Cited by 70Muscle Physiology and DisordersMuscle metabolism and nutritionPI3K/AKT/mTOR signaling in cancer

mTOR signaling regulates myotube hypertrophy by modulating protein synthesis, rDNA transcription, and chromatin remodeling

von Walden, Ferdinand, Liu, Chang, Aurigemma, Nicole, Nader, Gustavo A.·2016·American Journal of Physiology-Cell Physiology

Abstract

Ribosome production is an early event during skeletal muscle hypertrophy and precedes muscle protein accretion. Signaling via mTOR is crucial for ribosome production and hypertrophy; however, the mechanisms by which it regulates these processes remain to be identified. Herein, we investigated the activation of mTOR signaling in hypertrophying myotubes and determined that mTOR coordinates various aspects of gene expression important for ribosome production. First, inhibition of translation with cycloheximide had a more potent effect on protein synthesis than rapamycin indicating that mTOR function during hypertrophy is not on general, but rather on specific protein synthesis. Second, blocking Pol II transcription had a similar effect as Rapamycin and, unexpectedly, revealed the necessity of Pol II transcription for Pol I transcription, suggesting that mTOR may regulate ribosome production also by controlling Class II genes at the transcriptional level. Third, Pol I activity is essential for rDNA transcription and, surprisingly, for protein synthesis as selective Pol I inhibition blunted rDNA transcription, protein synthesis, and the hypertrophic response of myotubes. Finally, mTOR has nuclear localization in muscle, which is not sensitive to rapamycin. Inhibition of mTOR signaling by rapamycin disrupted mTOR-rDNA promoter interaction and resulted in altered histone marks indicative of repressed transcription and formation of higher-order chromatin structure. Thus mTOR signaling appears to regulate muscle hypertrophy by affecting protein synthesis, Class I and II gene expression, and chromatin remodeling.

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Crossref · 10.1152/ajpcell.00144.2016

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Authors
von Walden, F., Liu, C., Aurigemma, N., & Nader, G. A.
Affiliations
  • Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
  • Karolinska Institutet (SE)
  • Noll Laboratory, Department of Kinesiology and Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania; and
  • Pennsylvania State University (US)
Corresponding author
Nader, Gustavo A.
Venue
American Journal of Physiology-Cell Physiology
Published
2016-10-01
Volume
311
Issue
4
Pages
C663-C672
ISSN
  • 0363-6143 (ISSN-L)
  • 1522-1563
OpenAlex
W2513728460
Cited by
70
References
43
Citations by year
2026: 4 · 2025: 4 · 2024: 4 · 2023: 9 · 2022: 6 · 2021: 8 · 2020: 7 · 2019: 10 · 2018: 7 · 2017: 11
FWCI
4.85
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Physiology-Cell Physiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Vetenskapsrådet (Swedish Research Council) (VRK2008-67X-20797-01-04)
  • Centrum for Idrottsforskning (Sweden) (P2011-01-0133)
  • Kung Gustaf V:s 80 Arsfon (FAI2009-0065)
  • Reumatikerforbundet (Sweden) (R-21211)
  • Diabetesfonden (Sweden) (DIA2012-071)
  • Karolinska Institute Strategic Diabetes Program
  • Dept. of Kinesiology, The Pennsylvania State University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • 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
Keywords
mTOR signaling, skeletal muscle hypertrophy, myotubes, rDNA transcription, protein synthesis, chromatin remodeling, histone modifications, rapamycin, cycloheximide, muscle protein accretion
MeSH terms
Animals, DNA, Ribosomal, Hypertrophy, Muscle Proteins, Muscular Diseases, Promoter Regions, Genetic, Ribosomes, Transcription, Genetic, Signal Transduction, Muscle, Skeletal, Muscle Fibers, Skeletal, Chromatin Assembly and Disassembly, Cell Line, Tumor, Mice, TOR Serine-Threonine Kinases

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