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Comparative Study
. 2004 Nov;114(10):1518-26.
doi: 10.1172/JCI21889.

Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins

Charlotte Ling  1 , Pernille Poulsen, Emma Carlsson, Martin Ridderstråle, Peter Almgren, Jørgen Wojtaszewski, Henning Beck-Nielsen, Leif Groop, Allan Vaag
Affiliations
Comparative Study

Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins

Charlotte Ling et al. J Clin Invest. 2004 Nov.

Abstract

Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPARgamma coactivator 1alpha (PGC-1alpha) and PGC-1beta genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1alpha gene. Insulin increased and aging reduced skeletal muscle PGC-1alpha and PGC-1beta mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1alpha Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1alpha in a complex fashion. Whereas expression of PGC-1alpha in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1beta expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1alpha and PGC-1beta expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1alpha and PGC-1beta on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.

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Figures

Figure 1
Figure 1
Effects of insulin and age on human skeletal muscle PGC-1α and PGC-1β mRNA levels. Skeletal muscle specimens were taken from young (n = 86) and elderly (n = 68) twins before and after a hyperinsulinemic clamp. RNA was prepared and analyzed for PGC-1α (A) and PGC-1β (B) mRNA expression, together with the internal standard cyclophilin A using TaqMan Real-Time PCR with an ABI 7900 system. The PGC-1α/cyclophilin A ratio and the PGC-1β/cyclophilin A ratio were calculated for each sample, and the ratios are presented in the figure. Results are expressed as the mean ± SEM. *P ≤ 0.05.
Figure 2
Figure 2
The effect of age on the association between skeletal muscle PGC-1α and PGC-1β mRNA expression and the PGC-1α Gly482Ser polymorphism. (A) PGC-1α and (B) PGC-1β mRNA expression, as measured by TaqMan Real-Time PCR (ABI 7900), in skeletal muscles of young and elderly twins before and after a hyperinsulinemic clamp, representing Gly/Gly (n = 38 and n = 29 for young and elderly, respectively) and Gly/Ser + Ser/Ser (n = 48 and n = 39 for young and elderly, respectively) PGC-1α-482 genotypes. The level of PGC-1α and PGC-1β transcripts are normalized to the mRNA level of endogenous cyclophilin A. The PGC-1α/cyclophilin A ratio and the PGC-1β/cyclophilin A ratio were calculated for each sample, and the ratios are presented in the figure. Results are expressed as the mean ± SEM. *P ≤ 0.05.
Figure 3
Figure 3
Schematic model demonstrating factors influencing the mRNA expression of PGC-1α and PGC-1β in skeletal muscle, as well as the role of these two transcriptional coactivators on glucose and lipid metabolism. Glucose 6P, glucose-6-phosphate.
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