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

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 miR210 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.