Prematurity blunts the insulin- and amino acid-induced stimulation of translation initiation and protein synthesis in skeletal muscle of neonatal pigs

Authors: RUDAR, MARKO - Children'S Nutrition Research Center (CNRC); NABERHUIS, JANE - Children'S Nutrition Research Center (CNRC); SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC); NGUYEN, HANH - Children'S Nutrition Research Center (CNRC); STOLL, BARBARA - Children'S Nutrition Research Center (CNRC); STYLE, CANDACE - Michael Debakey Va Medical Center; VERLA, MARIATU - Michael Debakey Va Medical Center; OLUTOYE, OLUYINKA - Michael Debakey Va Medical Center; BURRIN, DOUG - Children'S Nutrition Research Center (CNRC); FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/11/2021
Publication Date: 3/4/2021
Citation: Rudar, M., Naberhuis, J.K., Suryawan, A., Nguyen, H.V., Stoll, B., Style, C.C., Verla, M.A., Olutoye, O.O., Burrin, D.G., Fiorotto, M.L. 2021. Prematurity blunts the insulin- and amino acid-induced stimulation of translation initiation and protein synthesis in skeletal muscle of neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 320(3):E551–E565. https://doi.org/10.1152/ajpendo.00203.2020.
DOI: https://doi.org/10.1152/ajpendo.00203.2020

Interpretive Summary: Approximately 1 in 10 infants in the United States is born prematurely. At an equivalent postconceptional age, infants born prematurely often have lower body weight, less lean mass, greater adiposity, impairments to motor and cognitive functions, and increased risk for developing type 2 diabetes, obesity, and cardiovascular disease compared to infants born at term. Moreover, extrauterine growth faltering is a major complication of premature birth but the underlying cause is poorly understood. We have previously demonstrated that prematurity blunts the feeding-induced stimulation of translation initiation signaling and protein synthesis in the skeletal muscle of a neonatal piglet model of the human infant. The objective of the current study was to determine whether the blunted feeding response is mediated by reduced responsiveness to insulin, amino acids, or both. Pigs were delivered by Cesarean section, either preterm or at term, and fed by total parenteral nutrition for 4 days until the separate effects of physiological increases in insulin and amino acids were determined using pancreatic-substrate clamp procedures. Indices of amino acid and insulin signaling to mechanistic target of rapamycin complex 1 (mTORC1), translation initiation, and protein synthesis were measured after 2 h. The results show that the activation of both the amino acid and insulin signaling pathways that lead to mTORC1-dependent translation initiation and protein synthesis were stimulated by amino acids and insulin in skeletal muscle of term and preterm pigs. However, the responses were lower in preterm than in those born at term. These results suggest that preterm birth blunts both the insulin- and amino acid-induced activation of translation initiation and protein synthesis in skeletal muscle, thereby limiting the anabolic response to feeding. This anabolic resistance likely contributes to the high prevalence of extrauterine growth restriction in prematurity.

Technical Abstract: Extrauterine growth restriction in premature infants is largely attributed to reduced lean mass accretion and is associated with long-term morbidities. Previously, we demonstrated that prematurity blunts the feeding-induced stimulation of translation initiation signaling and protein synthesis in skeletal muscle of neonatal pigs. The objective of the current study was to determine whether the blunted feeding response is mediated by reduced responsiveness to insulin, amino acids, or both. Pigs delivered by Cesarean section preterm (PT; 103 d, n = 25) or at term (T; 112 d, n = 26) were subject to euinsulinemic-euaminoacidemic-euglycemic (FAST),hyperinsulinemic-euaminoacidemic-euglycemic (INS), or euinsulinemic-hyperaminoacidemic euglycemic (AA) clamps 4 d after delivery. Indices of mechanistic target of rapamycin complex 1(mTORC1) signaling and fractional protein synthesis rates were measured after 2 h. While longissimus dorsi (LD) muscle protein synthesis increased in response to both INS and AA, the increase was 28% lower in PT than T. Upstream of mTORC1, Akt phosphorylation, an index of insulin signaling, was increased with INS but was 40% less in PT than T. The abundances of mTOR/RagA and mTOR/RagC, indices of amino acid signaling, increased with AA but were 25% less in PT than T. Downstream of mTORC1, eIF4E/eIF4G abundance was increased by both INS and AA but attenuated by prematurity. These results suggest that preterm birth blunts both insulin- and amino acid-induced activation of mTORC1 and protein synthesis in skeletal muscle, thereby limiting the anabolic response to feeding. This anabolic resistance likely contributes to the high prevalence of extrauterine growth restriction in prematurity.