FTO-Eci1 Axis Mediates Exercise-Induced Cardioprotection in Pressure Overload Mice

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 <i>Eci1</i> 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 <i>Eci1</i> m⁶A and decreased protein levels, leading to abnormal lipid accumulation. Exercise could reverse these effects. <i>Eci1</i> 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.