The initiation phase of mRNA translation is a key target for the regulation of protein synthesis in skeletal muscle. Translation initiation is mediated by a number of factors which are collectively referred to as eukaryotic initiation factors (eIF). Our general hypothesis is that the factors governing translational control of muscle protein synthesis are responsive not only to the prevailing plasma concentrations of amino acids, but also to the direction in which concentration of leucine changes. The specific mechanism whereby amino acids affect the rate of muscle protein synthesis in vivo is governed by the interplay of the various initiation factors. We propose that a sufficient amount of amino acids are required to repress the phosphorylation state of eIF2alpha (which reflects charging of tRNA) and to maintain the activity of eukaryotic initiation factor (eIF)2B for the basal rate of muscle protein synthesis to be maintained. Further, responses to potential activation of other pathways will be inadequate to result in increased muscle protein synthesis unless there is sufficient charging of tRNA and activity of eIF2B. We propose that in the circumstance of an adequate basal amount of amino acids the transient stimulation of muscle protein synthesis by an increase in amino acid availability is mediated via an mTOR-dependent signaling pathway resulting in an increased phosphorylation of the eIF4E binding protein 1 (4E-BP1) and the 70KDa ribosomal protein S6 kinase (S6K1). In addition, leucine has a specific stimulatory effect on synthesis by activating an mTOR-independent (ie, rapamycin- insensitive) signaling pathway resulting in an increased phosphorylation of eIF4G. We will investigate a series of specific hypotheses related to these general proposals using a porcine model that enable us to make frequent, rapid measurements of both muscle protein synthesis and the various initiation factors. The results will clarify the mechanisms whereby amino acids regulate muscle protein synthesis, and the ultimate benefit of this information will be in terms of designing appropriate nutritional support in a variety of clinical settings.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Nutrition Study Section (NTN)
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Lymn, Richard W
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University of Texas Medical Br Galveston
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Tuvdendorj, Demidmaa; Børsheim, Elisabet; Sharp, Carwyn P et al. (2015) Amino Acid Availability Regulates the Effect of Hyperinsulinemia on Skin Protein Metabolism in Pigs. J Biol Chem 290:17776-83
Tuvdendorj, Demidmaa; Chinkes, David L; Zhang, Xiao-Jun et al. (2011) Skeletal muscle is anabolically unresponsive to an amino acid infusion in pediatric burn patients 6 months postinjury. Ann Surg 253:592-7
Katsanos, Christos S; Aarsland, Asle; Cree, Melanie G et al. (2009) Muscle protein synthesis and balance responsiveness to essential amino acids ingestion in the presence of elevated plasma free fatty acid concentrations. J Clin Endocrinol Metab 94:2984-90
Zhang, Xiao-jun; Chinkes, David L; Wolfe, Robert R (2008) The anabolic effect of arginine on proteins in skin wound and muscle is independent of nitric oxide production. Clin Nutr 27:649-56
Zhang, Xiao-Jun; Irtun, Oivind; Chinkes, David L et al. (2008) Acute responses of muscle protein metabolism to reduced blood flow reflect metabolic priorities for homeostasis. Am J Physiol Endocrinol Metab 294:E551-7
Katsanos, Christos S; Chinkes, David L; Paddon-Jones, Douglas et al. (2008) Whey protein ingestion in elderly persons results in greater muscle protein accrual than ingestion of its constituent essential amino acid content. Nutr Res 28:651-8
Wolfe, Robert R; Song, Juquan; Sun, Jinchun et al. (2007) Total aminoacyl-transfer RNA pool is greater in liver than muscle in rabbits. J Nutr 137:2333-8
Katsanos, Christos S; Kobayashi, Hisamine; Sheffield-Moore, Melinda et al. (2006) A high proportion of leucine is required for optimal stimulation of the rate of muscle protein synthesis by essential amino acids in the elderly. Am J Physiol Endocrinol Metab 291:E381-7
Wolfe, Robert R (2006) The underappreciated role of muscle in health and disease. Am J Clin Nutr 84:475-82
Highstead, R Grant; Tipton, Kevin D; Creson, Daniel L et al. (2005) Incidence of associated events during the performance of invasive procedures in healthy human volunteers. J Appl Physiol 98:1202-6

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