Cited by 1,583Muscle Physiology and DisordersMuscle metabolism and nutritionSignaling Pathways in Disease

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Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways

Rommel, Christian, Bodine, Sue C., Clarke, Brian A., Rossman, Roni, Nunez, Lorna, Stitt, Trevor N., Yancopoulos, George D., Glass, David J.·2001·Nature Cell Biology

DOI 10.1038/ncb1101-1009

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Abstract

Skeletal muscle is composed of multinucleated fibres, formed after the differentiation and fusion of myoblast precursors. Skeletal muscle atrophy and hypertrophy refer to changes in the diameter of these pre-existing muscle fibres. The prevention of atrophy would provide an obvious clinical benefit; insulin-like growth factor 1 (IGF-1) is a promising anti-atrophy agent because of its ability to promote hypertrophy. However, the signalling pathways by which IGF-1 promotes hypertrophy remain unclear, with roles suggested for both the calcineurin/NFAT (nuclear factor of activated T cells) pathway and the PtdIns-3-OH kinase (PI(3)K)/Akt pathway. Here we employ a battery of approaches to examine these pathways during the hypertrophic response of cultured myotubes to IGF-1. We report that Akt promotes hypertrophy by activating downstream signalling pathways previously implicated in activating protein synthesis: the pathways downstream of mammalian target of rapamycin (mTOR) and the pathway activated by phosphorylating and thereby inhibiting glycogen synthase kinase 3 (GSK3). In contrast, in addition to demonstrating that calcineurin does not mediate IGF-1-induced hypertrophy, we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.

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Authors: Rommel, C., Bodine, S. C., Clarke, B. A., Rossman, R., Nunez, L., Stitt, T. N., Yancopoulos, G. D., & Glass, D. J.
Affiliations: Regeneron (United States) (US)
Corresponding author: Glass, David J.
ORCID: Bodine, Sue C.
Clarke, Brian A.
Stitt, Trevor N.
Glass, David J.
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2001-10-05
Volume: 3
Issue: 11
Pages: 1009-1013
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/ncb1101-1009
OpenAlex: W1530473805
Cited by: 1,583
References: 24
Citations by year: 2026: 29 · 2025: 37 · 2024: 60 · 2023: 48 · 2022: 73 · 2021: 72 · 2020: 60 · 2019: 63 · 2018: 75 · 2017: 68 · 2016: 71 · 2015: 78 · 2014: 82 · 2013: 107 · 2012: 101
FWCI: 12.69
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
Funders: Regeneron Pharmaceuticals
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords: insulin-like growth factor I, skeletal muscle hypertrophy, myotubes, PI3K/Akt signaling, mTOR, glycogen synthase kinase-3, calcineurin, NFAT, muscle atrophy, protein synthesis
MeSH terms: Phosphoinositide-3 Kinase Inhibitors, Animals, Carrier Proteins, Cell Differentiation, Cell Line, Insulin-Like Growth Factor I, Muscular Atrophy, Phosphoproteins, Phosphorylation, Protein Kinases, Proto-Oncogene Proteins, Signal Transduction, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Muscle, Skeletal, Cell Cycle Proteins, Calcineurin, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3, Eukaryotic Initiation Factors, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Mice, TOR Serine-Threonine Kinases

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Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways

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