Gao Song, Durstine J Larry, Koh Ho-Jin, Carver Wayne E, Frizzell Norma, Carson James A
Department of Exercise Science, University of South Carolina, Columbia, South Carolina.
Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina.
Am J Physiol Cell Physiol. 2017 Nov 1;313(5):C487-C500. doi: 10.1152/ajpcell.00112.2017. Epub 2017 Aug 2.
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.
白细胞介素-6（IL-6）和白血病抑制因子（LIF）是细胞因子IL-6家族的成员，在骨骼肌质量调节中发挥着公认的矛盾作用，与生长和萎缩均有关联。超负荷或肌肉收缩可诱导肌肉中IL-6和LIF表达短暂增加，这对肌肉肥大具有调节作用。然而，参与这种调节的细胞机制尚未完全明确。雷帕霉素复合物1（mTORC1）依赖性肌纤维蛋白合成的诱导是肌肉肥大已确定的调节因子，但细胞因子IL-6家族在这一过程中的作用了解甚少。因此，我们研究了给予IL-6和LIF对C2C12肌管中mTORC1信号传导和蛋白合成的急性影响。通过给予特异性小干扰RNA（siRNA）或药物抑制剂，研究了糖蛋白130（gp130）受体以及包括磷酸肌醇3激酶（PI3K）-蛋白激酶B（Akt）-mTORC1和信号转导子及转录激活子3（STAT3）-细胞因子信号传导抑制因子3（SOCS3）在内的下游信号通路的作用。急性给予IL-6和LIF可诱导蛋白合成，同时伴有STAT3激活、Akt-mTORC1激活以及SOCS3表达增加。gp130 siRNA敲低和Akt抑制均阻断了这种蛋白合成的诱导。有趣的是，STAT3抑制或Akt下游mTORC1信号传导抑制并未完全阻断IL-6或LIF诱导的蛋白合成。SOCS3 siRNA敲低增加了基础蛋白合成，并延长了IL-6和LIF诱导蛋白合成的持续时间。这些结果表明，IL-6或LIF均可激活gp130-Akt信号轴，该信号轴通过不依赖mTORC1的机制在培养的肌管中诱导蛋白合成。然而，IL-6或LIF诱导的SOCS3对肌管蛋白合成的激活具有负调节作用。
