Regular exercise enhances heart function and metabolism. The N6-methyladenosine (m⁶A) RNA modification is related to myocardial homeostasis, with the demethylase fat mass and obesity-associated protein (FTO) crucial for myocardial remodeling. However, its role in exercise-induced heart protection is unclear. We analyzed m⁶A levels and methylation enzymes to evaluate FTO changes in transverse aortic constriction (TAC) mice hearts after six weeks of treadmill exercise. Further in vivo experiments explored the effect of FTO. High-throughput sequencing identified the target gene enoyl-CoA delta isomerase 1 (Eci1). Cardiac-specific Eci1 knockout mice were used to assess the role of Eci1. The influence of FTO on Eci1 expression was explored by eliminating demethylase activity. The results showed that exercise increased FTO expression in TAC mice hearts. Reducing FTO in the heart diminishes exercise benefits. The differential m⁶A-modified genes in TAC mice hearts were enriched in fatty acid metabolism, with increased methylation of Eci1 m⁶A and decreased protein levels, leading to abnormal lipid accumulation. Exercise could reverse these effects. Eci1 knockout partially weakened exercise benefits. FTO regulated Eci1 expression via m⁶A modification, and inhibiting FTO demethylase activity blunted its protective effects on hypertrophic cardiomyocytes. Thus, FTO modulates Eci1 expression through m⁶A-dependent mechanisms, facilitates fatty acid metabolism and mitigates pressure overload-induced heart failure during exercise.

Most cardiovascular diseases are accompanied by cardiac remodeling, but physical exercise can mitigate and decelerate this process. Retinol-binding protein 4 (RBP4) has been associated with cardiovascular disease in both basic research and clinical settings. Therefore, the present study aimed to investigate the mechanism underlying RBP4 in exercise ameliorating cardiac remodeling. Our findings indicate that mice model of angiotensin Ⅱ (Ang Ⅱ)-induced cardiac hypertrophy exhibited elevated blood pressure, impaired cardiac function, increased myocardial fibrosis, and mitochondrial degradation, alongside elevated RBP4 levels in myocardial tissue. A 9-week aerobic exercise regimen improved these indexes and decreased RBP4 expression. The cell surface receptor stimulated by retinoic acid 6 (STRA6), which serves as a membrane receptor for RBP4, is implicated in the activation of the Wnt/β-catenin signaling pathway, with its knockdown potentially inhibiting this pathway. Our subsequent analyses identified a significant upregulation of the STRA6 protein in myocardial tissue of the mice model of cardiac hypertrophy. Further investigations showed that total β-catenin levels remained unchanged, there was an increase in nuclear β-catenin, which enhanced the expression of matrix metalloproteinase 7 (MMP7) and cyclooxygenase 2 (COX2). These alterations were reversed following exercise intervention. The results suggest that RBP4 enhances STRA6 expression in cardiac hypertrophy mice hearts and facilitates β-catenin nuclear translocation and transcriptional activity, leading to elevated levels of MMP7 and COX2 expression. Aerobic exercise appears to attenuate the myocardial inflammatory response by reducing RBP4 expression and inhibiting the Wnt/β-catenin pathway, thereby ameliorating Ang Ⅱ-induced cardiac remodeling.