The effects of daily dose of intense exercise on cardiac responses and atrial fibrillation.

Atrial fibrillation (AF) is a supraventricular tachyarrhythmia that is strongly associated with cardiovascular (CV) disease and sedentary lifestyles. Despite the benefits of exercise on overall health, AF incidence in high-level endurance athletes rivals that of CV disease patients, suggesting a J-shaped relationship with AF. To investigate the dependence of AF vulnerability on exercise, we varied daily swim durations (120, 180 or 240 min day-1 ) in 7-week-old male CD1 mice. We assessed mice after performing equivalent amounts of cumulative work during swimming (i.e. ∼700 L O2  kg-1 ), as determined from O2 consumption rates ( V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ ). The mean V ̇ O 2 ${\dot V_{{{\mathrm{O}}_2}}}$ during exercise increased progressively throughout the training period and was indistinguishable between the swim groups. Consistent with similar improvements in aerobic conditioning induced by swimming, skeletal muscle mitochondria content increased (P = 0.027) indistinguishably between exercise groups. Physiological ventricular remodelling, characterized by mild hypertrophy and left ventricular dilatation, was also similar between exercised mice without evidence of ventricular arrhythmia inducibility. By contrast, prolongation of daily swim durations caused progressive and vagal-dependent heart rate reductions (P = 0.008), as well as increased (P = 0.005) AF vulnerability. As expected, vagal inhibition prolonged (P = 0.013) atrial refractoriness, leading to reduced AF vulnerability, although still inducible in the 180 and 240 min swim groups. Accordingly, daily swim dose progressively increased atrial hypertrophy (P = 0.003), fibrosis (P < 0.001) and macrophage accumulation (P = 0.006) without differentially affecting the ventricular tissue properties. Thus, increasing daily exercise duration drives progressively adverse atrial-specific remodelling and vagal-dependent AF vulnerability despite robust and beneficial aerobic conditioning and physiological remodelling of ventricles and skeletal muscle. KEY POINTS: Previous studies have suggested that a J-shaped dose-response relationship exists between physical activity and cardiovascular health outcomes, with moderate exercise providing protection against many cardiovascular disease conditions, whereas chronic endurance exercise can promote atrial fibrillation (AF). We found that AF vulnerability increased alongside elevated atrial hypertrophy, fibrosis and inflammation as daily swim exercise durations in mice were prolonged (i.e. ≥180 min day-1 for 6 weeks). The MET-h week-1 (based on O2  measurements during swimming) needed to induce increased AF vulnerability mirrored the levels linked to AF in athletes. These adverse atria effects associated with excessive daily exercise occurred despite improved aerobic conditioning, skeletal muscle adaptation and physiological ventricular remodelling. We suggest that atrial-specific changes observed with exercise arise from excessive elevations in venous filling pressures during prolonged exercise bouts, which we argue has implications for all AF patients because elevated atrial pressures occur in most cardiovascular disease conditions as well as ageing which are linked to AF.

Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.

BACKGROUND: Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported. METHODS: Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux. RESULTS: WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner. CONCLUSIONS: Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.