Department of Exercise Science, University of South Carolina , Columbia, South Carolina.
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine , Columbia, South Carolina.
Am J Physiol Cell Physiol. 2018 Jul 1;315(1):C91-C103. doi: 10.1152/ajpcell.00063.2018. Epub 2018 Apr 11.
Systemic cytokines and contractile activity are established regulators of muscle protein turnover. Paradoxically, the IL-6 cytokine family, which shares the ubiquitously expressed membrane gp130 receptor, has been implicated in skeletal muscle's response to both contractions and cancer-induced wasting. Although we have reported that tumor-derived cachectic factors could suppress stretch-induced protein synthesis in cultured myotubes, the ability of systemic cytokines to disrupt in vivo eccentric contraction-induced protein synthesis has not been established. Therefore, we examined whether systemic IL-6 regulates basal and eccentric contraction-induced protein synthesis through muscle gp130 signaling. Systemic IL-6 overexpression was performed for 2 wk, and we then examined basal and eccentric contraction-induced protein synthesis and mammalian target of rapamycin complex 1 (mTORC1) signaling in tibialis anterior muscle of male wild-type, muscle-specific gp130 receptor knockout, and tumor-bearing Apc mice. Systemic IL-6 overexpression suppressed basal protein synthesis and mTORC1 signaling independently of IL-6 level, which was rescued by muscle gp130 loss. Interestingly, only high systemic IL-6 levels suppressed eccentric contraction-induced protein synthesis. Systemic IL-6 overexpression in precachectic tumor-bearing Apc mice accelerated cachexia development, which coincided with suppressed basal and eccentric contraction-induced muscle protein synthesis. The suppression of eccentric contraction-induced protein synthesis by IL-6 occurred independently of mTORC1 activation. Collectively, these findings demonstrate that basal protein synthesis suppression was more sensitive to circulating IL-6 compared with the induction of protein synthesis by eccentric contraction. However, systemic IL-6 can interact with the cancer environment to suppress eccentric contraction-induced protein synthesis independently of mTORC1 activation.
系统细胞因子和收缩活动是肌肉蛋白质周转的既定调节因子。矛盾的是，IL-6 细胞因子家族与普遍表达的膜 gp130 受体共享，与骨骼肌对收缩和癌症引起的消瘦的反应有关。虽然我们已经报告说肿瘤来源的恶病质因子可以抑制培养的肌管中拉伸诱导的蛋白质合成，但系统细胞因子是否能够破坏体内离心收缩诱导的蛋白质合成尚未确定。因此，我们研究了全身 IL-6 是否通过肌肉 gp130 信号转导调节基础和离心收缩诱导的蛋白质合成。全身过表达 IL-6 持续 2 周，然后检查胫骨前肌中基础和离心收缩诱导的蛋白质合成以及哺乳动物雷帕霉素靶蛋白复合物 1 (mTORC1) 信号转导。在野生型、肌肉特异性 gp130 受体敲除和肿瘤荷瘤 Apc 小鼠中，全身 IL-6 过表达抑制了基础蛋白合成和 mTORC1 信号转导，而与 IL-6 水平无关，这被肌肉 gp130 缺失所挽救。有趣的是，只有高系统 IL-6 水平抑制离心收缩诱导的蛋白质合成。在 precachectic 肿瘤荷瘤 Apc 小鼠中全身过表达 IL-6 加速恶病质的发展，这与基础和离心收缩诱导的肌肉蛋白合成抑制相一致。IL-6 对离心收缩诱导的蛋白质合成的抑制与 mTORC1 激活无关。总之，这些发现表明与离心收缩诱导的蛋白质合成相比，基础蛋白合成的抑制对循环 IL-6 更敏感。然而，全身 IL-6 可以与癌症环境相互作用，独立于 mTORC1 激活来抑制离心收缩诱导的蛋白质合成。
