Author(s): NAKAO, K., MAEDA, S., IEMITSU, M., Institution: RITSUMEIKAN UNIVERSITY, Country: JAPAN, Abstract-ID: 2789

INTRODUCTION:
Mitochondria play a central role in myocardial energy supply, and mitochondrial oxidative capacity declines with aging. Aerobic exercise training may attenuate age-related declines in the myocardial oxidative metabolism (1). Nuclear respiratory factor-1 (NRF-1) regulates nuclear-encoded mitochondrial oxidative metabolic genes, including cytochrome c (Cyt c), and induces mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA replication and transcription. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) enhances NRF-1 transcriptional activity through coactivation. However, the effects of aging and exercise training on myocardial PGC-1α–NRF-1 signaling and oxidative metabolism remain unclear. Therefore, we examined whether aerobic exercise training enhances PGC-1α–NRF-1-dependent transcription and improves myocardial oxidative function in aged rats.
METHODS:
We used the hearts of male young sedentary Wistar rats (Young-CON; 4 months old, n = 7), aged sedentary rats (Aged-CON; 23 months old, n = 7), and aged swim-trained rats (Aged-Ex; 23 months old, trained for 8 weeks, 5 days/week, 90 min/day, n = 7). PGC-1α protein expression was measured by Western blotting analysis. NRF-1 DNA-binding activity to promoter regions of Cyt c and TFAM was assessed using gel-mobility shift assay. Expression levels of NRF-1, TFAM and Cyt c mRNA were quantified by real-time RT-PCR with TaqMan probes. Enzyme activity of citrate synthase (CS) and cytochrome c oxidase (COX), as well as ATP concentration were measured. Data were analyzed using one-way ANOVA followed by Fisher’s least significant difference (LSD) test. Statistical significance was set at p < 0.05.
RESULTS:
Swim training decreased body weight and increased epitrochlearis muscle CS activity (p < 0.05, vs. Aged-CON), confirming the training effect. Myocardial CS and COX enzyme activities 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 (p < 0.05). Myocardial PGC-1α protein levels were 1.7 ± 0.1, 1.0 ± 0.1, and 1.5 ± 0.1 A.U. in Young-CON, Aged-CON, and Aged-Ex, respectively (p < 0.05). In parallel, myocardial PGC-1α mRNA and NRF-1 mRNA expression, NRF-1 DNA-binding activity to Cyt c and TFAM promoter regions, and mRNA expression levels of Cyt c and TFAM, 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 (each p < 0.05).
CONCLUSION:
These findings suggest that transcriptional regulation via the PGC-1α–NRF-1 pathway may contribute to the age-related decline in cardiac mitochondrial energy metabolism and may be involved in its improvement by exercise training.

Reference
(1) Am J Physiol Heart Circ Physiol 283: H1750-H1760, 2002.