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Cited by 282Muscle metabolism and nutritionPI3K/AKT/mTOR signaling in cancerMuscle Physiology and Disorders

Mammalian Target of Rapamycin Complex 1 Activation Is Required for the Stimulation of Human Skeletal Muscle Protein Synthesis by Essential Amino Acids1–3

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Dickinson, Jared M., Fry, Christopher S., Drummond, Micah J., Gundermann, David M., Walker, Dillon K., Glynn, Erin L., Timmerman, Kyle L., Dhanani, Shaheen +2 more·2011·The Journal of Nutrition
DOI 10.3945/jn.111.139485PMC PMC3077888
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Abstract

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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  • Rapamycin prevented the increased muscle protein synthesis triggered by resistance exercise in humans.

    “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]

    The Discussion (page not provided) reports that previous work from the authors’ laboratory found rapamycin blocked resistance-exercise-induced increases in muscle protein synthesis. But this paper’s own human experiment tested essential amino acid ingestion, not resistance exercise; its References identify Drummond et al. (2009) as the earlier exercise study. (LLM, conf=0.87)

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  • The failure of older adults to upregulate c-Myc and 45S pre-rRNA occurs despite normal or hyperactive acute mTORC1 signaling.

    “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]

    The Participants section describes eight young adults, and the study examines mTORC1 signaling after essential amino acid ingestion, not exercise in older adults. The Introduction and Discussion address mTORC1 and muscle protein synthesis, but the passages found for c-Myc, 45S pre-rRNA, and elderly exercise responses do not report the claimed failure or establish that it occurs despite normal or hyperactive signaling. Page numbers were unavailable in our copy. (LLM, conf=0.76)

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  • In mice, deletion of mTORC1 leads to high muscle atrophy, and in humans, daily ingestion of 10 g essential amino acids induces a 60% increase in muscle protein synthesis levels that is absent when mTORC1 inhibitors are simultaneously administered, confirming mTORC1 is a key regulator of protein synthesis.

    “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]

  • Whey is rich in essential amino acids, especially leucine, and consuming it boosts muscle protein synthesis.

    “Whey protein has a high essential amino acid (EAA) content, particularly leucine, and its ingestion stimulates muscle protein synthesis (MPS) (11).”

    From A randomized controlled trial of the impact of protein supplementation on leg lean mass and integrated muscle protein synthesis during inactivity and energy restriction in older persons (2018) · cites this paper as [11]

  • Activation of mTORC1 is required for increases in protein synthesis with amino acids and resistance exercise.

    “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]

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  1. atom percent excess), after conversion to phenylethylamine, in relation to protein turnover studies by gas chromatography/electron ionization mass spectrometry. Rapid Commun Mass Spectrom. 1992;6:421-4.

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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)
DOI
10.3945/jn.111.139485
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
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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