Acute myotube protein synthesis regulation by IL-6-related cytokines
Open accessAbstract
IL-6 and leukemia inhibitory factor (LIF), members of the IL-6 family of cytokines, play recognized paradoxical roles in skeletal muscle mass regulation, being associated with both growth and atrophy. Overload or muscle contractions can induce a transient increase in muscle IL-6 and LIF expression, which has a regulatory role in muscle hypertrophy. However, the cellular mechanisms involved in this regulation have not been completely identified. The induction of mammalian target of rapamycin complex 1 (mTORC1)-dependent myofiber protein synthesis is an established regulator of muscle hypertrophy, but the involvement of the IL-6 family of cytokines in this process is poorly understood. Therefore, we investigated the acute effects of IL-6 and LIF administration on mTORC1 signaling and protein synthesis in C2C12 myotubes. The role of glycoprotein 130 (gp130) receptor and downstream signaling pathways, including phosphoinositide 3-kinase (PI3K)-Akt-mTORC1 and signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3), was investigated by administration of specific siRNA or pharmaceutical inhibitors. Acute administration of IL-6 and LIF induced protein synthesis, which was accompanied by STAT3 activation, Akt-mTORC1 activation, and increased SOCS3 expression. This induction of protein synthesis was blocked by both gp130 siRNA knockdown and Akt inhibition. Interestingly, STAT3 inhibition or Akt downstream mTORC1 signaling inhibition did not fully block the IL-6 or LIF induction of protein synthesis. SOCS3 siRNA knockdown increased basal protein synthesis and extended the duration of the protein synthesis induction by IL-6 and LIF. These results demonstrate that either IL-6 or LIF can activate gp130-Akt signaling axis, which induces protein synthesis via mTORC1-independent mechanisms in cultured myotubes. However, IL-6- or LIF-induced SOCS3 negatively regulates the activation of myotube protein synthesis.
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Acutely elevated muscle-derived IL-6 acts directly on the liver to promote gluconeogenesis and stimulates adipose tissue lipolysis to increase free fatty acid mobilization and oxidation.
“It acts directly on the liver to promote gluconeogenesis, maintaining blood glucose stability, while simultaneously stimulating adipose tissue lipolysis to increase free fatty acid mobilization and oxidation for contracting muscles [32,33].”
From Exercise-Induced Myokines in Obesity-Related Metabolic Disorders and Cardiovascular Protection: A Narrative Review (2026) · cites this paper as [32]
Both IL-6 and LIF activate myotube mTORC1 signaling in a time- and dose-dependent fashion.
“It has further been shown that both IL-6 and LIF activate myotube mTORC1 signaling in a time- and dose-dependent fashion (52).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [52]
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- Authors
- Gao, S., Durstine, J. L., Koh, H.-J., Carver, W. E., Frizzell, N., & Carson, J. A.
- Affiliations
- University of South Carolina (US)
- Corresponding author
- Carson, James A.
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2017-11-01
- Volume
- 313
- Issue
- 5
- Pages
- C487-C500
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- PMC
- PMC5792171
- OpenAlex
- W2741175738
- Cited by
- 69
- References
- 72
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 2 · 2023: 7 · 2022: 15 · 2021: 10 · 2020: 6 · 2019: 4 · 2018: 7
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA121249)
- 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
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-6, leukemia inhibitory factor, IL-6 family cytokines, mTORC1 signaling, gp130, STAT3, SOCS3, Akt signaling, skeletal muscle hypertrophy, C2C12 myotubes, muscle atrophy
- MeSH terms
- Animals, Cells, Cultured, Protein Biosynthesis, Interleukin-6, Cytokines, Muscle Fibers, Skeletal, Myoblasts, Cell Proliferation, Mice, Leukemia Inhibitory Factor
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