Preterm birth alters the feeding-induced activation of Akt signaling in the muscle of neonatal piglets

Authors: SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC); RUDAR, MARKO - Auburn University; NABERHUIS, JANE - Children'S Nutrition Research Center (CNRC); FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC); DAVIS, TERESA - Children'S Nutrition Research Center (CNRC)

Submitted to: Pediatric Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/27/2022
Publication Date: 11/19/2022
Citation: Suryawan, A., Rudar, M., Naberhuis, J.K., Fiorotto, M.L., Davis, T.A. 2022. Preterm birth alters the feeding-induced activation of Akt signaling in the muscle of neonatal piglets. Pediatric Research. 93(7):1891-1898. https://doi.org/10.1038/s41390-022-02382-4.
DOI: https://doi.org/10.1038/s41390-022-02382-4

Interpretive Summary: Preterm infants frequently experience growth faltering after they are born and have a lower lean body mass later in life than infants born at full term. Studies using the infant pig as a model for the human infant investigated the intracellular mechanisms that contribute to the reduced growth of lean tissue in the premature infant. Piglets were delivered at preterm or term, and the activation of the insulin signaling pathway that regulates protein synthesis was measured at 3 d of age, while fasted or after being fed by mouth. The study showed that the activation of positive regulators of the insulin signaling pathway that regulates Akt activation and protein synthesis was reduced in skeletal muscle of the preterm after a meal. In contrast, the activation of negative regulators of this pathway was enhanced in the preterm after a meal. These altered responses to feeding likely contribute to the reduced growth of lean tissue and extrauterine growth restriction of premature infants. These results may provide potential molecular targets for intervention to enhance lean growth in preterm infants.

Technical Abstract: 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.