Maternal obesity, AMP-activated protein kinase, and fetal skeletal muscle development

Maternal obesity during gestation programs offspring to obesity and type 2 diabetes in adulthood. Skeletal muscle is the major peripheral tissue responsive to insulin. The prenatal stage is crucial for skeletal muscle development. AMP-activated protein kinase (AMPK) is involved in both skeletal muscle development and etiology of obesity. In this study, we investigated the effects of maternal obesity on fetal skeletal muscle development, AMPK activity, and their association with fetal origins of obesity and type 2 diabetes.;Using the obese pregnant ewe model, we showed that myogenesis was attenuated and the diameter of primary muscle fibers was smaller in fetal skeletal muscle born to obese dams (OB). Wingless and Int (Wnt)/beta-Catenin signaling pathway promotes myogenesis and inhibits adipogenesis. The Wnt/beta-catenin signaling was down-regulated in OB fetal muscle, which was associated with inflammatory response in fetal muscle due to maternal obesity. Moreover, AMPK activity was reduced while the expression of adipogenic marker peroxisome proliferator-activated receptor (PPAR) gamma was increased in OB fetal muscle. In 3T3-L1 cell lines, pharmacological activation of AMPK inhibited the expression of PPARgamma and reduced the presence of adipocytes, while pharmacological inhibition of AMPK enhanced the expression of PPARgamma. These data suggest that AMPK activity is inversely related to adipogenesis in fetal sheep muscle and 3T3-L1 cells.;In the diet-induced obesity mouse model, we also observed the down-regulation of AMPK activity, myogenic markers, and mitochondrial content and function, while the up-regulation of PPARgamma in the skeletal muscle of offspring born to obese dams (OB). Maternal metformin administration to obese mice during gestation and lactation activated AMPK activity and prevented these changes in OB offspring skeletal muscle, which suggested that maternal administration of metformin might improve OB offspring muscle function.;Besides, we investigated the role of AMPK in skeletal muscle protein degradation in C2C12 myotubes. The data showed that pharmacological activation of AMPK stimulated two muscle specific ubiquitin ligases expression, indicating that acute AMPK activation may promote muscle protein degradation.;In summary, our data show that maternal obesity affects fetal skeletal muscle development which has long-term effects on offspring properties, and AMPK is a key mediator affecting fetal skeletal muscle development.