PGC-1[alpha] regulation by exercise training and its influences on muscle function and insulin sensitivity

The peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) coactivator-1[alpha] (PGC-l[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 [Ca.sup.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 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 ([less than or equal to] 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 (~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. endurance exercise; angiogenesis; mitochondria; fatty acid metabolism; glucose doi: 10.1152/ajpendo.00755.2009.