Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/30/2004
Publication Date: 1/11/2005
Citation: Escobar, J., Frank, J.W., Suryawan, A., Nguyen, H.V., Kimball, S.R., Jefferson, L.S., Davis, T.A. 2005. Physiological rise in plasma leucine stimulates muscle protein synthesis in neonatal pigs by enhancing translation initiation factor activation. American Journal of Physiology, Endocrinology, and Metabolism. 288(5):E914-E921. Interpretive Summary: Growth is very rapid in the newborn because feeding stimulates the synthesis of proteins in all tissues of the body. This response to feeding is, in part, mediated by the post-feeding increase in amino acid levels. However, it is not known whether specific amino acids play more important roles than other amino acids in stimulating protein synthesis. In this study in which we used newborn pigs as a model of the human, we wished to determine whether the branched chain amino acid, leucine, affects the stimulation of protein synthesis by amino acids. We further wished to identify the intracellular signaling pathways that regulate the response. Our work shows that the rise in leucine alone in the blood after a meal increases protein synthesis in skeletal muscle but not in the liver. Our work further identified the intracellular signaling proteins that respond to leucine in skeletal muscle. This information furthers the scientific understanding of the mechanisms underlying the response of different parts of the body to nourishment, and will help us find optimal ways of supporting the proper growth and development of babies.
Technical Abstract: Protein synthesis in skeletal muscle of adult rats increases in response to oral gavage of supraphysiological doses of leucine. However, the effect on protein synthesis of a physiological rise in plasma leucine has not been investigated in neonates, an anabolic population highly sensitive to amino acids and insulin. Therefore, in the current study, fasted pigs were infused intra-arterially with leucine (0, 200, or 400 micromol.kg [-1].h [-1]), and protein synthesis was measured after 60 or 120 min. Protein synthesis was increased in muscle, but not in liver, at 60 min. At 120 min, however, protein synthesis returned to baseline levels in muscle but was reduced below baseline values in liver. The increase in protein synthesis in muscle was associated with increased plasma leucine of 1.5- to 3-fold and no change in plasma insulin. Leucine infusion for 120 min reduced plasma essential amino acid levels. Phosphorylation of eukaryotic initiation factor (eIF)-4E-binding protein-1 (4E-BP1), ribosomal protein (rp) S6 kinase, and rpS6 was increased, and the amount of eIF4E associated with its repressor 4E-BP1 was reduced after 60 and 120 min of leucine infusion. No change in these biomarkers of mRNA translation was observed in liver. Thus a physiological increase in plasma leucine stimulates protein synthesis in skeletal muscle of neonatal pigs in association with increased eIF4E availability for eIF4F assembly. This response appears to be insulin independent, substrate dependent, and tissue specific. The results suggest that the branched-chain amino acid leucine can act as a nutrient signal to stimulate protein synthesis in skeletal muscle of neonates.