Amino acids augment muscle protein synthesis in neonatal pigs during acute endotoxemia by stimulating mTOR-dependent translation initiation

Authors: ORELLANA, RENAN - BAYLOR COLLEGE MED; JEYAPALAN, ASUMTHIA - BAYLOR COLLEGE MED; ESCOBAR, JEFFERY - BAYLOR COLLEGE MED; FRANK, JASON - BAYLOR COLLEGE MED; NGUYEN, HANH - BAYLOR COLLEGE MED; Suryawan, Agus; Davis, Teresa

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/2007
Publication Date: 9/11/2007
Citation: Orellana, R.A., Jeyapalan, A., Escobar, J., Frank, J.W., Nguyen, H.V., Suryawan, A., Davis, T.A. 2007. Amino acids augment muscle protein synthesis in neonatal pigs during acute endotoxemia by stimulating mTOR-dependent translation initiation. American Journal of Physiology-Endocrinology and Metabolism. 293(5):E1416-E1425.

Interpretive Summary: The presence of bacterial endotoxin in the blood can induce a number of derangements, including muscle wasting. This muscle wasting is in part due to a reduction in the synthesis of muscle proteins. We have used the neonatal pig as a model of the human neonate to examine the mechanisms that are involved in the regulation of protein synthesis in muscle during bacterial endotoxemia and to identify treatments that can be used to improve muscle growth. In this paper, we demonstrate that the synthesis of muscle proteins increases in response to treatment with amino acids when the newborn pigs are ill from bacterial endotoxin in the blood. We further identified the intracellular signaling mechanisms that regulate the increased synthesis of muscle proteins when amino acids are given to newborn pigs that are ill with bacterial endotoxemia. These findings suggest that amino acid supplementation may help to reduce the malnutrition triggered by bacterial endotoxin in the muscle of the newborns and to improve muscle growth.

Technical Abstract: In skeletal muscle of adults, sepsis reduces protein synthesis by depressing translation initiation and induces resistance to branched-chain amino acid stimulation. Normal neonates maintain a high basal muscle protein synthesis rate that is sensitive to amino acid stimulation. In the present study, we determined the effect of amino acids on protein synthesis in skeletal muscle and other tissues in septic neonates. Overnight-fasted neonatal pigs were infused with endotoxin (LPS, 0 and 10 µg•kg(-1)•h(-1), whereas glucose and insulin were maintained at fasting levels; amino acids were clamped at fasting or fed levels. In the presence of fasting insulin and amino acids, LPS reduced protein synthesis in longissimus dorsi (LD) and gastrocnemius muscles and increased protein synthesis in the diaphragm, but had no effect in masseter and heart muscles. Increasing amino acids to fed levels accelerated muscle protein synthesis in LD, gastrocnemius, masseter, and diaphragm. LPS stimulated protein synthesis in liver, lung, spleen, pancreas, and kidney in fasted animals. Raising amino acids to fed levels increased protein synthesis in liver of controls, but not LPS-treated animals. The increase in muscle protein synthesis in response to amino acids was associated with increased mTOR, 4E-BP1, and S6K1 phosphorylation and eIF4G-eIF4E association in control and LPS-infused animals. These findings suggest that amino acids stimulate skeletal muscle protein synthesis during acute endotoxemia via mTOR-dependent ribosomal assembly despite reduced basal protein synthesis rates in neonatal pigs. However, provision of amino acids does not further enhance the LPS-induced increase in liver protein synthesis.