15 Impact of prematurity on the nutritional regulation of growth

Abstract Extrauterine growth restriction is common in premature infants and is largely attributed to reduced lean mass accretion. This reduced lean growth likely contributes to their increased lifelong risk for obesity and type 2 diabetes. There is critical need to identify mechanisms for the reduced growth and to develop targeted nutritional therapies to improve lean accretion. We showed in neonatal pigs born at term that post-meal surges in insulin and amino acids independently activate insulin and amino acid signaling pathways that stimulate mechanistic target of rapamycin complex 1 (mTORC1)-dependent translation initiation and protein synthesis in skeletal muscle. These anabolic actions promote more efficient use of amino acids for muscle protein synthesis and sustain rapid early postnatal growth rates. In contrast, preterm birth reduces relative weight gain and blunts the protein synthetic response in muscle to feeding. The reduced protein synthesis response in the preterm is due to reduced insulin- and amino acid-induced activation of mTORC1. This anabolic resistance to feeding likely contributes to the high prevalence of extrauterine growth restriction and reduced lean mass in prematurity. Supplementation with leucine, an essential amino acid and potent agonist of mTORC1, enhances translation initiation and protein synthesis in skeletal muscle and overall lean growth of neonatal pigs born at term. In the preterm, leucine supplementation also increases mTORC1 activity and protein synthesis, but higher doses are required. This suggests that the anabolic resistance of preterm muscle can be overcome by nutritional therapies targeted to stimulate mTORC1 signaling and protein synthesis and promote lean gain.