S6 kinase inactivation impairs growth and translational target phosphorylation in muscle cells maintaining proper regulation of protein turnover
Abstract
A defect in protein turnover underlies multiple forms of cell atrophy. Since S6 kinase (S6K)-deficient cells are small and display a blunted response to nutrient and growth factor availability, we have hypothesized that mutant cell atrophy may be triggered by a change in global protein synthesis. By using mouse genetics and pharmacological inhibitors targeting the mammalian target of rapamycin (mTOR)/S6K pathway, here we evaluate the control of translational target phosphorylation and protein turnover by the mTOR/S6K pathway in skeletal muscle and liver tissues. The phosphorylation of ribosomal protein S6 (rpS6), eukaryotic initiation factor-4B (eIF4B), and eukaryotic elongation factor-2 (eEF2) is predominantly regulated by mTOR in muscle cells. Conversely, in liver, the MAPK and phosphatidylinositol 3-kinase pathways also play an important role, suggesting a tissue-specific control. S6K deletion in muscle mimics the effect of the mTOR inhibitor rapamycin on rpS6 and eIF4B phosphorylation without affecting eEF2 phosphorylation. To gain insight on the functional consequences of these modifications, methionine incorporation and polysomal distribution were assessed in muscle cells. Rates and rapamycin sensitivity of global translation initiation are not altered in S6K-deficient muscle cells. In addition, two major pathways of protein degradation, autophagy and expression of the muscle-specific atrophy-related E3 ubiquitin ligases, are not affected by S6K deletion. Our results do not support a role for global translational control in the growth defect due to S6K deletion, suggesting specific modes of growth control and translational target regulation downstream of mTOR.
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Impairment of mTORC1 activity or its downstream target p70S6K1 impinges muscle mass.
“When mTORC1 activity [89] or the activity of its down stream target p70S6K1 [92,93] are impaired then muscle mass is impinged.”
From New strategies in sport nutrition to increase exercise performance (2016) · cites this paper as [92]
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- Authors
- Mieulet, V., Roceri, M., Espeillac, C., Sotiropoulos, A., Ohanna, M., Oorschot, V., Klumperman, J., Sandri, M., & Pende, M.
- Affiliations
- Inserm (FR)
- ORCID
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2007-08
- Volume
- 293
- Issue
- 2
- Pages
- C712-C722
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W2128007752
- Cited by
- 99
- References
- 53
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 2 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 8 · 2015: 4 · 2014: 7 · 2013: 9 · 2012: 8
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- Novartis Foundation
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- S6 kinase, mTOR signaling, skeletal muscle atrophy, protein turnover, translational regulation, S6 phosphorylation, eEF2 phosphorylation, rapamycin, muscle growth, liver, autophagy, E3 ubiquitin ligase, protein degradation, methionine incorporation, MAPK signaling, phosphatidylinositol 3-kinase
- MeSH terms
- Animals, Autophagy, Cells, Cultured, Insulin, Leucine, Liver, Male, Muscular Atrophy, Phosphorylation, Protein Kinases, Protein Biosynthesis, Signal Transduction, Calcium-Calmodulin-Dependent Protein Kinases, Mice, Knockout, Muscle, Skeletal, Muscle Fibers, Skeletal, Phosphatidylinositol 3-Kinases, Sirolimus, Mitogen-Activated Protein Kinases, Hepatocytes, Muscle Development, Ribosomal Protein S6, Ribosomal Protein S6 Kinases, 90-kDa, Eukaryotic Initiation Factors, Ubiquitin-Protein Ligases, Mice, Elongation Factor 2 Kinase, TOR Serine-Threonine Kinases
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