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Mammalian Target of Rapamycin Complex 1 Activation Is Required for the Stimulation of Human Skeletal Muscle Protein Synthesis by Essential Amino Acids1–3
Open accessAbstract
The relationship between mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis during instances of amino acid surplus in humans is based solely on correlational data. Therefore, the goal of this study was to use a mechanistic approach specifically designed to determine whether increased mTORC1 activation is requisite for the stimulation of muscle protein synthesis following L-essential amino acid (EAA) ingestion in humans. Examination of muscle protein synthesis and signaling were performed on vastus lateralis muscle biopsies obtained from 8 young (25 ± 2 y) individuals who were studied prior to and following ingestion of 10 g of EAA during 2 separate trials in a randomized, counterbalanced design. The trials were identical except during 1 trial, participants were administered a single oral dose of a potent mTORC1 inhibitor (rapamycin) prior to EAA ingestion. In response to EAA ingestion, an ~60% increase in muscle protein synthesis was observed during the control trial, concomitant with increased phosphorylation of mTOR (Ser(2448)), ribosomal S6 kinase 1 (Thr(389)), and eukaryotic initiation factor 4E binding protein 1 (Thr(37/46)). In contrast, prior administration of rapamycin completely blocked the increase in muscle protein synthesis and blocked or attenuated activation of mTORC1-signaling proteins. The inhibition of muscle protein synthesis and signaling was not due to differences in either extracellular or intracellular amino acid availability, because these variables were similar between trials. These data support a fundamental role for mTORC1 activation as a key regulator of human muscle protein synthesis in response to increased EAA availability. This information will be useful in the development of evidence-based nutritional therapies targeting mTORC1 to counteract muscle wasting associated with numerous clinical conditions.
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“This includes a study in humans showing that the mTORC1 inhibitor rapamycin prevented the increased muscle protein synthesis triggered by resistance exercise (28).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [28]
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In the citing paper
“In mice, the deletion of mTORC1 leads to high muscle atrophy, and in humans, the daily ingestion of 10 g of essential amino acids induces a 60% increase in muscle protein synthesis levels that is absent when mTORC1 inhibitors are simultaneously administered, confirming that mTORC1 is a key regulator of protein synthesis (24, 25).”
From Sarcopenic obesity: epidemiology, pathophysiology, cardiovascular disease, mortality, and management (2023) · cites this paper as [25]
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In the citing paper
“Crucially, Dickinson and Fry established that this failure occurs despite normal or hyperactive acute mTORC1 signaling in the elderly following exercise [19].”
From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [19]
Experimental — accuracy not yet measuredIn the citing paper
“Whey protein has a high essential amino acid (EAA) content, particularly leucine, and its ingestion stimulates muscle protein synthesis (MPS) (11).”
In the citing paper
“Activation of mTORC1 is required for increases in protein synthesis with amino acids [90] and resistance exercise [91].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [90]
In the citing paper
“mTORC1 is well defined as essential to loading induced muscle growth in rodents [89] and stimulus induced increases in MPS in humans [90,91].”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [90]
In the citing paper
“So while the data are clear that mTORC1 is required for load-induced growth [89], resistance exercise [91] and feeding [90], it is still very unclear if manipulating mTORC1 above what occurs physiologically will lead to enhanced muscle growth.”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [90]
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Citations
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Metadata
- Authors
- Dickinson, J. M., Fry, C. S., Drummond, M. J., Gundermann, D. M., Walker, D. K., Glynn, E. L., Timmerman, K. L., Dhanani, S., Volpi, E., & Rasmussen, B. B.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Rasmussen, Blake B.
- ORCID
- Venue
- The Journal of Nutrition
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 141
- Issue
- 5
- Pages
- 856-862
- ISSN
- 0022-3166 (ISSN-L)
- PMC
- PMC3077888
- OpenAlex
- W2116606180
- Cited by
- 282
- References
- 44
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 12 · 2023: 14 · 2022: 20 · 2021: 23 · 2020: 12 · 2019: 21 · 2018: 21 · 2017: 14 · 2016: 24 · 2015: 20 · 2014: 28 · 2013: 26 · 2012: 20
- FWCI
- 11.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Nutrition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NIH T32, UL1TR000071, AG024832)
- National Institute on Aging (P30AG024832)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR049877)
- National Center for Research Resources (UL1RR029876)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32-HD-07539, T32HD007539)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- mTORC1 signaling, muscle protein synthesis, essential amino acids, rapamycin, vastus lateralis, eIF4E-binding protein 1, mTOR phosphorylation, amino acid availability, muscle atrophy, nutritional therapy
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Adult, Amino Acids, Essential, Biopsy, Needle, Enzyme Activation, Female, Humans, Kinetics, Male, Muscle Proteins, Phosphoproteins, Phosphorylation, Protein Processing, Post-Translational, Proteins, Signal Transduction, Up-Regulation, Muscle, Skeletal, Cell Cycle Proteins, Sirolimus, Ribosomal Protein S6 Kinases, 90-kDa, Multiprotein Complexes, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Quadriceps Muscle, Young Adult, TOR Serine-Threonine Kinases
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