Signaling Pathways Involved in Translational Control of Protein Synthesis in Skeletal Muscle by Leucine
Open accessAbstract
Numerous reports established that in skeletal muscle the indispensable branched-chain amino acid leucine is unique in its ability to initiate signal transduction pathways that modulate translation initiation. Oral administration of leucine stimulates protein synthesis in association with hyperphosphorylation of the translational repressor, eukaryotic initiation factor (eIF) 4E binding protein 1 (4E-BP1), resulting in enhanced availability of the mRNA cap-binding protein eIF4E, for binding eIF4G and forming the active eIF4F complex. In addition, leucine enhances phosphorylation of the 70-kDa ribosomal protein S6 kinase (S6K1). These results suggest that leucine upregulates protein synthesis in skeletal muscle by enhancing both the activity and synthesis of proteins involved in mRNA translation. The stimulatory effects of leucine on translation initiation are mediated in part through the protein kinase mammalian target of rapamycin (mTOR), where both insulin signaling and leucine signaling converge to promote a maximal response.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A 3-6 g daily dose of L-leucine might be beneficial for those engaged in strenuous endurance and/or resistance training.
“there are reports that a 3–6 g daily dose of L-leucine might be beneficial for those engaged in strenuous endurance and/or resistance training [75]”
From International Society of Sports Nutrition Position Stand: nutritional considerations for single-stage ultra-marathon training and racing (2019) · cites this paper as [75]
L-leucine may support the upregulation of muscle protein synthesis, influencing mRNA translation and the mTOR cell-signalling pathway.
“the literature suggests that L-leucine may support the upregulation of muscle protein synthesis, influencing mRNA translation and the mTOR cell-signalling pathway [75]”
From International Society of Sports Nutrition Position Stand: nutritional considerations for single-stage ultra-marathon training and racing (2019) · cites this paper as [75]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Hara, K., Yonezawa, K., Weng, Q.-P., Kozlowski, M. T., BELHAM, C. M., & Avruch, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14484 · Cited by 1,370 · see citing works
Pause, A., Belsham, G. J., Gingras, A., Donzé, O., Lin, T.-A., Lawrence, J. C., & Sonenberg, N. (1994) · Nature · doi:10.1038/371762a0 · Cited by 1,242 · see citing works
RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1
Burnett, P. E., Barrow, R. K., Cohen, N. A., Snyder, S. H., & Sabatini, D. M. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.4.1432 · Cited by 1,139 · see citing works
Navé, B., Ouwens, M., Withers, D., Alessi, D. R., & Shepherd, P. (1999) · Biochemical Journal · doi:10.1042/bj3440427 · Cited by 972 · see citing works
Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm.
Fulks, R. M., Li, J. B., & Goldberg, A. L. (1975) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)42013-9 · Cited by 914 · see citing works
Anthony, J. C., Yoshizawa, F., Anthony, T. G., Vary, T. C., Jefferson, L. S., & Kimball, S. R. (2000) · Journal of Nutrition · doi:10.1093/jn/130.10.2413 · Cited by 804 · see citing works
Self-citationLeucine. A possible regulator of protein turnover in muscle.
Buse, M. G., & Reid, S. S. (1975) · Journal of Clinical Investigation · doi:10.1172/jci108201 · Cited by 744 · see citing works
Initiation of Protein Synthesis in Eukaryotic Cells
Pain, V. M. (1996) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1996.00747.x · Cited by 712 · see citing works
Bidirectional modulation of insulin action by amino acids.
Patti, M., Brambilla, E., Luzi, L., Landaker, E. J., & Kahn, C. R. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1326 · Cited by 491 · see citing works
Anthony, J. C., Anthony, T. G., Kimball, S. R., Vary, T. C., & Jefferson, L. S. (2000) · Journal of Nutrition · doi:10.1093/jn/130.2.139 · Cited by 469 · see citing works
Self-citationKimball, S., Shantz, L., Horetsky, R. L., & Jefferson, L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.11647 · Cited by 382 · see citing works
Self-citationGarlick, P. J., & Grant, I. S. (1988) · Biochemical Journal · doi:10.1042/bj2540579 · Cited by 286 · see citing works
Influence of amino acid availability on protein turnover in perfused skeletal muscle
Li, J. B., & Jefferson, L. S. (1978) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(78)90103-4 · Cited by 276 · see citing works
Self-citationThe effect of insulin infusion and food intake on muscle protein synthesis in postabsorptive rats
Garlick, P. J., Fern, M., & Preedy, V. R. (1983) · Biochemical Journal · doi:10.1042/bj2100669 · Cited by 267 · see citing works
Xu, G. H., Kwon, G., Marshall, C. A., Lin, T.-A., Lawrence, J. C., & McDaniel, M. L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.43.28178 · Cited by 237 · see citing works
Leucine Supplementation Enhances Skeletal Muscle Recovery in Rats Following Exercise
Anthony, J. C., Anthony, T. G., & Layman, D. K. (1999) · Journal of Nutrition · doi:10.1093/jn/129.6.1102 · Cited by 226 · see citing works
Self-citationAvailability of eIF4E regulates skeletal muscle protein synthesis during recovery from exercise
Anthony, T. G., Anthony, T. G., Kimball, S. R., Paul, G. L., Layman, D. K., & Jefferson, L. S. (1998) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1998.274.2.c406 · Cited by 204 · see citing works
Self-citationMammalian TOR Controls One of Two Kinase Pathways Acting upon nPKCδ and nPKCε*
Parekh, D., Ziegler, W., Yonezawa, K., Hara, K., & Parker, P. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.49.34758 · Cited by 183 · see citing works
Nygârd, O., & NILSSON, L. (1990) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1990.tb19087.x · Cited by 162 · see citing works
Effect of dietary protein on translation initiation in rat skeletal muscle and liver
Yoshizawa, F., Kimball, S. R., Vary, T. C., & Jefferson, L. S. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.5.e814 · Cited by 154 · see citing works
Self-citationFailure of leucine to stimulate protein synthesis in vivo
McNurlan, M. A., Fern, E. B., & Garlick, P. J. (1982) · Biochemical Journal · doi:10.1042/bj2040831 · Cited by 148 · see citing works
The protein kinase C and protein kinase C related gene families.
Dekker, L., Palmer, R. H., & Parker, P. J. (1995) · Current Opinion in Structural Biology · doi:10.1016/0959-440x(95)80103-0 · Cited by 122 · see citing works
Kumar, V., Pandey, P., Sabatini, D., Kumar, M., Majumder, P., Bharti, A., Carmichael, G., Kufe, D., & Kharbanda, S. (2000) · EMBO Journal · doi:10.1093/emboj/19.5.1087 · Cited by 113 · see citing works
Effects of Leucine on in Vitro Protein Synthesis and Degradation in Rat Skeletal Muscles
Hong, S.-O. C., & Layman, D. K. (1984) · Journal of Nutrition · doi:10.1093/jn/114.7.1204 · Cited by 90 · see citing works
Modulation of Translation Initiation in Rat Skeletal Muscle and Liver in Response to Food Intake
Yoshizawa, F., Kimball, S. R., & Jefferson, L. S. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.7652 · Cited by 86 · see citing works
Self-citationPostprandial stimulation of muscle protein synthesis is independent of changes in insulin
Svanberg, E., Jefferson, L. S., Lundholm, K., & Kimball, S. R. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.272.5.e841 · Cited by 80 · see citing works
Self-citationGlucocorticoids oppose translational control by leucine in skeletal muscle.
Shah, O., Anthony, J. C., Kimball, S., & Jefferson, L. (2000) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.5.e1185 · Cited by 68 · see citing works
Self-citationYoshizawa, F., Endo, M., Ide, H., et al. (1995) · The Journal of Nutritional Biochemistry · doi:10.1016/0955-2863(95)00018-u · Cited by 55 · see citing works
In vitro effect of branched chain amino acids on the ribosomal cycle in muscles of fasted rats.
Buse, M. G., Atwell, R., & Mancusi, V. J. (1979) · PubMed · Cited by 50 · see citing works
Mechanisms of translational control in liver and skeletal muscle
Kimball, S. R., & Jefferson, L. S. (1994) · Biochimie · doi:10.1016/0300-9084(94)90077-9 · Cited by 31 · see citing works
Self-citationInitiation of protein synthesis in eukaryotes
Voorma, H. O., Thomas, A. A. M., & Heugten, H. A. A. V. (1994) · Molecular Biology Reports · doi:10.1007/bf00986956 · Cited by 22 · see citing works
Branched Chain Amino and Keto Acids as Regulators of Insulin and Glucagon Release
Malaisse, W. J. (2015) · KARGER eBooks · doi:10.1159/000410888 · Cited by 16 · see citing works
In vivo effect of ?-leucine administration on protein synthesis in mice
Funabiki, R. (1992) · The Journal of Nutritional Biochemistry · doi:10.1016/0955-2863(92)90014-a · Cited by 16 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Jefferies, H.B.J. & Thomas, G. (1996) Ribosomal protein S6 phosphorylation and signal transduction. In: Translational Control (Hershey, J.W.B., Mathews, M. B. & Sonenberg, N., eds.), pp. 389 -409. Cold Spring Harbor Laboratory Press, Plainview, NY.
Cited by
Sorted by citations
Wilkinson, D. J., Hossain, T., Hill, D. S., Phillips, B. E., Crossland, H., Williams, J., Loughna, P., Churchward‐Venne, T. A., Breen, L., Phillips, S. M., et al. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.253203 · Cited by 484 · see citing works
Berrazaga, I., Micard, V., Gueugneau, M., & Walrand, S. (2019) · Nutrients · doi:10.3390/nu11081825 · Cited by 477 · see citing works
Leucine Regulates Translation Initiation of Protein Synthesis in Skeletal Muscle after Exercise
Norton, L. E., & Layman, D. K. (2006) · The Journal of Nutrition · doi:10.1093/jn/136.2.533s · Cited by 333 · see citing works
Wilson, G. J., Wilson, J. M., & Manninen, A. H. (2008) · Nutrition & Metabolism · doi:10.1186/1743-7075-5-1 · Cited by 306 · see citing works
Increased Protein Intake Reduces Lean Body Mass Loss during Weight Loss in Athletes
METTLER, S., MITCHELL, N., & TIPTON, K. D. (2010) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e3181b2ef8e · Cited by 288 · see citing works
Physiopathological Mechanism of Sarcopenia
Walrand, S., Guillet, C., Salles, J., Cano, N., & Boirie, Y. (2011) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2011.03.005 · Cited by 235 · see citing works
Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence
Landi, F., Calvani, R., Tosato, M., Martone, A., Ortolani, E., Savera, G., D’Angelo, E., Sisto, A., & Marzetti, E. (2016) · Nutrients · doi:10.3390/nu8050295 · Cited by 218 · see citing works
Dietary protein requirements and adaptive advantages in athletes
Phillips, S. M. (2012) · British Journal Of Nutrition · doi:10.1017/s0007114512002516 · Cited by 199 · see citing works
Lacroix, M., Bos, C., Léonil, J., Airinei, G., Luengo, C., Daré, S., Benamouzig, R., Fouillet, H., Fauquant, J., Tomé, D., et al. (2006) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/84.5.1070 · Cited by 194 · see citing works
Cardiac atrophy in women following bed rest
Dorfman, T. A., Levine, B. D., Tillery, T., Peshock, R. M., Hastings, J. L., Schneider, S. M., Macias, B. R., Biolo, G., & Hargens, A. R. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01162.2006 · Cited by 189 · see citing works
Whey protein supplementation during resistance training augments lean body mass
Volek, J. S., Volk, B. M., Gómez, A. L., Kunces, L. J., Kupchak, B. R., Freidenreich, D. J., Aristizabal, J. C., Saenz, C., Dunn-Lewis, C., Ballard, K. D., et al. (2013) · Journal of the American College of Nutrition · doi:10.1080/07315724.2013.793580 · Cited by 181 · see citing works
The impact of protein quality on the promotion of resistance exercise-induced changes in muscle mass
Phillips, S. M. (2016) · Nutrition & Metabolism · doi:10.1186/s12986-016-0124-8 · Cited by 168 · see citing works
Stec, M. J., Kelly, N. A., Many, G. M., Windham, S. T., Tuggle, S. C., & Bamman, M. M. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00486.2015 · Cited by 161 · see citing works
Tiller, N. B., Roberts, J. D., Beasley, L., Chapman, S., Pinto, J. M., Smith, L., Wiffin, M., Russell, M., Sparks, S. A., Duckworth, L., et al. (2019) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-019-0312-9 · Cited by 164 · see citing works
Current Concepts and Unresolved Questions in Dietary Protein Requirements and Supplements in Adults
Phillips, S. M. (2017) · Frontiers in Nutrition · doi:10.3389/fnut.2017.00013 · Cited by 145 · see citing works
Devries, M. C., McGlory, C., Bolster, D. R., Kamil, A., Rahn, M., Harkness, L., Baker, S. K., & Phillips, S. M. (2018) · The Journal of Nutrition · doi:10.1093/jn/nxy091 · Cited by 141 · see citing works
Protein Considerations for Optimising Skeletal Muscle Mass in Healthy Young and Older Adults
Witard, O., Wardle, S., Macnaughton, L., Hodgson, A., & Tipton, K. (2016) · Nutrients · doi:10.3390/nu8040181 · Cited by 132 · see citing works
Thermodynamics of weight loss diets
Fine, E. J., & Feinman, R. D. (2004) · Nutrition & Metabolism · doi:10.1186/1743-7075-1-15 · Cited by 124 · see citing works
Protein Quantity and Quality at Levels above the RDA Improves Adult Weight Loss
Layman, D. K. (2004) · Journal of the American College of Nutrition · doi:10.1080/07315724.2004.10719435 · Cited by 114 · see citing works
Koopman, R., Verdijk, L. B., Beelen, M., Gorselink, M., Kruseman, A. N., Wagenmakers, A. J. M., Kuipers, H., & van Loon, L. J. C. (2008) · British Journal Of Nutrition · doi:10.1017/s0007114507812013 · Cited by 104 · see citing works
The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes
Gran, P., & Cameron-Smith, D. (2011) · BMC Physiology · doi:10.1186/1472-6793-11-10 · Cited by 95 · see citing works
Growing older with health and vitality: a nexus of physical activity, exercise and nutrition
Witard, O. C., McGlory, C., Hamilton, D. L., & Phillips, S. M. (2016) · Biogerontology · doi:10.1007/s10522-016-9637-9 · Cited by 91 · see citing works
Protein-Amino Acid Metabolism Disarrangements: The Hidden Enemy of Chronic Age-Related Conditions
Pasini, E., Corsetti, G., Aquilani, R., Romano, C., Picca, A., Calvani, R., & Dioguardi, F. (2018) · Nutrients · doi:10.3390/nu10040391 · Cited by 71 · see citing works
Prospective views for whey protein and/or resistance training against age-related sarcopenia
Liao, Y., Peng, Z., Chen, L., Zhang, Y., Cheng, Q., Nüssler, A. K., Bao, W., Liu, L., & Yang, W. (2019) · Aging and Disease · doi:10.14336/ad.2018.0325 · Cited by 68 · see citing works
Kephart, W. C., Wachs, T. D., Mac Thompson, R., Brooks Mobley, C., Fox, C. D., McDonald, J. R., Ferguson, B. S., Young, K. C., Nie, B., Martin, J. S., et al. (2016) · Amino Acids · doi:10.1007/s00726-015-2125-8 · Cited by 62 · see citing works
Zhu, M. J., Du, M., Nijland, M. J., Nathanielsz, P. W., Hess, B. W., Moss, G. E., & Ford, S. P. (2009) · Placenta · doi:10.1016/j.placenta.2009.02.001 · Cited by 54 · see citing works
Remodeling of lipid metabolism by dietary restriction of essential amino acids
Anthony, T. G., Morrison, C. D., & Gettys, T. W. (2013) · Diabetes · doi:10.2337/db12-1613 · Cited by 52 · see citing works
Anthony, T. G., Mirek, E. T., Bargoud, A. R., Phillipson-Weiner, L., DeOliveira, C. M., Wetstein, B., Graf, B. L., Kuhn, P. E., & Raskin, I. (2015) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2015-0301 · Cited by 25 · see citing works
Self-citationJi, X., Ye, X., Ji, S., Zhang, S., Wang, Y., Zhou, Z., Xiang, D., & Luo, B. (2025) · Nutrients · doi:10.3390/nu17162579 · Cited by 12 · see citing works
Piri Damaghi, M., Mirzababaei, A., Moradi, S., Daneshzad, E., Tavakoli, A., Clark, C. C. T., & Mirzaei, K. (2022) · British Journal of Nutrition · doi:10.1017/s0007114521001550 · Cited by 11 · see citing works
- Authors
- Anthony, J. C., Anthony, T. G., Kimball, S. R., & Jefferson, L. S.
- Affiliations
- Pennsylvania State University (US)
- Corresponding author
- Jefferson, Leonard S.
- Venue
- The Journal of Nutrition
- Publisher
- Elsevier BV
- Published
- 2001-03
- Volume
- 131
- Issue
- 3
- Pages
- 856S-860S
- ISSN
- 0022-3166 (ISSN-L)
- OpenAlex
- W2172174202
- Cited by
- 434
- References
- 33
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 11 · 2023: 17 · 2022: 15 · 2021: 17 · 2020: 5 · 2019: 15 · 2018: 21 · 2017: 16 · 2016: 21 · 2015: 25 · 2014: 20 · 2013: 34 · 2012: 23
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- leucine, skeletal muscle, protein synthesis, translation initiation, branched-chain amino acids, 4E-BP1, eIF4E, eIF4F, S6K1, mTOR signaling, insulin signaling, translational regulation
- MeSH terms
- Animals, Immunosuppressive Agents, Insulin, Leucine, Muscle Proteins, Phosphorylation, RNA, Messenger, Protein Biosynthesis, Signal Transduction, Muscle, Skeletal, Sirolimus, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
