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Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle

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Greenhaff, P. L., Karagounis, L. G., Peirce, N., Simpson, E. J., Hazell, M., Layfield, R., Wackerhage, H., Smith, K. +3 more·2008·American Journal of Physiology-Endocrinology and Metabolism
DOI 10.1152/ajpendo.90411.2008PMC PMC2536736
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Abstract

We determined the effects of intravenous infusion of amino acids (AA) at serum insulin of 5, 30, 72, and 167 mU/l on anabolic signaling, expression of ubiquitin-proteasome components, and protein turnover in muscles of healthy young men. Tripling AA availability at 5 mU/l insulin doubled incorporation of [1- 13 C]leucine [i.e., muscle protein synthesis (MPS), P < 0.01] without affecting the rate of leg protein breakdown (LPB; appearance of d 5 -phenylalanine). While keeping AA availability constant, increasing insulin to 30 mU/l halved LPB ( P < 0.05) without further inhibition at higher doses, whereas rates of MPS were identical to that at 5 mU/l insulin. The phosphorylation of PKB Ser 473 and p70 S6k Thr 389 increased concomitantly with insulin, but whereas raising insulin to 30 mU/l increased the phosphorylation of mTOR Ser 2448 , 4E-BP1 Thr 37/46 , or GSK3β Ser 9 and decreased that of eEF2 Thr 56 , higher insulin doses to 72 and 167 mU/l did not augment these latter responses. MAFbx and proteasome C2 subunit proteins declined as insulin increased, with MuRF-1 expression largely unchanged. Thus increasing AA and insulin availability causes changes in anabolic signaling and amounts of enzymes of the ubiquitin-proteasome pathway, which cannot be easily reconciled with observed effects on MPS or LPB.

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  • Post-workout carbohydrate supplementation likely exerts minimal influence from a muscle development standpoint provided adequate protein is consumed.

    “This would suggest that post-workout carbohydrate supplementation likely exerts minimal influence from a muscle development standpoint provided adequate protein is consumed.”

    From International society of sports nutrition position stand: nutrient timing (2017) · cites this paper as [102]

    The Results (Leg Protein Turnover and MPS; page unavailable) show that amino acids increased muscle protein synthesis without an insulin increase, and higher insulin did not increase synthesis further. But raising insulin from 5 to 30 mU/l reduced leg protein breakdown by about 50%. The paper did not test post-workout carbohydrate supplementation or muscle development, so it does not establish that carbohydrate has minimal influence when protein intake is adequate. (LLM, conf=0.86)

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  • Insulin-mediated effects that reduce muscle protein breakdown peak at low to moderate levels of insulin (~15-30 μIU/mL) that can be achieved by consumption of a 45-g dose of whey protein isolate alone.

    “insulin-mediated effects that reduce muscle protein breakdown peaks at low to moderate levels of insulin (~15–30 μIU/mL) [103, 104] that can be achieved by consumption of a 45-g dose of whey protein isolate alone [105].”

    From International Society of Sports Nutrition Position Stand: protein and exercise (2017) · cites this paper as [103]

  • Insulin-mediated effects on reducing proteolysis plateau within a range of ~ 15-30 μIU/mL, and these levels are achieved by consuming a 45 g bolus of whey protein isolate alone.

    “However, insulin-mediated effects on reducing proteolysis plateau within a range of ~ 15–30 μIU/mL [102, 103], and these levels are achieved by consuming a 45 g bolus of whey protein isolate alone [104].”

    From International society of sports nutrition position stand: nutrient timing (2017) · cites this paper as [102]

  • When insulin is infused to supra-physiological levels, mTORC1 is potently activated without a concomitant increase in muscle protein synthesis.

    “However, when insulin is infused to supra-physiological levels mTORC1 is potently activated without a concomitant increase in muscle protein synthesis [99].”

    From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [99]

  • Only a fraction of maximal mTORC1 activity (~30%) is required to fully saturate muscle protein synthesis.

    “Furthermore, only a fraction of maximal mTORC1 activity (~30%) is required to fully saturate muscle protein synthesis [98,99].”

    From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [99]

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Authors
Greenhaff, P. L., Karagounis, L. G., Peirce, N., Simpson, E. J., Hazell, M., Layfield, R., Wackerhage, H., Smith, K., Atherton, P., Selby, A., & Rennie, M. J.
Affiliations
University of Nottingham (GB)
ORCID
Venue
American Journal of Physiology-Endocrinology and Metabolism
Publisher
American Physiological Society
Published
2008-09
Volume
295
Issue
3
Pages
E595-E604
ISSN
  • 0193-1849 (ISSN-L)
  • 1522-1555
DOI
10.1152/ajpendo.90411.2008
PMC
PMC2536736
OpenAlex
W2125928541
Semantic Scholar
0463a09989b15e85aec2abe1f6101dd196c7a191
Cited by
495
References
36
Citations by year
2026: 8 · 2025: 7 · 2024: 20 · 2023: 18 · 2022: 20 · 2021: 26 · 2020: 23 · 2019: 26 · 2018: 28 · 2017: 41 · 2016: 32 · 2015: 41 · 2014: 32 · 2013: 36 · 2012: 28
FWCI
15.75
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Pfizer
  • Wellcome Trust (056885)
  • Medical Research Council
  • Biotechnology and Biological Sciences Research Council (BB/X5106971, BB/C516779/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
amino acids, insulin, muscle protein synthesis, muscle protein degradation, ubiquitin-proteasome system, atrogin-1, MuRF1, anabolic signaling, mTOR, p70 S6 kinase, 4E-BP1, GSK3β, elongation factor 2, leucine incorporation, human skeletal muscle
MeSH terms
Adult, Amino Acids, Blood Glucose, Dose-Response Relationship, Drug, Humans, Hypoglycemic Agents, Insulin, Male, Muscle Proteins, Phosphorylation, Protein Kinases, Regional Blood Flow, RNA, RNA, Messenger, Blotting, Western, Signal Transduction, Gene Expression, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Ribosomal Protein S6 Kinases, 70-kDa, Ubiquitin-Protein Ligase Complexes, Proteasome Endopeptidase Complex, TOR Serine-Threonine Kinases

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