title: PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity.
abstract: The peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha (PGC-1alpha) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of 1) the role of PGC-1alpha in exercise-mediated muscle adaptation and 2) the possible insulin-sensitizing role of PGC-1alpha. To these ends, the following questions are addressed. 1) How is PGC-1alpha regulated, 2) what adaptations are indeed dependent on PGC-1alpha action, 3) is PGC-1alpha altered in insulin resistance, and 4) are PGC-1alpha-knockout and -transgenic mice suitable models for examining therapeutic potential of this coactivator? In skeletal muscle, an orchestrated signaling network, including Ca(2+)-dependent pathways, reactive oxygen species (ROS), nitric oxide (NO), AMP-dependent protein kinase (AMPK), and p38 MAPK, is involved in the control of contractile protein expression, angiogenesis, mitochondrial biogenesis, and other adaptations. However, the p38gamma MAPK/PGC-1alpha regulatory axis has been confirmed to be required for exercise-induced angiogenesis and mitochondrial biogenesis but not for fiber type transformation. With respect to a potential insulin-sensitizing role of PGC-1alpha, human studies on type 2 diabetes suggest that PGC-1alpha and its target genes are only modestly downregulated (< or =34%). However, studies in PGC-1alpha-knockout or PGC-1alpha-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1alpha does not have an insulin-sensitizing role. In contrast, a modest ( approximately 25%) upregulation of PGC-1alpha, within physiological limits, does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38gamma MAPK-PGC-1alpha regulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1alpha, within physiological limits, have revealed its insulin-sensitizing effects.
authors.affiliation: Center for Skeletal Muscle Research, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, USA.
authors.forename: Vitor A
authors.initials: VA
authors.lastname: Lira
authors.forename: Carley R
authors.initials: CR
authors.lastname: Benton
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D015444:Exercise / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology; D051379:Mice; D018482:Muscle, Skeletal / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010809:Physical Fitness / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D005947:Glucose