocytes. We further identified miR-210 target genes, cyclin-dependent kinase 10 (CDK10) and ephrin-A3 (EFNA3), that regulate cardiomyocyte proliferation and apoptosis. Finally, miR-210 KO and WT rats were subjected to swimming exercise followed by I/R injury. We demonstrated that miR-210 crucially contributed to exercise-driven cardioprotection against I/R injury. In summary, this study elucidates the role of miR-210, an exercise-responsive miRNA, in promoting the proliferative activity of cardiomyocytes during physiological cardiac growth. Furthermore, miR-210 plays an essential role in mediating the protective effects of exercise against cardiac I/R injury. Our findings suggest exercise as a potent nonpharmaceutical intervention for inducing miR-210, which can alleviate I/R injury and promote cardioprotection.