mTOR signaling regulates myotube hypertrophy by modulating protein synthesis, rDNA transcription, and chromatin remodeling
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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mTOR signaling enhances ribosome biogenesis in skeletal muscle cells in vitro by modifying chromatin at the rDNA promoter.
“Von Walden et al. (2016) later demonstrated that mTOR signaling enhances ribosome biogenesis in skeletal muscle cells in vitro by modifying chromatin at the rDNA promoter.”
From Skeletal Muscle Ribosome and Mitochondrial Biogenesis in Response to Different Exercise Training Modalities (2021) · cites this paper as Von Walden et al. (2016)
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Can Chromatin Accessibility be Exploited for Axon Regeneration?
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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.
- ORCID
- Nader, Gustavo A.
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- 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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