Acute myotube protein synthesis regulation by IL-6-related cytokines

Song Gao, J. Larry Durstine, Ho Jin Koh, Wayne E. Carver, Norma Frizzell, James Carson

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)C487-C500
JournalAmerican Journal of Physiology - Cell Physiology
Volume313
Issue number5
DOIs
StatePublished - Nov 1 2017

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Skeletal Muscle Fibers
Leukemia Inhibitory Factor
Interleukin-6
Cytokines
Proteins
STAT3 Transcription Factor
Small Interfering RNA
Glycoproteins
Muscles
Hypertrophy
1-Phosphatidylinositol 4-Kinase
Muscle Contraction
Transcriptional Activation
Atrophy
mechanistic target of rapamycin complex 1
Skeletal Muscle

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Cite this

Acute myotube protein synthesis regulation by IL-6-related cytokines. / Gao, Song; Durstine, J. Larry; Koh, Ho Jin; Carver, Wayne E.; Frizzell, Norma; Carson, James.

In: American Journal of Physiology - Cell Physiology, Vol. 313, No. 5, 01.11.2017, p. C487-C500.

Research output: Contribution to journalArticle

Gao, Song ; Durstine, J. Larry ; Koh, Ho Jin ; Carver, Wayne E. ; Frizzell, Norma ; Carson, James. / Acute myotube protein synthesis regulation by IL-6-related cytokines. In: American Journal of Physiology - Cell Physiology. 2017 ; Vol. 313, No. 5. pp. C487-C500.
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abstract = "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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