Exercise training attenuates aging-associated mitochondrial dysfunction in rat skeletal muscle: role of PGC-1α.

Aged skeletal muscle demonstrates declines in muscle mass and deterioration of mitochondrial content and function. Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) plays an important role in promoting muscle mitochondrial biogenesis in response to exercise training, but its role in senescent muscle is not clear. In the present study we hypothesize that a downregulation of the PGC-1α signaling pathway contributes to mitochondrial deterioration in aged muscle whereas endurance training ameliorates the deficits. Three groups of Fischer 344/BNF1 rats were used: young, sedentary (Y, 4 months); old, sedentary (O, 22 months); and old trained (OT, 22 months), subjected to treadmill running at 17.5 m/min, 10% grade for 45 min/day, 5 days/week for 12-weeks. PGC-1α mRNA and nuclear PGC-1α protein content in the soleus muscle were both decreased in O vs. Y rats, whereas OT rats showed a 2.3 and 1.8-fold higher PGC-1α content than O and Y rats, respectively (P<0.01). Mitochondrial transcription factor A (Tfam), cytochrome c (Cyt c) and mitochondrial (mt) DNA contents were significantly decreased in O vs. Y rats, but elevated by 2.2 (P<0.01), 1.4 (P<0.05) and 2.4-fold (P<0.01), respectively, in OT vs. O rats. In addition, Tfam and mtDNA showed 1.6 and 1.8-fold (P<0.01) higher levels, respectively, in OT vs. Y rats. These adaptations were accompanied by significant increases in the expression of the phosphorylated form of AMP-activated kinase (AMPK) (P<0.01), p38 mitogen-activated kinase (MAPK) (P<0.05) and silent mating type information regulator 2 homolog 1 (SIRT1) (P<0.01) in OT rats. Furthermore, OT rats showed great levels of phosphorylation in cAMP responsive element binding protein (p-CREB) and DNA binding compared to O and Y rats. These data indicate that endurance training can attenuate aging-associated decline in mitochondrial protein synthesis in skeletal muscle partly due to upregulation of PGC-1α signaling.

Kang C ，Chung E ，Diffee G ，Ji LL ... -  《-》

Effect of lifelong resveratrol supplementation and exercise training on skeletal muscle oxidative capacity in aging mice; impact of PGC-1α.

The present study tested the hypothesis that lifelong resveratrol (RSV) supplementation counteracts an age-associated decrease in skeletal muscle oxidative capacity through peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α and that RSV combined with lifelong exercise training (EX) exerts additive effects through PGC-1α in mice. 3 month old PGC-1α whole body knockout (KO) and wild type (WT) littermate mice were placed in cages with or without running wheel and fed either standard chow or standard chow with RSV supplementation (4 g/kg food) for 12 months. Young (3 months of age), sedentary mice on standard chow served as young controls. A graded running performance test and a glucose tolerance test were performed 2 and 1 week, respectively, before euthanization where quadriceps and extensor digitorum longus (EDL) muscles were removed. In PGC-1α KO mice, quadriceps citrate synthase (CS) activity, mitochondrial (mt)DNA content as well as pyruvate dehydrogenase (PDH)-E1α, cytochrome (Cyt) c and vascular endothelial growth factor (VEGF) protein content were 20-75% lower and, EDL capillary-to-fiber (C:F) ratio was 15-30% lower than in WT mice. RSV and/or EX had no effect on the C:F ratio in EDL. CS activity (P=0.063) and mtDNA content (P=0.013) decreased with age in WT mice, and CS activity, mtDNA content, PDH-E1α protein and VEGF protein increased ~1.5-1.8-fold with lifelong EX in WT, but not in PGC-1α KO mice, while RSV alone had no significant effect on these proteins. Lifelong EX increased activity/content of oxidative proteins, mtDNA and angiogenic proteins in skeletal muscle through PGC-1α, while RSV supplementation alone had no effect. Combining lifelong EX and RSV supplementation had no additional effect on skeletal muscle oxidative and angiogenic proteins.

Ringholm S ，Olesen J ，Pedersen JT ，Brandt CT ，Halling JF ，Hellsten Y ，Prats C ，Pilegaard H ... -  《-》

Exercise activation of muscle peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling is redox sensitive.

Kang C ，O'Moore KM ，Dickman JR ，Ji LL ... -  《-》

Endurance exercise increases the SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1alpha protein expressions in rat skeletal muscle.

Suwa M ，Nakano H ，Radak Z ，Kumagai S ... -  《METABOLISM-CLINICAL AND EXPERIMENTAL》

Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle.

Gurd BJ ，Yoshida Y ，McFarlan JT ，Holloway GP ，Moyes CD ，Heigenhauser GJ ，Spriet L ，Bonen A ... -  《-》