Regulation of skeletal muscle protein synthesis in the preterm pig by intermittent leucine pulses during continuous parenteral feeding

Authors: RUDAR, MARKO - Auburn University; SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC); NGUYEN, HANH - Children'S Nutrition Research Center (CNRC); CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC); VONDEROHE, CATLIN - Children'S Nutrition Research Center (CNRC); STOLL, BARBARA - Children'S Nutrition Research Center (CNRC); Burrin, Douglas - Doug; FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC); DAVIS, TERESA - Children'S Nutrition Research Center (CNRC)

Submitted to: American Society for Parenteral and Enteral Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2022
Publication Date: 2/8/2023
Citation: Rudar, M., Suryawan, A., Nguyen, H.V., Chacko, S.K., Vonderohe, C., Stoll, B., Burrin, D.G., Fiorotto, M.L., Davis, T.A. 2023. Regulation of skeletal muscle protein synthesis in the preterm pig by intermittent leucine pulses during continuous parenteral feeding. American Society for Parenteral and Enteral Nutrition. https://doi.org/10.1002/jpen.2450.
DOI: https://doi.org/10.1002/jpen.2450

Interpretive Summary: Although nutrition management of premature infants has improved in recent years, most preterm infants grow slowly. Cumulative deficits in energy and protein intake in infants that need prolonged intravenous feeding, called parenteral nutrition, can adversely affect body composition. The composition of the body weight gain in premature infants is likely to have more fat mass and less lean mass than in infants who are born at term. Using the neonatal pig as a highly translatable preclinical model for the human infant, our laboratory has previously showed that supplementation with the amino acid, leucine during continuous enteral nutrition can increase the synthesis of protein in skeletal muscle and increase muscle growth in neonates born at term. In this study, we aimed to determine the impact of leucine on protein synthesis in neonatal pigs born preterm that are receiving continuous parenteral nutrition. We found that supplementation with leucine increased circulating leucine concentrations but did not increase the activation of the intracellular signaling pathways that regulate protein synthesis in muscle. These findings are in stark contrast to pigs born at term who benefit from leucine during continuous enteral feeding. However, these data support our previous findings in the preterm piglet model which showed that the anabolic growth responses in muscle to nutrition are blunted by prematurity. These results are directly relevant to the clinical care of premature infants because current nutritional support is often unable to match the growth rate and body composition that approximate a normal fetus of the same gestational age.

Technical Abstract: Extrauterine growth restriction is a common complication of preterm birth. Leucine (Leu) is an agonist for the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway that regulates translation initiation and protein synthesis in skeletal muscle. Previously, we showed that intermittent intravenous pulses of Leu to neonatal pigs born at term receiving continuous enteral nutrition increases muscle protein synthesis and lean mass accretion. Our objective was to determine the impact of intermittent intravenous pulses of Leu on muscle protein anabolism in preterm neonatal pigs administered continuous parenteral nutrition. Following preterm delivery (on day 105 of 115 gestation), pigs were fitted with umbilical artery and jugular vein catheters and provided continuous parenteral nutrition. Four days after birth, pigs were assigned to receive intermittent Leu (1600 umol kg-1h-1; n=8) or alanine (1600 umol kg-1 h-1; n=8) parenteral pulses every 4h for 28h. Anabolic signaling and fractional protein synthesis were determined in skeletal muscle. Leu concentration in the longissimus dorsi and gastrocnemius muscles increased in the leucine (LEU) group compared with the alanine (ALA) group (P<0.0001). Despite the Leu-induced disruption of the Sestrin2/GATOR2 complex, which inhibits mTORC1 activation, in these muscles (P<0.01), the abundance of mTOR/RagA and mTOR/RagC was not different. Accordingly, mTORC1-dependent activation of 4EBP1, S6K1, eIF4E/eIF4G, and protein synthesis were not different in any muscle between the LEU and ALA groups. Intermittent pulses of Leu do not enhance muscle protein anabolism in preterm pigs supplied continuous parenteral nutrition.