PGC-1α is required for training-induced prevention of age-associated decline in mitochondrial enzymes in mouse skeletal muscle

Centre of Inflammation and Metabolism & Copenhagen Muscle Research Centre, Department of Biology, Section of Molecular, Integrative Physiology, University of Copenhagen, Copenhagen, Denmark.
Experimental gerontology (Impact Factor: 3.49). 05/2010; 45(5):336-42. DOI: 10.1016/j.exger.2010.01.011
Source: PubMed


The aim of the present study was to test the hypothesis that exercise training prevents an age-associated decline in skeletal muscle mitochondrial enzymes through a PGC-1alpha dependent mechanism. Whole body PGC-1alpha knock-out (KO) and littermate wildtype (WT) mice were submitted to long term running wheel exercise training or a sedentary lifestyle from 2 to 13 month of age. Furthermore, a group of approximately 4-month-old mice was used as young untrained controls. There was in both genotypes an age-associated approximately 30% decrease in citrate synthase (CS) activity and superoxide dismutase (SOD)2 protein content in 13-month-old untrained mice compared with young untrained mice. However, training prevented the age-associated decrease in CS activity and SOD2 protein content only in WT mice, but long term exercise training did increase HKII protein content in both genotypes. In addition, while CS activity and protein expression of cytc and SOD2 were 50-150% lower in skeletal muscle of PGC-1alpha mice than WT mice, the expression of the pro-apoptotic protein Bax and the anti-apoptotic Bcl2 was approximately 30% elevated in PGC-1alpha KO mice. In conclusion, the present findings indicate that PGC-1alpha is required for training-induced prevention of an age-associated decline in CS activity and SOD2 protein expression in skeletal muscle.

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    • "PGC-1a is able to regulate mitochondrial content largely due to its capacity to coactivate multiple transcription factors, more specifically genes involved in the regulation of nuclear genes encoding mitochondrial proteins (NUG- EMPs). PGC-1a is also important for mediating contractile activity-induced mitochondrial adaptations (Geng et al. 2010; Uguccioni and Hood 2011), particularly during the aging process (Leick et al. 2010). Skeletal muscle has an exceptional capability to adapt to exercise, and the molecular basis for these adaptive responses is currently under intensive investigation (Egan and Zierath 2013). "
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    ABSTRACT: PGC-1α is an important transcriptional coactivator that plays a key role in mediating mitochondrial biogenesis. Within seconds of the onset of contractile activity, a number of rapid cellular events occur that form part of the initial signaling processes involved in PGC-1α gene regulation, such as elevations in cytoplasmic calcium, AMPK and p38 activation, and elevated ROS production. We observed that basal levels of PGC-1α promoter activity were more sensitive to resting Ca2+ levels, compared to ROS, p38 or, AMPK signaling. Moreover, enhanced PGC-1α transcription and post-translational activity on DNA were a result of the activation of multiple signal transduction pathways during contractile activity of myotubes. AMPK, ROS, and Ca2+ appear to be necessary for the regulation of contractile activity-induced PGC-1α gene expression, governed partly through p38 MAPK and CaMKII activity. Whether these signaling pathways are arranged as a linear sequence of events, or as largely independent pathways during contractile activity, remains to be determined.
    05/2014; 2(5). DOI:10.14814/phy2.12008
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    • "Spontaneous exercise resulted in a significantly higher level of this protein at 26 and 29 months of age when compared with the sedentary animals (See Figure 3, Panel B). PGC-1α protects against skeletal muscle atrophy [54] and it is required for training-induced prevention of the age-associated decline in mitochondria [55]. Moreover, it has been recently shown that increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging [56]. "
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    ABSTRACT: Life expectancy at birth in the first world has increased from 35 years at the beginning of the 20th century to more than 80 years now. The increase in life expectancy has resulted in an increase in age-related diseases and larger numbers of frail and dependent people. The aim of our study was to determine whether life-long spontaneous aerobic exercise affects lifespan and healthspan in mice. Male C57Bl/6J mice, individually caged, were randomly assigned to one of two groups: sedentary (n = 72) or spontaneous wheel-runners (n = 72). We evaluated longevity and several health parameters including grip strength, motor coordination, exercise capacity (VO2max) and skeletal muscle mitochondrial biogenesis. We also measured the cortical levels of the brain-derived neurotrophic factor (BDNF), a neurotrophin associated with brain plasticity. In addition, we measured systemic oxidative stress (malondialdehyde and protein carbonyl plasma levels) and the expression and activity of two genes involved in antioxidant defense in the liver (that is, glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD)). Genes that encode antioxidant enzymes are considered longevity genes because their over-expression may modulate lifespan. Aging was associated with an increase in oxidative stress biomarkers and in the activity of the antioxidant enzymes, GPx and Mn-SOD, in the liver in mice. Life-long spontaneous exercise did not prolong longevity but prevented several signs of frailty (that is, decrease in strength, endurance and motor coordination). This improvement was accompanied by a significant increase in the mitochondrial biogenesis in skeletal muscle and in the cortical BDNF levels. Life-long spontaneous exercise does not prolong lifespan but improves healthspan in mice. Exercise is an intervention that delays age-associated frailty, enhances function and can be translated into the clinic.
    09/2013; 2(1):14. DOI:10.1186/2046-2395-2-14
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    • "Although only CS activity and mtDNA content decreased significantly in skeletal muscle with age in the present study, the observed increase in oxidative and angiogenic proteins in skeletal muscle with exercise training shows that aging skeletal muscle benefits from regular physical activity and underlines the major impact regular physical activity has on the oxidative capacity of aging skeletal muscle. The relatively short average distance run by the mice in the present study (~6 km/week) and our previous study (Leick et al., 2010) is of notice, and highlights that the beneficial effects of exercise training on skeletal "
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    ABSTRACT: 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 (ET) exerts additive effects through PGC-1α in mice. 3month old PGC-1α whole body knockout (KO) and wildtype (WT) littermate mice were placed in cages with or without running wheel and fed either standard chow or standard chow with RSV supplementation (4g/kg food) for 12month. Young (3month 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 1week, 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 was 20-75 % lower and, EDL capillary-to-fiber (C:F) ratio was 15-30 % lower than in WT mice. RSV and/or ET had no effect on 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 ET in WT, but not in PGC-1α KO mice, while RSV alone had no significant effect on these proteins. Lifelong ET 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 ET and RSV supplementation had no additive effect on skeletal muscle oxidative and angiogenic proteins.
    Experimental gerontology 08/2013; 48(11). DOI:10.1016/j.exger.2013.08.012 · 3.49 Impact Factor
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