High altitude regulates the expression of AMPK pathways in human placenta

Abstract

High-altitude (>2500 m) residence augments the risk of intrauterine growth restriction (IUGR) and preeclampsia likely due, in part, to uteroplacental hypoperfusion. Previous genomic and transcriptomic studies in humans and functional studies in mice and humans suggest a role for AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR. AMPK is a metabolic sensor activated by hypoxia that is ubiquitously expressed in vascular beds and placenta. Methods: We measured gene expression and protein levels of AMPK and its upstream regulators and downstream targets in human placentas from high (>2500 m) vs. moderate (~1700 m) and low (~100 m) altitude. Results: We found that phosphorylated AMPK protein levels and its downstream target TSC2 were increased in placentas from high and moderate vs. low altitude, whereas the phosphorylated form of the downstream target translation repressor protein 4E-BP1 was increased in high compared to moderate as well as low altitude placentas. Mean birth weights progressively fell with increasing altitude but no infants, by study design, were clinically growth-restricted. Gene expression analysis showed moderate increases in PRKAG2, encoding the AMPK γ2 subunit, and mechanistic target of rapamycin, MTOR, expression. Discussion: These results highlight a differential regulation of placental AMPK pathway activation in women residing at low, moderate or high altitude during pregnancy, suggesting AMPK may be serving as a metabolic regulator for integrating hypoxic stimuli with placental function.

Differential Changes in Akt and AMPK Phosphorylation Regulating mTOR Activity in the Placentas of Pregnancies Complicated by Fetal Growth Restriction and Gestational Diabetes Mellitus With Large-For-Gestational Age Infants

“…Unlike Akt, only a few studies with inconsistent results compared the changes in AMPK and its phosphorylation in the placentas between women with normal pregnancies and those with pregnancies complicated by FGR ( 32 , 36 ). Similar to a previous report from women living at high altitude with FGR ( 36 ), we found increased levels of phosphorylated AMPK in the placentas of women with FGR pregnancies than in those of women with normal pregnancies, although the same change was not observed in another report ( 32 ). Inconsistent results also exist between studies using different animal models of FGR ( 35 , 37 ).…”

Maternal, placental, and fetal Insulin-Like Growth Factor-I (IGF-1) and IGF Binding proteins (IGFBPs) in Diabetic pregnancies: Effects on fetal growth and birth size.

“…In the placenta of obese women with GDM, gene expression for AMPK was reduced, whereas the downstream regulator of mTOR, p70S6KB1 was raised. (50,51) Summary of Key findings: (figure 1 and 2)…”

Effect of Genetically Reduced Maternal Myostatin on Late Gestation Maternal, Fetal, and Placental Metabolomes in Mice

“…Thus, it is possible that the seemingly reduced fatty acid oxidation observed in fetal serum from Mstn +/− mothers was a result of the lower AMP and AMPK levels. Elevated pAMPK was found in placentas from IUGR and high-altitude pregnancies and in the hypothalamus of rats that had experienced growth restriction [ 49 , 50 , 51 ]. Myostatin knockout has been shown to inhibit AMPK in mouse skeletal muscle [ 52 ] but myostatin treatment inhibited AMPK activity in cultured myoblasts.…”