Preterm Birth Alters the Feeding-Induced Activation of Akt Signaling in the Muscle of Neonatal Piglets

Authors

Agus Suryawan
Marko Rudar
Jane K Naberhuis
Marta L Fiorotto
Teresa A Davis

Publication Date

6-1-2023

Journal

Pediatric Research

DOI

10.1038/s41390-022-02382-4

PMID

36402914

PMCID

PMC10195917

PubMedCentral® Posted Date

7-10-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Infant, Newborn, Pregnancy, Humans, Animals, Swine, Female, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases, Premature Birth, Cesarean Section, Animals, Newborn, Infant, Premature, Muscle, Skeletal, Phosphotransferases (Phosphate Group Acceptor), Ubiquitins

Abstract

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.

IMPACT: 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.