The peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1α (PGC-1α) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of a) the role of PGC-1α in exercise-mediated muscle adaptation and b) the possible insulin-sensitizing role of PGC-1α. To these ends the following questions are addressed: i) how is PGC-1α regulated, ii) what adaptations are indeed dependent on PGC-1α action, iii) is PGC-1α altered in insulin resistance and iv) are PGC-1α knockout and transgenic mice suitable models for examining therapeutic potential of this co-activator. 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 p38γ mitogen-activated protein kinase (MAPK)/PGC-1α 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-1α, human studies on type 2 diabetes suggest that PGC-1α and its target genes are only modestly down-regulated (< 34%). However, studies in PGC-1α knockout or PGC-1α transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1α does not have an insulin-sensitizing role. In contrast, a modest (~25%) upregulation of PGC-1α, within physiologic 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 p38γ MAPK/PGC-1α regulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1α, within physiologic limits, have revealed its insulin-sensitizing effects.
- endurance exercise
- fatty acid metabolism
- Copyright © 2009, American Journal of Physiology - Endocrinology and Metabolism