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(Journal of Nutrition. 2000;130:2413-2419.)
© 2000 The American Society for Nutritional Sciences


Article

Leucine Stimulates Translation Initiation in Skeletal Muscle of Postabsorptive Rats via a Rapamycin-Sensitive Pathway1

Joshua C. Anthony, Fumiaki Yoshizawa, Tracy Gautsch Anthony, Thomas C. Vary, Leonard S. Jefferson and Scot R. Kimball2

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033

2To whom correspondence should be addressed.

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.


KEY WORDS: • leucine • protein synthesis • translation initiation • skeletal muscle • rats




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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
M. D. Sans, S.-H. Lee, L. G. D'Alecy, and J. A. Williams
Feeding activates protein synthesis in mouse pancreas at the translational level without increase in mRNA
Am J Physiol Gastrointest Liver Physiol, September 1, 2004; 287(3): G667 - G675.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
Z. Liu, G. Li, S. R. Kimball, L. A. Jahn, and E. J. Barrett
Glucocorticoids modulate amino acid-induced translation initiation in human skeletal muscle
Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E275 - E281.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
D. R. Bolster, T. C. Vary, S. R. Kimball, and L. S. Jefferson
Leucine Regulates Translation Initiation in Rat Skeletal Muscle Via Enhanced eIF4G Phosphorylation
J. Nutr., July 1, 2004; 134(7): 1704 - 1710.
[Abstract] [Full Text]


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J. Nutr.Home page
D. K. Layman and J. I. Baum
Dietary Protein Impact on Glycemic Control during Weight Loss
J. Nutr., April 1, 2004; 134(4): 968S - 973S.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
Z. Liu, Y. Wu, E. W. Nicklas, L. A. Jahn, W. J. Price, and E. J. Barrett
Unlike insulin, amino acids stimulate p70S6K but not GSK-3 or glycogen synthase in human skeletal muscle
Am J Physiol Endocrinol Metab, April 1, 2004; 286(4): E523 - E528.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
I. G. Brodsky, D. Suzara, T. A. Hornberger, P. Goldspink, K. E. Yarasheski, S. Smith, J. Kukowski, K. Esser, and S. Bedno
Isoenergetic Dietary Protein Restriction Decreases Myosin Heavy Chain IIx Fraction and Myosin Heavy Chain Production in Humans
J. Nutr., February 1, 2004; 134(2): 328 - 334.
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Am. J. Physiol. Endocrinol. Metab.Home page
C. H. Lang, R. A. Frost, N. Deshpande, V. Kumar, T. C. Vary, L. S. Jefferson, and S. R. Kimball
Alcohol impairs leucine-mediated phosphorylation of 4E-BP1, S6K1, eIF4G, and mTOR in skeletal muscle
Am J Physiol Endocrinol Metab, December 1, 2003; 285(6): E1205 - E1215.
[Abstract] [Full Text] [PDF]


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Eur Respir JHome page
R.T. Jagoe and M.P.K.J. Engelen
Muscle wasting and changes in muscle protein metabolism in chronic obstructive pulmonary disease
Eur. Respir. J., November 2, 2003; 22(46_suppl): 52s - 63s.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
N. Hashimoto and H. Hara
Dietary Amino Acids Promote Pancreatic Protease Synthesis at the Translation Stage in Rats
J. Nutr., October 1, 2003; 133(10): 3052 - 3057.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
C. J. Lynch, B. Halle, H. Fujii, T. C. Vary, R. Wallin, Z. Damuni, and S. M. Hutson
Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR
Am J Physiol Endocrinol Metab, October 1, 2003; 285(4): E854 - E863.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
S. R. Kimball, R. A. Orellana, P. M. J. O'Connor, A. Suryawan, J. A. Bush, H. V. Nguyen, M. C. Thivierge, L. S. Jefferson, and T. A. Davis
Endotoxin induces differential regulation of mTOR-dependent signaling in skeletal muscle and liver of neonatal pigs
Am J Physiol Endocrinol Metab, September 1, 2003; 285(3): E637 - E644.
[Abstract] [Full Text] [PDF]


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Am. J. Clin. Nutr.Home page
E. Volpi, H. Kobayashi, M. Sheffield-Moore, B. Mittendorfer, and R. R Wolfe
Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults
Am. J. Clinical Nutrition, August 1, 2003; 78(2): 250 - 258.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
L. S. Jefferson and S. R. Kimball
Amino Acids as Regulators of Gene Expression at the Level of mRNA Translation
J. Nutr., June 1, 2003; 133(6): 2046S - 2051.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
I. Rieu, C. Sornet, G. Bayle, J. Prugnaud, C. Pouyet, M. Balage, I. Papet, J. Grizard, and D. Dardevet
Leucine-Supplemented Meal Feeding for Ten Days Beneficially Affects Postprandial Muscle Protein Synthesis in Old Rats
J. Nutr., April 1, 2003; 133(4): 1198 - 1205.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
D. K. Layman, H. Shiue, C. Sather, D. J. Erickson, and J. Baum
Increased Dietary Protein Modifies Glucose and Insulin Homeostasis in Adult Women during Weight Loss
J. Nutr., February 1, 2003; 133(2): 405 - 410.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
D. K. Layman
The Role of Leucine in Weight Loss Diets and Glucose Homeostasis
J. Nutr., January 1, 2003; 133(1): 261S - 267.
[Abstract] [Full Text] [PDF]


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J. Clin. Endocrinol. Metab.Home page
Z. Liu, L. A. Jahn, L. Wei, W. Long, and E. J. Barrett
Amino Acids Stimulate Translation Initiation and Protein Synthesis through an Akt-Independent Pathway in Human Skeletal Muscle
J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5553 - 5558.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
Z. Liu and E. J. Barrett
Human protein metabolism: its measurement and regulation
Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1105 - E1112.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
C. J. Lynch, B. J. Patson, J. Anthony, A. Vaval, L. S. Jefferson, and T. C. Vary
Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue
Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E503 - E513.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
J. C. Anthony, C. H. Lang, S. J. Crozier, T. G. Anthony, D. A. MacLean, S. R. Kimball, and L. S. Jefferson
Contribution of insulin to the translational control of protein synthesis in skeletal muscle by leucine
Am J Physiol Endocrinol Metab, May 1, 2002; 282(5): E1092 - E1101.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
S. R. Kimball
Regulation of Global and Specific mRNA Translation by Amino Acids
J. Nutr., May 1, 2002; 132(5): 883 - 886.
[Abstract] [Full Text] [PDF]


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Hum ReprodHome page
F. D. Houghton1, J. A. Hawkhead, P. G. Humpherson, J. E. Hogg, A. H. Balen, A. J. Rutherford, and H. J. Leese
Non-invasive amino acid turnover predicts human embryo developmental capacity
Hum. Reprod., April 1, 2002; 17(4): 999 - 1005.
[Abstract] [Full Text] [PDF]


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DiabetesHome page
J. C. Anthony, A. K. Reiter, T. G. Anthony, S. J. Crozier, C. H. Lang, D. A. MacLean, S. R. Kimball, and L. S. Jefferson
Orally Administered Leucine Enhances Protein Synthesis in Skeletal Muscle of Diabetic Rats in the Absence of Increases in 4E-BP1 or S6K1 Phosphorylation
Diabetes, April 1, 2002; 51(4): 928 - 936.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
D. Dardevet, C. Sornet, G. Bayle, J. Prugnaud, C. Pouyet, and J. Grizard
Postprandial Stimulation of Muscle Protein Synthesis in Old Rats Can Be Restored by a Leucine-Supplemented Meal
J. Nutr., January 1, 2002; 132(1): 95 - 100.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
J. S. Greiwe, G. Kwon, M. L. McDaniel, and C. F. Semenkovich
Leucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscle
Am J Physiol Endocrinol Metab, September 1, 2001; 281(3): E466 - E471.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
T. G. Anthony, J. C. Anthony, F. Yoshizawa, S. R. Kimball, and L. S. Jefferson
Oral Administration of Leucine Stimulates Ribosomal Protein mRNA Translation but Not Global Rates of Protein Synthesis in the Liver of Rats
J. Nutr., April 1, 2001; 131(4): 1171 - 1176.
[Abstract] [Full Text]


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J. Nutr.Home page
J. C. Anthony, T. G. Anthony, S. R. Kimball, and L. S. Jefferson
Signaling Pathways Involved in Translational Control of Protein Synthesis in Skeletal Muscle by Leucine
J. Nutr., March 1, 2001; 131(3): 856S - 860.
[Abstract] [Full Text]


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J. Biol. Chem.Home page
F. Tremblay and A. Marette
Amino Acid and Insulin Signaling via the mTOR/p70 S6 Kinase Pathway. A NEGATIVE FEEDBACK MECHANISM LEADING TO INSULIN RESISTANCE IN SKELETAL MUSCLE CELLS
J. Biol. Chem., October 5, 2001; 276(41): 38052 - 38060.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Endocrinol. Metab.Home page
S. R. Kimball, P. A. Farrell, H. V. Nguyen, L. S. Jefferson, and T. A. Davis
Developmental decline in components of signal transduction pathways regulating protein synthesis in pig muscle
Am J Physiol Endocrinol Metab, March 1, 2002; 282(3): E585 - E592.
[Abstract] [Full Text] [PDF]




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