The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia
The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia
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DOI：
10.1128/mcb.00184-19
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发表时间：
2019-08-01
影响因子：
5.3
通讯作者：
Kumar, Ashok
中科院分区：
文献类型：
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作者：
Bohnert, Kyle R.;Goli, Praneeth;Kumar, Ashok
骨骼肌萎缩会导致癌症患者的发病率和死亡率。越来越多的证据表明，在包括癌症在内的多种分解代谢条件下，骨骼肌中内质网(ER)应激和未折叠蛋白反应(UPR)途径的标志物都会增加。然而，UPR的信号机制和单个手臂在骨骼肌群调节中的作用仍然很大程度上是未知的。在本研究中，我们证明了在Lewis肺癌(LLC)癌症恶病质模型中，骨骼肌中Toll样受体(TLRs)和髓系分化初级反应基因88(MyD88)的基因表达增加。靶向消融MyD88可抑制LLC荷瘤小鼠骨骼肌质量和力量的丧失。抑制MyD88可减弱LLC诱导的小鼠骨骼肌UPR的激活。此外，肌肉特异性缺失X-box结合蛋白1(XBP1)是UPR的IRE1α臂的主要下游靶标，可以改善LLC荷瘤小鼠的肌肉萎缩。我们的结果还表明，过表达一种活性形式的XBP1导致培养的肌管萎缩。相反，XBP1基因敲除可抑制LLC或C26腺癌细胞条件培养液对肌管的萎缩。总之，我们的结果表明，TLR/MyD88介导的XBP1激活导致LLC荷瘤小鼠骨骼肌萎缩。
Skeletal muscle wasting causes both morbidity and mortality of cancer patients. Accumulating evidence suggests that the markers of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways are increased in skeletal muscle under multiple catabolic conditions, including cancer. However, the signaling mechanisms and the role of individual arms of the UPR in the regulation of skeletal muscle mass remain largely unknown. In the present study, we demonstrated that gene expression of Toll-like receptors (TLRs) and myeloid differentiation primary response gene 88 (MyD88) was increased in skeletal muscle in a Lewis lung carcinoma (LLC) model of cancer cachexia. Targeted ablation of MyD88 inhibits the loss of skeletal muscle mass and strength in LLC tumor-bearing mice. Inhibition of MyD88 attenuates the LLC-induced activation of the UPR in skeletal muscle of mice. Moreover, muscle-specific deletion of X-box binding protein 1 (XBP1), a major downstream target of IRE1 alpha arm of the UPR, ameliorates muscle wasting in LLC tumor-bearing mice. Our results also demonstrate that overexpression of an active form of XBP1 caused atrophy in cultured myotubes. In contrast, knockdown of XBP1 inhibits myotube atrophy in response to LLC or C26 adenocarcinoma cell conditioned medium. Collectively, our results demonstrate that TLR/MyD88-mediated activation of XBP1 causes skeletal muscle wasting in LLC tumor-bearing mice.