Amino acid-induced stimulation of translation initiation in rat skeletal muscle

Abstract

Vary, Thomas C., Leonard S. Jefferson, and Scot R. Kimball. Amino acid-induced stimulation of translation initiation in rat skeletal muscle. Am. J. Physiol. 277 (Endocrinol. Metab. 40): E1077-E1086, 1999.-Amino acids stimulate protein synthesis in skeletal muscle by accelerating translation initiation. In the two studies described herein, we examined mechanisms by which amino acids regulate translation initiation in perfused skeletal muscle hindlimb preparation of rats. In the first study, the effects of supraphysiological amino acid concentrations on eukaryotic initiation factors (eIF) 2B and 4E were compared with physiological concentrations of amino acids. Amino acid supplementation stimulated protein synthesis twofold. No changes were observed in eIF2B activity, in the amount of eIF4E associated with the eIF4E-binding protein (4E-BP1), or in the phosphorylation of 4E-BP1. The abundance of eIF4E bound to eIF4G and the extent of phosphorylation of eIF4E were increased by 800 and 20%, respectively. In the second study, we examined the effect of removing leucine on translation initiation when all other amino acids were maintained at supraphysiological concentrations. Removal of leucine from the perfusate decreased the rate of protein synthesis by 40%. The inhibition of protein synthesis was associated with a 40% decrease in eIF2B activity and an 80% fall in the abundance of eIF4E · eIF4G complex. The fall in eIF4G binding to eIF4E was associated with increased 4E-BP1 bound to eIF4E and a reduced phosphorylation of 4E-BP1. In contrast, the extent of phosphorylation of eIF4E was unaffected. We conclude that formation of the active eIF4E · eIF4G complex controls protein synthesis in skeletal muscle when the amino acid concentration is above the physiological range, whereas removal of leucine reduces protein synthesis through changes in both eIF2B and eIF4E. leucine; eukaryotic initiation factors 4E, 4G, and 2B; 4E-binding protein 1 AMINO ACIDS play a regulatory role in modulating both protein synthesis and protein degradation in a wide range of tissues. Much evidence indicates that a major portion of the increase in skeletal muscle protein synthesis in vivo by refeeding after a brief starvation is independent of changes in anabolic hormones (insulin) and is attributable to amino acids themselves (44, 53). During in vitro perfusion or incubation of skeletal muscles, inclusion of amino acids at 5 or 10 times normal plasma concentrations stimulates protein synthesis (16,19,28,33). Likewise, infusion of amino acids to achieve a relative hyperaminoacidemia stimulates protein synthesis in muscle in vivo (1,2,15,30,(43)(44)(45). Besides amino acids functioning as precursors, they also appear to have a regulatory role for protein synthesis. Amino acids increase rates of protein synthesis by enhancing translation efficiency (19, 28), through stimulating peptide-chain initiation relative to elongation (28). Of all the amino acids, the branched-chain amino acids (leucine, isoleucine, and valine) have a unique role in this pro...

Tissue-Specific Regulation of Mitochondrial and Cytoplasmic Protein Synthesis Rates by Insulin

“…It is possible that the composition of amino acids in commercially available mixtures results in an imbalance of amino acids profile in the circulation, which by itself may prevent protein synthesis. All available evidence (53)(54)(55)(56)(57)(58) indicates that the effect of amino acids on protein synthesis is complex and depends on the type of amino acid mixture administered. In addition, the duration of administration of amino acids may be a factor that determines the effect of amino acids on protein synthesis.…”

An increase in essential amino acid availability upregulates amino acid transporter expression in human skeletal muscle

“…One focus of attention has been on the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), an amino acid sensor (5) and central regulator of translation initiation and elongation (3). Although the mTORC1 pathway has been extensively studied in skeletal muscle of human and rodent models following EAA ingestion or infusion (4,11,14,44), less information is available describing the relationship between amino acid transport mechanisms and mTORC1 signaling, especially in human skeletal muscle.…”

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