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Leucine: A Potent Nutrient Signal for Protein Synthesis in Neonates
Teresa A. Davis, Marta L. Fiorotto, Agus Suryawan, and Daniel Columbus
USDA/ARS Children’s Nutrition Research Center, Dept. Pediatrics, Baylor College of Medicine, Houston, TX
Neonates are highly efficient at utilizing their dietary amino acids for skeletal muscle growth. In the neonatal pig, the sharp increase in muscle protein synthesis after eating is triggered by the rise in amino acids and insulin. Amino acids and insulin induce protein synthesis by activating independent signaling pathways that converge at mechanistic target of rapamycin complex 1 (mTORC1), leading to the activation of key regulators of translation. Leucine is the most effective single amino acid in triggering translation initiation factor activation. Although most information on leucine’s action on mTORC1-dependent translation initiation has been generated from studies performed in cell culture, studies in the neonatal pig have identified components of the amino acid signaling pathway that regulate protein synthesis in vivo. Acute parenteral leucine administration at physiological levels increases muscle protein synthesis in neonatal pigs and this effect is due to the activation of mTORC1 and its downstream targets, including eukaryotic initiation factor 4E-binding protein 1 and ribosomal protein S6 kinase-1. Although acute administration of the other branched-chain amino acids, isoleucine and valine, are ineffective, the leucine metabolites, α-ketoisocaproic acid and β-hydroxy-β-methylbutyrate, stimulate muscle protein synthesis by activating mTORC1-dependent translation. The stimulation of protein synthesis by parenteral leucine can be sustained for prolonged periods, but is dependent on maintenance of the supply of other amino acids to support protein synthesis. Pulsatile administration of leucine during continuous orogastric feeding of a milk replacer enhances muscle protein synthesis by stimulating translation initiation. Enteral leucine supplementation of a low protein meal stimulates protein synthesis similar to a high protein meal but this effect is diminished but not blocked with more prolonged supplementation. Further studies are needed to establish whether the anabolic effects of leucine can be sustained chronically to promote lean growth. (Supported by NIH AR444474, NIH HD072891, USDA NIFA 2013-67015-20438, and USDA/ARS 6250-51000-055)
Keywords: Amino acids, Growth, Swine, Muscle, Nutrition