Mechanistic Role of Sestrin2 in Exercise-Mediated Cardioprotection Against Obesity-Related Cardiomyopathy

Exercise is one of the safe and effective methods to improve obesity and its complications, but the mechanism has not been fully elucidated. Sestrin2 (SESN2) is a stress-induced protein that protects cells from stress damage. The role and mechanism of SESN2 in the improvement of obesity-induced cardiac dysfunction by exercise are still unclear. Male C57BL/6J mice were used to prepare a high-fat diet-induced obesity mouse model and conducted aerobic exercise training. After training, echocardiography was used to evaluate the cardiac function of mice, and HE and Masson staining were used to assess the extent of cardiac damage. Cell experiments were conducted using the H9C2 cell line derived from embryonic rat hearts, with the intervention of palmitic acid ester and exogenous SESN2. We detected indicators related to myocardial cell damage, fibrosis, inflammation, and oxidative stress, as well as the activation level of the AMPK-PGC-1α signaling pathway. The results showed that aerobic exercise significantly inhibited myocardial fibrosis, inflammation, oxidative stress, and cell damage in HFD mice, upregulated cardiac SESN2 expression, and activated the AMPK-PGC-1α signaling pathway. Cell experiments have found that exogenous SESN2 pretreatment alleviates palmitate-induced injury, inflammation, and oxidative stress in H9C2 cardiomyocytes, and activates the AMPK-PGC-1α signaling pathway. This indicates that aerobic exercise significantly upregulates the expression of SESN2 and activates the AMPK-PGC-1α signaling pathway, which is potentially involved in alleviating myocardial inflammation, oxidative stress, cardiac fibrosis and cardiac dysfunction in HFD mice.