Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway

J Nutr. 2000 Oct;130(10):2413-9. doi: 10.1093/jn/130.10.2413.


The objectives of the present study were twofold: 1) to determine whether leucine is unique among the branched-chain amino acids (BCAA) in its ability to stimulate protein synthesis in skeletal muscle of food-deprived rats; and 2) to investigate whether changes in muscle protein synthesis after leucine administration involve a signaling pathway that includes the protein kinase mammalian target of rapamycin (mTOR). In the first set of experiments, food-deprived (18 h) male rats (200 g) were orally administered saline or 270 mg valine, isoleucine or leucine. In the second set of experiments, food-deprived rats were injected intravenously with rapamycin (0.75 mg/kg), a specific inhibitor of mTOR, before leucine administration. Only leucine stimulated protein synthesis in skeletal muscle above saline-treated controls (P: < 0.05). Furthermore, leucine was most effective among the BCAA at enhancing phosphorylation of eukaryotic initiation factor (eIF), 4E binding protein 1 (4E-BP1) and the 70-kDa ribosomal protein S6 kinase (S6K1). Leucine-dependent hyperphosphorylation of 4E-BP1 increased the availability of eIF4E to form the active eIF4G.eIF4E complex. To a lesser extent, isoleucine also enhanced phosphorylation of 4E-BP1 and S6K1. Rapamycin inhibited protein synthesis in both leucine-treated and food-deprived rats. Additionally, rapamycin prevented the stimulatory effects of leucine on eIF4E availability for binding eIF4G and inhibited leucine-dependent phosphorylation of S6K1. The data demonstrate that leucine is unique among the BCAA in its ability to stimulate protein synthesis in muscle of food-deprived rats. We show for the first time that leucine-dependent stimulation of translation initiation in vivo occurs via a rapamycin-sensitive pathway.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins*
  • Electrophoresis, Polyacrylamide Gel
  • Eukaryotic Initiation Factor-4E
  • Food Deprivation
  • Food*
  • Intracellular Signaling Peptides and Proteins
  • Isoleucine / pharmacology
  • Leucine / pharmacology*
  • Male
  • Muscle Proteins / biosynthesis*
  • Muscle Proteins / genetics
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Peptide Initiation Factors / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Biosynthesis / drug effects*
  • Rats
  • Rats, Sprague-Dawley
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / pharmacology*
  • Valine / pharmacology


  • Carrier Proteins
  • Eif4ebp1 protein, rat
  • Eukaryotic Initiation Factor-4E
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Peptide Initiation Factors
  • Phosphoproteins
  • Isoleucine
  • Ribosomal Protein S6 Kinases
  • Leucine
  • Valine
  • Sirolimus