PGC-1α regulation by exercise training and its influences on muscle function and insulin sensitivity

Lira VA, Benton CR, Yan Z, Bonen A. PGC-1 alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab 299: E145-E161, 2010. First published April 6, 2010; doi:10.1152/ajpendo.00755.2009.-The peroxisome proliferator-activated receptor-gamma (PPAR gamma) coactivator-1 alpha (PGC-1 alpha) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of 1) the role of PGC-1 alpha in exercise-mediated muscle adaptation and 2) the possible insulin-sensitizing role of PGC-1 alpha. To these ends, the following questions are addressed. 1) How is PGC-1 alpha regulated, 2) what adaptations are indeed dependent on PGC-1 alpha action, 3) is PGC-1 alpha altered in insulin resistance, and 4) are PGC-1 alpha-knockout and -transgenic mice suitable models for examining therapeutic potential of this coactivator? In skeletal muscle, an orchestrated signaling network, including Ca2+-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 p38 gamma MAPK/PGC-1 alpha 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-1 alpha, human studies on type 2 diabetes suggest that PGC-1 alpha and its target genes are only modestly downregulated (<= 34%). However, studies in PGC-1 alpha-knockout or PGC-1 alpha-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1 alpha does not have an insulin-sensitizing role. In contrast, a modest (similar to 25%) upregulation of PGC-1 alpha, 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 p38 gamma MAPK-PGC-1 alpha regulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1 alpha, within physiological limits, have revealed its insulin-sensitizing effects.