United States Department of Agriculture/Agricultural Research Service, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
Department of Animal Sciences, Auburn University, Auburn, AL, 36849, USA.
Pediatr Res. 2023 Jun;93(7):1891-1898. doi: 10.1038/s41390-022-02382-4. Epub 2022 Nov 19.
Postnatal lean mass accretion is commonly reduced in preterm infants. This study investigated mechanisms involved in the blunted feeding-induced activation of Akt in the skeletal muscle of preterm pigs that contributes to lower protein synthesis rates.
On day 3 following cesarean section, preterm and term piglets were fasted or fed an enteral meal. Activation of Akt signaling pathways in skeletal muscle was determined.
Akt1 and Akt2, but not Akt3, phosphorylation were lower in the skeletal muscle of preterm than in term pigs (P < 0.05). Activation of Akt-positive regulators, PDK1 and mTORC2, but not FAK, were lower in preterm than in term (P < 0.05). The formation of Akt complexes with GAPDH and Hsp90 and the abundance of Ubl4A were lower in preterm than in term (P < 0.05). The abundance of Akt inhibitors, PHLPP and SHIP2, but not PTEN and IP6K1, were higher in preterm than in term pigs (P < 0.05). PP2A activation was inhibited by feeding in term but not in preterm pigs (P < 0.05).
Our results suggest that preterm birth impairs regulatory components involved in Akt activation, thereby limiting the anabolic response to feeding. This anabolic resistance likely contributes to the reduced lean accretion following preterm birth.
The Akt-mTORC1 pathway plays an important role in the regulation of skeletal muscle protein synthesis in neonates. This is the first evidence to demonstrate that, following preterm birth, the postprandial activation of positive regulators of Akt in the skeletal muscle is reduced, whereas the activation of negative regulators of Akt is enhanced. This anabolic resistance of Akt signaling in response to feeding likely contributes to the reduced accretion of lean mass in premature infants. These results may provide potential novel molecular targets for intervention to enhance lean growth in preterm neonates.
早产儿出生后的瘦体重增加通常会减少。本研究调查了导致早产儿蛋白质合成率较低的骨骼肌中 Akt 受喂养刺激的激活作用减弱的相关机制。
在剖宫产术后第 3 天，对早产儿和足月产小猪进行禁食或喂养肠内喂养。确定骨骼肌中 Akt 信号通路的激活情况。
与足月产小猪相比，早产儿骨骼肌中的 Akt1 和 Akt2 磷酸化水平较低（P<0.05），但 Akt3 磷酸化水平无差异。Akt 的正向调节因子 PDK1 和 mTORC2 的激活水平低于足月产小猪（P<0.05），而 FAK 的激活水平则没有差异。Akt 与 GAPDH 和 Hsp90 形成复合物的水平以及 Ubl4A 的丰度均低于足月产小猪（P<0.05）。Akt 抑制剂 PHLPP 和 SHIP2 的丰度高于足月产小猪（P<0.05），而 Akt 抑制剂 PTEN 和 IP6K1 的丰度则没有差异。PP2A 的激活在足月产小猪中受到喂养的抑制，但在早产儿中则不受影响（P<0.05）。
我们的结果表明，早产会损害 Akt 激活相关的调节成分，从而限制了对喂养的合成代谢反应。这种合成代谢抵抗可能是导致早产儿出生后瘦体重减少的原因之一。
Akt-mTORC1 通路在调节新生儿骨骼肌蛋白质合成中起着重要作用。这是首次证明，在早产儿中，骨骼肌中 Akt 的正向调节因子在餐后的激活作用减弱，而 Akt 的负向调节因子的激活作用增强。这种对喂养的 Akt 信号转导的合成代谢抵抗可能是导致早产儿瘦体重减少的原因之一。这些结果可能为干预提供潜在的新的分子靶点，以增强早产儿的瘦体生长。
