Endurance Exercise-induced Anabolic Balance And Redox Buffering Capacity Is Associated With Mitochondrial Fusion

PURPOSE: Endurance exercise has been known to be an important activator of anabolism for physiological ventricular hypertrophy, a regulator of redox balance, and a promotor of mitochondrial remodeling. However, molecular mechanisms of how these elements in the heart interact to adjust cardiac function via EE remain unclear. This study examined the interrelationship between anabolic signaling regulations (an AKT-mTOR-p70s6k-PP2A axis), redox regulatory systems (antioxidant enzymes and lipid and protein oxidation), and mitochondrial turnover regulation (fusion and fission). METHODS: Sixteen C57BL/6 mice were randomly assigned to either endurance exercise (EE, n = 8) or control sedentary group (CON, n = 8). EE mice performed 60 min of treadmill running at 15 m/min (70-80% VO2 max) on a 0% grade 5 days per week for 6 weeks. Hearts were excised and collected immediately, 1 hour after the final exercise session. One section of tissues from the left ventricular free wall was homogenized for isolating mitochondria and cytosol, and the other section was homogenized to collect whole tissue lysate for Western blot analyses. RESULTS: Our data showed that autophagy coincided with anabolic (AKT and mTOR) and catabolic (AMPK) signaling activation. Interestingly, despite mTOR activation, activities of mTOR downstream target p70s6k were downregulated via enhanced protein phosphatase 2A activities. More importantly, our data revealed that EE-induced reduced state (low protein oxidation levels, evidenced by protein carbonylation and lipid peroxidation observed by the HNE analysis) downregulates antioxidant enzymes (MnSOD, PRX III, Catalase, and GPX). These improved redox balance buffering capacities promoted mitochondrial fusion (OPA1 and MFN1) and suppressed fission (BNIP3, DRP1, and PARKIN). CONCLUSIONS: Our data suggests that EE can coactivate anabolic and catabolic signaling pathways and modulate redox buffering capacity based on the redox state. Finally, this study indicates that an enhanced reduced state may be the key element that promotes mitochondrial fusion.