The placental mTOR-pathway: correlation with early growth trajectories following intrauterine growth restriction?

Abstract

Idiopathic intrauterine growth restriction (IUGR) is a result of impaired placental nutrient supply. Newborns with IUGR exhibiting postnatal catch-up growth are of higher risk for cardiovascular and metabolic co-morbidities in adult life. Mammalian target of rapamycin (mTOR) was recently shown to function as a placental nutrient sensor. Thus, we determined possible correlations of members of the placental mTOR signaling cascade with auxologic parameters of postnatal growth. The protein expression and activity of mTOR-pathway signaling components, Akt, AMP-activated protein kinase α, mTOR, p70S6kinase1 and insulin receptor substrate-1 were analysed via western blotting in IUGR v. matched appropriate-for-gestational age (AGA) placentas. Moreover, mTOR was immunohistochemically stained in placental sections. Data from western blot analyses were correlated with retrospective auxological follow-up data at 1 year of age. We found significant catch-up growth in the 1st year of life in the IUGR group. MTOR and its activated form are immunohistochemically detected in multiple placental compartments. We identified correlations of placental mTOR-pathway signaling components to auxological data at birth and at 1 year of life in IUGR. Analysis of the protein expression and phosphorylation level of mTOR-pathway components in IUGR and AGA placentas postpartum, however, did not reveal pathognomonic changes. Our findings suggest that the level of activated mTOR correlates with early catch-up growth following IUGR. However, the complexity of signals converging at the mTOR nexus and its cellular distribution pattern seem to limit its potential as biomarker in this setting.

Paeoniflorin attenuates gestational diabetes via Akt/mTOR pathway in a rat model

“…mTOR can also affect the fetal growth through the regulation of placental development and function (13). Studies suggested that the placental mTOR is upregulated in pregnancies complicated by GDM, and mTOR overactivation is linked to fetal macrosomia (14,15).…”

Critical role of mTOR, PPARγ and PPARδ signaling in regulating early pregnancy decidual function, embryo viability and feto-placental growth

“…In addition to the well-known role of mTOR modulating placental nutrient transport and mitochondrial respiration and thereby regulating fetal growth (Kavitha et al, 2014), a recent study in which rapamycin was given to rats during late pregnancy has shown that mTOR signaling is involved in the programming of heart defects in the offspring (Hennig et al, 2017). Moreover, placental mTOR signaling activity in IUGR correlates with growth during the first year of life (Fahlbusch et al, 2015). Therefore, mTOR signaling appears to play an important role in determining growth and survival from early pregnancy to the postnatal period.…”

Placental mTOR Signaling and Sexual Dimorphism in Metabolic Health across the Lifespan of Offspring

“…These findings suggest impaired mTOR signaling may directly or indirectly disrupt placental cell growth pathways. Interestingly, placental mTOR protein levels have been correlated with early catch-up growth following FGR [21], which in turn may link mTOR-associated FGR to adverse metabolic outcomes, such as obesity, in childhood and beyond. Direct genetic deletion of mTOR from the placental trophoblasts of mice conferred a significant reduction in newborn body weight that manifested in sexually dimorphic outcomes in insulin resistance and obesity in the adult offspring [18].…”