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we report on that astragaloside IV attenuates hypoxia-induced cardiac hypertrophy via calpain-1-mediated mTOR activation. This is significant because our findings could be applied in the clinic for that astragaloside IV is effective against hypoxia-induced cardiac hypertrophy, apoptosis and autophagy, it is likely to be of great interest to the clinicians. Astragaloside IV (AsIV), one of the main active ingredients of Astragalus membranaceus, has been reported to have cardioprotective effects. However, the effect and mechanism of AsIV on hypoxia-induced myocardial hypertrophy are unclear. The aim of this study was to evaluate the effect of AsIV on hypoxia-induced cardiac injury by focusing on calpain-1 (CAPN1)-mediated mTOR activation. Hypoxia-induced cardiac hypertrophy was carried out in CAPN1 knockout and wild-type C57BL/6 mice in vivo and in H9C2 cells in vitro. The effects of AsIV, CAPN1 inhibition and 3-MA on hypertrophy, apoptosis, autophagy, [Ca2+]i, and the expression levels of CAPN1 and mTOR were assayed in cardiac tissue and H9C2 cells. The results showed that AsIV, as well as CAPN1 knockout, attenuated cardiac hypertrophy, apoptosis, and autophagy induced by hypoxia in mice, effects that were confirmed at the H9C2 cell level. In addition, AsIV treatment, CAPN1 inhibition and 3-MA increased p-mTOR expression and decreased [Ca2+]i, accompanied by decreased CAPN1 expression. Furthermore, H9C2 cells overexpressing CAPN1 with lentivirus infection aggravated hypoxia-induced myocardial hypertrophy, apoptosis, and p-mTOR inhibition. Notably, the effects of CAPN1 overexpression on cardiac injury and p-mTOR inhibition were reversed by AsIV treatment. In summary, our data indicated that AsIV could ameliorate hypoxia-induced cardiac hypertrophy by inhibiting apoptosis and autophagy via CAPN1-mediated mTOR activation.