Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1β gene expression in twins

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 dizygodc 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-lalpha 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-lalpha in a complex fashion. Whereas expression of PGC-la in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-lbeta expression was positively related to fat oxidation and non-oxidative glucose metabolism. We conclude that skeletal muscle PGC-lalpha and PGC-1beta expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-lalpha 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.