Maternal protein restriction in rats leads to reduced PGC-1α expression via altered DNA methylation in skeletal muscle.

ABSTRACT

Intrauterine growth retardation (IUGR) is thought to program insulin resistance, type 2 diabetes and other metabolic diseases in later life. Skeletal muscle is an important tissue involved in regulating the metabolism. We therefore hypothesized that the regulation of glucose- and lipid-related genes in skeletal muscle may contribute to metabolic changes in rats with IUGR. In this study, IUGR rats were bred from pregnant rats fed a protein-restricted (PR) diet. Insulin resistance (IR)-related metabolic parameters and the expression of key regulatory IR genes such as peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) and glucose transporter 4 (GLUT4) were measured in skeletal muscle from 18-month-old female IUGR rats. The methylation status of promoters of PGC-1α and GLUT4 were assessed in the same tissues. During the aging process, IUGR rats exhibited catch-up growth and obesity. In old age, they showed impaired glucose tolerance demonstrated by high glucose and insulin AUC (area under the curve) values. The expression of glucose transporter 4 (GLUT4) and PGC-1α in skeletal muscle was significantly reduced in IUGR rats. Mean CpG island methylation in the PGC-1α promoter sequence was significantly increased. These results suggest that a PR diet during gestation may induce epigenetic changes, such as DNA methylation, in the promoters of specific genes. The changes may affect gene expression and account for the metabolic alterations in female rats with IUGR.