The accretion of skeletal muscle mass is a dominant component of neonatal growth. The long-term objective is to define the mechanisms by which nutrients and hormones mediate the high rate of skeletal muscle protein deposition in neonates, with the goal of identifying new strategies to optimize the nutritional management of low birth weight infants. Previous work showed that the feeding-induced stimulation of muscle protein synthesis is mediated independently by insulin and amino acids and is effected by enhanced activation of translation initiation. The insulin response is associated with a heightened responsiveness of the insulin signaling pathway in immature muscle. However, neither the contribution of individual amino acids and glucose to the feeding response, nor the cellular mechanisms responsible for the loss in the insulin and nutrient sensitivity of muscle protein synthesis with development have been elucidated. This proposal tests the hypotheses that: 1) The postprandial rise in leucine alone can stimulate muscle protein synthesis in neonates by modulating translation initiation factor activity; 2) The postprandial rise in glucose enhances the feeding-induced stimulation of muscle protein synthesis in neonates by activating the insulin/nutrient signaling pathway, independently of insulin; and 3) Down-regulation in the activity of the insulin/nutrient signaling pathway with development blunts the nutrient and insulin sensitivity of muscle protein synthesis. The following aims are proposed to address these hypotheses.
In Aim 1, the effect of a physiological rise in leucine on muscle protein synthesis and translation initiation factor activity will be determined using in vivo kinetic measurement of muscle protein synthesis and determination of the activity of the translation initiation factors required for mRNA binding to the 40S ribosomal subunit.
In Aim 2, the effect of a physiological rise in glucose on muscle protein synthesis and the activity of the insulin/nutrient signaling pathway that regulates translation initiation will be assessed from measurements of muscle protein synthesis and the activities of insulin/nutrient signaling proteins and translation initiation factors.
In Aim 3, the relative contributions of positive versus negative signaling regulators in effecting the developmental decline in the sensitivity of muscle protein synthesis to insulin and nutrients will be determined. All studies will use pancreatic-substrate clamps and will be performed in 7- and 26-day-old pigs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044474-09
Application #
6776500
Study Section
Special Emphasis Panel (ZRG1-REB (03))
Program Officer
Nuckolls, Glen H
Project Start
1996-07-20
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
9
Fiscal Year
2004
Total Cost
$325,735
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Manjarín, Rodrigo; Columbus, Daniel A; Solis, Jessica et al. (2018) Short- and long-term effects of leucine and branched-chain amino acid supplementation of a protein- and energy-reduced diet on muscle protein metabolism in neonatal pigs. Amino Acids 50:943-959
Manjarín, Rodrigo; Columbus, Daniel A; Suryawan, Agus et al. (2016) Leucine supplementation of a chronically restricted protein and energy diet enhances mTOR pathway activation but not muscle protein synthesis in neonatal pigs. Amino Acids 48:257-267
Manjarín, Rodrigo; Suryawan, Agus; Koo, Sue J et al. (2016) Insulin modulates energy and substrate sensing and protein catabolism induced by chronic peritonitis in skeletal muscle of neonatal pigs. Pediatr Res 80:744-752
Hernandez-García, Adriana; Manjarín, Rodrigo; Suryawan, Agus et al. (2016) Amino acids, independent of insulin, attenuate skeletal muscle autophagy in neonatal pigs during endotoxemia. Pediatr Res 80:448-51
Hernandez-García, Adriana D; Columbus, Daniel A; Manjarín, Rodrigo et al. (2016) Leucine supplementation stimulates protein synthesis and reduces degradation signal activation in muscle of newborn pigs during acute endotoxemia. Am J Physiol Endocrinol Metab 311:E791-E801
Columbus, Daniel A; Steinhoff-Wagner, Julia; Suryawan, Agus et al. (2015) Impact of prolonged leucine supplementation on protein synthesis and lean growth in neonatal pigs. Am J Physiol Endocrinol Metab 309:E601-10
Layman, Donald K; Anthony, Tracy G; Rasmussen, Blake B et al. (2015) Defining meal requirements for protein to optimize metabolic roles of amino acids. Am J Clin Nutr 101:1330S-1338S
Columbus, Daniel A; Fiorotto, Marta L; Davis, Teresa A (2015) Leucine is a major regulator of muscle protein synthesis in neonates. Amino Acids 47:259-70
Reynolds, Lawrence P; Wulster-Radcliffe, Meghan C; Aaron, Debra K et al. (2015) Importance of Animals in Agricultural Sustainability and Food Security. J Nutr 145:1377-9
Davis, Teresa A; Fiorotto, Marta L; Suryawan, Agus (2015) Bolus vs. continuous feeding to optimize anabolism in neonates. Curr Opin Clin Nutr Metab Care 18:102-8

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