Cytokines IL6 and LIF can differentially regulate myotube protein synthesis
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IL6 and LIF are members of the IL6 family of cytokines that have recognized paradoxical regulatory roles in skeletal muscle mass, but there are gaps in our understanding of the cellular mechanisms that contribute to this regulatory dichotomy. The IL6 family of cytokines can induce several upstream regulators of mTORC1, including PI3K/Akt, ERK1/2 and AMPK; these pathways have the ability to regulate muscle mTORC1 signaling and protein synthesis. However, mTORC1 signaling regulation of by the IL6 family of cytokines remains poorly understood. Therefore, we investigated the effects of IL6 and LIF dose and duration on mTORC1 signaling and protein synthesis in myotubes. C2C12 myotubes were treated with varying doses of IL6 or LIF for either a short (14h) or long duration (24h). Signaling through the gp130 receptor and downstream effectors, including PI3K/Akt, STAT3 and AMPK were investigated by specific siRNA or pharmaceutical inhibitors administration. The AktmTORC1 signaling axis and protein synthesis was induced by short term IL6 or LIF administration, which was blocked by siRNA knockdown of gp130 receptor or pharmaceutical inhibition of Akt signaling. Interestingly, inhibition of mTOR or STAT3 signaling decreased basal myotube protein synthesis, but did not block the protein synthesis induction by short term IL6 or LIF administration. Long term IL6 or LIF administration suppressed AktmTORC1 signaling and protein synthesis, which coincided with increased AMPK phosphorylation. However, inhibition of AMPK signaling by siRNA knockdown did not rescue the protein synthesis suppression by long term IL6 or LIF treatment. These results demonstrate that IL6 family of cytokines have the capacity to either activate or suppress myotube mTORC1 signaling and protein synthesis, and the ultimate effect depends on the degree of the cytokine exposure.Support or Funding InformationR01 CA121249 to J. A. Carson from the National Cancer Institute, P20 RR017698 to J. A. Carson from National Center for Research Resources Grant
