Exercise training improves mitochondrial oxidative energy metabolism through PGC-1α-dependent transcriptional pathway in the aged rat heart

Exercise training improves the age-induced decline in oxidative metabolic capacity in cardiac mitochondria. Nuclear respiratory factor-1 (NRF-1) signaling via peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) regulates genes encoding mitochondrial oxidative metabolic enzymes. However, the effects of aging and subsequent exercise training on fatty acid (FA) metabolism-related gene expression via the myocardial PGC-1α–NRF-1 pathway, and the relevance of these changes to improvements in myocardial FA metabolic function, remain unclear. In this study, we examined the hearts of the following male Wistar rats: young sedentary rats (Young-CON; 4 months old), aged sedentary rats (Aged-CON; 23 months old), and aged swim-trained rats (Aged-Ex; 23 months old, trained for 8 weeks, 5 days/week, 90 min/day). Myocardial PGC-1α mRNA and protein levels; myocardial NRF-1 mRNA expression levels; NRF-1 DNA-binding activity to promoter regions of mitochondrial oxidative-metabolism-related genes; and mRNA expression levels of cytochrome c oxidase and cytochrome c , which are NRF-1 target genes, were significantly lower in the Aged-CON group than in the Young-CON group, and significantly higher in the Aged-Ex group than in the Aged-CON group. Furthermore, myocardial enzyme activities associated with mitochondrial oxidative metabolism and ATP concentration were significantly lower in the Aged-CON group than in the Young-CON group and significantly higher in the Aged-Ex group than in the Aged-CON group. These findings suggest that transcriptional regulation via the PGC-1α–NRF-1 pathway may contribute to the age-related decline in mitochondrial energy metabolism and may mediate its restoration by exercise training in the heart. • Exercise attenuated aging-related declines in myocardial PGC-1α and NRF-1 expression. • Exercise improved NRF-1 DNA-binding to TFAM and cytochrome c promoters in aged heart. • Exercise increased mtDNA-encoded ETC gene expression in aged myocardium. • Exercise improved oxidative enzyme activities and ATP levels in aged hearts. • PGC-1α–NRF-1 may mediate exercise-induced restoration of mitochondrial function.