Maternal obesity downregulates myogenesis and β-catenin signaling in fetal skeletal muscle

Abstract

Skeletal muscle is one of the primary tissues responsible for insulin resistance and type 2 diabetes (T2D). The fetal stage is crucial for skeletal muscle development. Obesity induces inflammatory responses, which might regulate myogenesis through Wnt/beta-catenin signaling. This study evaluated the effects of maternal obesity (>30% increase in body mass index) during pregnancy on myogenesis and the Wnt/beta-catenin and IKK/NF-kappaB pathways in fetal skeletal muscle using an obese pregnant sheep model. Nonpregnant ewes were assigned to a control group (C; fed 100% of National Research Council recommendations; n=5) or obesogenic (OB; fed 150% of National Research Council recommendations; n=5) diet from 60 days before to 75 days after conception (term approximately 148 days) when fetal semitendenosus skeletal muscle was sampled for analyses. Myogenic markers including MyoD, myogenin, and desmin contents were reduced in OB compared with C fetal semitendenosus, indicating the downregulation of myogenesis. The diameter of primary muscle fibers was smaller in OB fetal muscle. Phosphorylation of GSK3beta was reduced in OB compared with C fetal semitendenosus. Although the beta-catenin level was lower in OB than C fetal muscle, more beta-catenin was associated with FOXO3a in the OB fetuses. Moreover, we found phosphorylation levels of IKKbeta and RelA/p65 were both increased in OB fetal muscle. In conclusion, our data showed that myogenesis and the Wnt/beta-catenin signaling pathway were downregulated, which might be due to the upregulation of inflammatory IKK/NF-kappaB signaling pathways in fetal muscle of obese mothers.

Impact of maternal obesity on offspring obesity and cardiometabolic disease risk

“…In rats, young offspring of mothers fed a junk food diet either during gestation alone or during both gestation and lactation exhibited increased intramuscular lipid content, semitendinosus muscle atrophy, altered expression of genes important in muscle growth and metabolism (Bayol et al 2005) and reduced muscle force (Bayol et al 2009). Such changes may be programmed early in development, as reduced myogenesis and increased intramuscular fat have also been reported in skeletal muscle of late gestation foetal sheep exposed to maternal obesity, in association with increased expression of inflammatory markers and altered AMP-activated protein kinase signalling (Zhu et al 2008, Tong et al 2009, Yan et al 2010. These changes may play a role in altered muscle development and impact on later muscle size and strength.…”

“…Additionally, there appears to be an age-related decline in glucose/insulin homoeostasis in many programming models; in mice, offspring of obese mothers were found to be hyperinsulinaemic at 3 months of age (young adulthood), but male offspring had developed frank diabetes with reduced plasma insulin and decreased pancreatic insulin content by 6 months of age (Samuelsson et al 2008). It has been proposed that such an age-related decline in pancreatic function may be programmed at an early developmental stage; in sheep, maternal obesity is associated with increased foetal pancreatic weight and a marked increase in the number of insulin-positive cells per unit area of the foetal pancreas, perhaps reflecting enhanced early b-cell maturation (Ford et al 2009). However, such changes in early pancreatic development may result in premature postnatal b-cell loss and result in a predisposition to the development of obesity and metabolic dysfunction in adulthood (Ford et al 2009).…”

“…It has been proposed that such an age-related decline in pancreatic function may be programmed at an early developmental stage; in sheep, maternal obesity is associated with increased foetal pancreatic weight and a marked increase in the number of insulin-positive cells per unit area of the foetal pancreas, perhaps reflecting enhanced early b-cell maturation (Ford et al 2009). However, such changes in early pancreatic development may result in premature postnatal b-cell loss and result in a predisposition to the development of obesity and metabolic dysfunction in adulthood (Ford et al 2009). Recent studies in humans have started to examine the influence of maternal obesity on offspring glucose/insulin homoeostasis.…”

Maternal over-nutrition and offspring obesity predisposition: targets for preventative interventions

“…63 Evidence suggests an inflammatio-induced shift in fetal mesenchymal stem cells from myogenesis to adipogenesis, as identified in the fetal semitendinosus muscle of offspring from ewes exposed to maternal obesity in utero. 64 Unfortunately, currently available studies do not provide adequate maternal data to determine whether similar mechanisms may be at play in the rat and mouse models described above.…”

Pode o peso ao nascer influenciar o estado nutricional, os níveis de atividade física e a aptidão física relacionada à saúde de crianças e jovens?

“…Tais alterações podem resultar em consequências estruturais e funcionais a curto e a longo prazo 49 . As consequências podem ser disfunções pulmonares 43 , cardiovasculares 41 e alterações na estrutura e funções no mús-culo esquelético 50 , levando a um prejuízo no nível de aptidão física relacionada à saúde 42,43 .…”