Hyperactivation of autophagy contributes to high-intensity exercise-induced atrial fibrillation by activating cardiac necroptosis and inflammatory responses.

Abstract

OBJECTIVE: Our previous research indicated that moderate exercise protected against atrial fibrillation (AF) susceptibility in mice. However, the precise dose-dependent effects of exercise intensity on AF and the key regulatory mechanisms involved remained unclear. METHODS: C57BL/6 J mice were subjected to an 8-week exercise regimen consisting of either moderate-intensity exercise (60 min/session, once daily) or high-intensity exercise (90 min/session, twice daily). AF susceptibility, atrial electrical/structural remodeling, and molecular mechanisms were assessed. To investigate the role of autophagy in AF pathogenesis, the autophagy inhibitor 3-Methyladenine (3-MA; 15mg/kg/day) was administered to a subset of mice. RESULTS: High-intensity exercise for 5 weeks enhanced AF susceptibility in mice, whereas moderate exercise transiently reduced AF susceptibility during the first 3 weeks, an effect that diminished with prolonged training. High-intensity exercise induced pronounced electrical remodeling in the atria, manifesting as prolonged P-wave duration and PR interval, along with gap junction dysfunction. Additionally, it triggered substantial structural remodeling, including left atrial dilation and enhanced fibrosis. Pathophysiological investigation revealed that high-intensity exercise boosted systemic inflammation, atrial cardiomyocyte autophagy, and necroptosis, without affecting atrial apoptosis or oxidative stress. Importantly, inhibiting autophagy via 3-MA partially reversed high-intensity exercise -induced AF susceptibility and atrial remodeling by mechanistically suppressing necroptosis and inflammation signaling. CONCLUSION: Our findings highlight a pivotal role of autophagy hyperactivation in AF pathogenesis, likely mediated through necroptosis and subsequent inflammatory response. This study offers novel insights into the dose-dependent effects of exercise on AF and identifies autophagy as a potential therapeutic target.