PGC-1alpha 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: 3.34). 05/2010; 45(5):336-42. DOI: 10.1016/j.exger.2010.01.011
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Little is known about skeletal muscle adaptation to discontinuous endurance training. It has been suggested that accumulating 30 minutes of endurance exercise daily may result in similar adaptations in the working muscle as a 30 minute workbout. The purposes of the current investigation, therefore, were to conduct an 8-week continuous or discontinuous endurance training regimen and determine whether 1) treadmill exercise capacity differs between the two training paradigms; 2) the angiogenic and mitochondrial signaling pathways are differentially activated in the two training regimens. Twenty-four young adult male mice (FVB/NJ) were randomized into three groups: 1) control; 2) continuous treadmill endurance training for 30 minutes 5x/week (30T); or 3) discontinuous treadmill endurance training for a total of 30 minutes 5x/week for three, 10 minutes intervals with two hours rest between intervals (10T). Incremental exercise testing increased by 60% (p < 0.001) for both exercise groups compared to control. For the quadriceps muscle, anti-angiogenic regulators (TSP 1 and ADAMTS1) were reduced by 50-70% (p < 0.001) with either exercise paradigms. In addition, phosphorylation of p38 MAPK signaling increased by 50-300% (p < 0.001) which corresponded to an increase in PGC-1beta protein expression. These findings suggest that accumulating 30 minutes of endurance exercise in 10 minute sessions result in similar endurance training adaptations in skeletal muscle as a 30 minute workbout.
    Experimental physiology 11/2012; · 3.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Exercise triggers a pleiotropic response in skeletal muscle, which results in a profound remodeling of this tissue. Physical activity-dependent muscle fiber plasticity is regulated by a number of distinct signaling pathways. Even though most of these pathways are activated by different stimuli and in a temporally and spatially separated manner during exercise, many of the major signal transduction events converge on the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) by post-translationally modifying the PGC-1α protein, modulating PGC-1α gene expression or both. In turn, depending on the cellular context, PGC-1α regulates specific gene programs. Ultimately, PGC-1α modulates most of the transcriptional adaptations of skeletal muscle to exercise. In this review, the regulation and function of this pivotal transcriptional coactivator in muscle are discussed.
    Journal of Receptor and Signal Transduction Research 02/2010; 30(6):376-84. · 1.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Physiological Reports. 05/2014; 2(5).