PGC-1α Regulates Exercise Intensity-Dependent Atrial Remodeling and Fibrillation in Rats.

Abstract

Exercise has well-documented cardiovascular benefits, but excessive training has been associated with an increased risk of atrial fibrillation (AF). The molecular mechanisms linking exercise intensity to atrial remodeling and AF susceptibility remain incompletely understood. Here, we investigated the effects of varying treadmill exercise intensities on atrial structure, metabolism, and electrophysiology in rats. AF inducibility was assessed using burst pacing, and atrial dimensions were evaluated by echocardiography. Histology was performed to quantify fibrosis and lipid accumulation. Metabolic and signaling pathways were examined through biochemical assays and Western blotting. We found that exercise intensity exhibited a nonlinear, J-shaped relationship with AF susceptibility. Moderate training (B-Mod) resulted in the lowest AF incidence and duration, whereas high-intensity training (B-Int) produced frequent and sustained episodes. Echocardiography revealed atrial enlargement in sedentary (B-Sed) and B-Int groups but preserved dimensions in B-Mod. Histological analysis showed marked fibrosis in B-Int but only minimal changes in B-Mod, along with progressive lipid deposition and impaired glucose handling at higher intensities. Importantly, PGC-1α expression paralleled AF susceptibility, peaking at moderate intensity, and was associated with decreased TGF-β and enhanced MAPK signaling. Pharmacological inhibition of PGC-1α with SR-18292 abolished these protective adaptations, increased fibrosis, disrupted glucose-lipid balance, and eliminated the correlation between Kv1.5 expression and AF resistance. In summary, moderate-intensity exercise protects against AF by optimizing atrial remodeling, metabolism, and electrophysiology through PGC-1α-dependent pathways. Both insufficient and excessive training impair these adaptations, increasing AF susceptibility. These findings identify PGC-1α as a central regulator of atrial health and a potential therapeutic target for AF prevention.