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lüll PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity Lira VA; Benton CR; Yan Z; Bonen AAm J Physiol Endocrinol Metab 2010[Aug]; 299 (2): E145-61The 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.|Adaptation, Physiological/physiology[MESH]|Animals[MESH]|Biological Transport, Active/physiology[MESH]|Diabetes Mellitus, Type 2/metabolism[MESH]|Exercise/*physiology[MESH]|Glucose/metabolism[MESH]|Heat-Shock Proteins/*physiology[MESH]|Humans[MESH]|Insulin Resistance/*physiology[MESH]|Lipid Metabolism/physiology[MESH]|Mice[MESH]|Muscle, Skeletal/*physiology[MESH]|Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha[MESH]|Physical Fitness/*physiology[MESH]|Transcription Factors/*physiology[MESH] |