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

  • Int Immunopharmacol. 2026 Jan 15:169:116024. doi: 10.1016/j.intimp.2025.116024.
Yuping Fu  1 ,  Lingyan Jin  2 ,  Yudi Zhang  2 ,  Haoyu Gong  2 ,  Yifeng Zhang  3 ,  Peng Liu  2 ,  Tiannan Jiang  4 ,  Xinghua Qin  5 ,  Qiangsun Zheng  6
Affiliations
  • 1. Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 2. Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 3. School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China.
  • 4. Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
  • 5. School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China. Electronic address: [email protected].
  • 6. Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China. Electronic address: [email protected].
PMID: 41397335 DOI: 10.1016/j.intimp.2025.116024
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.

Keywords
Atrial fibrillation; Autophagy; High-intensity exercise; Inflammation; Necroptosis.
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