Endurance Exercise Rescues Cardiomyopathy in Mitochondrial DNA Mutator Mouse Model of Aging
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abstract
A causal role for mitochondrial DNA (mtDNA) mutagenesis in the etiology of age associated cardiomyopathy is supported by the polymerase gamma (PolG) mutator mouse, harbouring a proofreading‐deficient copy of PolG, which exhibits cardiac hypertrophy, mitochondrial dysfunction in cardiomyocytes, and reduced lifespan. Longitudinal studies demonstrate that endurance (END) training reduces risk of cardiovascular diseases and extends life expectancy. We aimed to delineate if END training can prevent cardiac abnormalities and attenuate mitochondrial dysfunction in heart of PolG mice. At 3‐mo, 36 PolG mice (♀ = ♂) were randomly assigned to sedentary (SED) or endurance training (15m/min for 45 min, 3x/week for 5 months) group. END suppressed cardiac hypertrophy (30%) and pathology (abnormal interventricular septal and free wall thickness), and increased mtDNA copy number (2‐fold), COX activity (38%) and lifespan of PolG mice (P<0.05). Using Roche NimbleGen mouse microarray platform, we observed that PolG‐SED hearts had ~100 DE genes (5% FDR) vs. wild‐type (WT) controls (P<0.05). END training normalized 22 DE genes in PolG heart to WT levels (P<0.05). We conclude that END training promotes cardiac mitochondrial oxidative capacity and partially normalizes the transcriptional signature to WT, contributing to the cardiac rejuvenation of PolG mice. We propose that END training is a valuable therapeutic intervention for attenuating cardiac pathology and related morbidity and mortality. (Funded by CIHR)
