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Review
. 2010 Aug;299(2):E145-61.
doi: 10.1152/ajpendo.00755.2009. Epub 2010 Apr 6.

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

Vitor A Lira  1 , Carley R Benton, Zhen Yan, Arend Bonen
Affiliations
Review

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

Vitor A Lira et al. Am J Physiol Endocrinol Metab. 2010 Aug.

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.

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Figures

Fig. 1.
Fig. 1.
Signaling pathways involved in exercise-induced peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) regulation in skeletal muscle. Current evidence suggests roles for calcineurin (CnA), CaMK, AMP-activated protein kinase (AMPK), and p38 MAPK in PGC-1α regulation. Thick arrows depict regulatory events required for exercise-mediated induction of PGC-1α and subsequent adaptations that have been confirmed by gene deletion studies in animal models. Thin arrows depict regulatory events that have been associated with PGC-1α regulation, but their requirement for the exercise-dependent induction of PGC-1α awaits further investigation (refer to text for details). ROS, reactive oxygen species.
Fig. 2.
Fig. 2.
Comparison between relative changes in PGC-1α overexpression (%) and changes in insulin-stimulated glucose utilization (%) in healthy animals. These data suggest that when PGC-1α expression is more than doubled (i.e., >100% increase), insulin-stimulated glucose utilization deteriorates sufficiently to result in insulin resistance (gray box). In contrast, increasing PGC-1α expression more modestly (<100%) increases insulin sensitivity (dotted box). These contrasting responses may reflect, in part, the differential effects of PGC-1α, depending on its level of overexpression, on intramuscular bioactive lipid accumulation that can interfere with insulin signaling. Data are from Refs. , , , , and , in which PGC-1α was overexpressed to varying levels in transgenic animals or in electrotransfected muscles. PGC-1α mRNA increase (%) was calculated relative to controls in these studies. Insulin-stimulated glucose utilization was based on various methods, and the increase (%) was calculated relative to controls.
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