Swim Exercise Mitigates <scp>BCAA</scp> ‐Induced Atrial Remodeling and <scp>AF</scp> Susceptibility via Inhibition of Bax‐Mediated Mitochondrial Apoptosis

Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, has been shown in our prior work to be mitigated by swim exercise. While accumulating evidence links elevated circulating branched-chain amino acids (BCAA) to cardiovascular disease, their specific involvement in AF pathogenesis and the anti-arrhythmic benefits conferred by exercise remain less understood. In this study, we investigated the effects of BCAA supplementation on AF susceptibility and the potential cardioprotective benefits of swim exercise. C57BL/6J mice were supplemented with 2% BCAA via drinking water, either alone or in combination with a swim exercise regimen (60 min/day, 5 days/week). After 16 weeks of BCAA supplementation, mice exhibited increased AF susceptibility, an effect attenuated by swim exercise. Electrical remodeling analysis revealed that BCAA supplementation enlarged the area and prolonged the duration of the P wave. In support of this, transcriptional profiling of ion channels indicated a tendency toward shortened action potentials following BCAA treatment. BCAA supplementation also induced noticeable atrial cardiomyocyte hypertrophy and fibrosis, hallmark features of atrial structural remodeling. Importantly, both electrical and structural remodeling induced by BCAA were mitigated by concurrent swim exercise. Mechanistic studies demonstrated that BCAA supplementation impaired systemic insulin sensitivity and activated Bax-mediated atrial apoptosis. Pharmacological inhibition of Bax with peptide V5 alleviated BCAA-induced cardiac apoptosis in primary neonatal rat cardiomyocytes. In conclusion, our results show that BCAA supplementation induces significant atrial remodeling and AF susceptibility in mice, effects that can be reversed by swim exercise, with Bax-mediated atrial apoptosis playing a crucial role in mediating this effect.