TWEAK/Fn14/UPR Signaling in Skeletal Muscle Wasting

摘要 骨骼肌萎缩/恶病质是许多慢性疾病的破坏性并发症 在一些州，如癌症和老年人口中也存在这种现象。肌肉萎缩涉及到体内的不平衡 蛋白质合成和降解率，功能性去神经，代谢异常， 以及线粒体内容和功能的丧失。调整是一种促炎细胞因子，可以结合 通过细胞表面受体Fn14激活多条细胞内信号通路。我们有 发现Fn14在肿瘤模型小鼠骨骼肌中的表达增加 恶病质和老年小鼠。骨骼肌特异性消融Fn14抑制骨骼肌萎缩 癌症恶病质的小鼠模型。微调抑制骨骼中蛋白质合成的速度 体内和体外的肌肉。此外，TWEEP-Fn14系统调节内质网应激- 诱导荷瘤小鼠骨骼肌未折叠蛋白反应(UPR)。此外, 我们的实验表明，靶向抑制PERK和/或IRE1/XBP1臂 UPR可促进小鼠骨骼肌中蛋白质的合成。然而，该组织的作用 TWEEP-Fn14系统和UPR通路在骨骼肌质量和功能调节中的作用 在癌症期间，恶病质和衰老仍然完全未知。在这个项目中，我们将 探讨TWEEP/Fn14/UPR信号轴在骨骼肌萎缩中的作用以及TWEEP/Fn14/UPR在骨骼肌萎缩中的作用 靶向基因消融Fn14或UPR组分可减轻大鼠骨骼肌萎缩 癌症恶病质和衰老过程中的临床前小鼠模型。根据我们的初步调查 结果，我们假设TWEE/Fn14系统通过以下途径导致骨骼肌萎缩 UPR的PERK和IRE1α/XBP1臂在衰老和癌症过程中的激活 恶病质。我们的具体目标是：(I)调查TWEE/Fn14系统在 衰老过程中骨骼肌萎缩和癌症恶病质，以及(Ii)探讨其机制 通过TWEE/Fn14诱导的UPR通路的激活导致骨骼肌萎缩 在衰老和癌症恶病质期间。我们提议的研究将确定关键的机制 对骨骼肌块的损失负责。这个项目的成功完成将 为开发治疗石棺减少症和癌症恶病质的新疗法提供了有力的基础。

ABSTRACT Skeletal muscle wasting/cachexia is a devastating complication of a number of chronic disease states, such as cancer and in the elderly population. Muscle wasting involves an imbalance in the rates of protein synthesis and degradation, functional denervation, metabolic abnormalities, and loss of mitochondrial content and function. TWEAK is a proinflammatory cytokine that binds to cell surface receptor Fn14 to activate multiple intracellular signaling pathways. We have found that the expression of Fn14 is increased in skeletal muscle of mouse models of cancer cachexia and in aged mice. Skeletal muscle-specific ablation of Fn14 inhibits muscle wasting in a murine model of cancer cachexia. TWEAK represses the rate of protein synthesis in skeletal muscle both in vivo and in vitro. Furthermore, the TWEAK-Fn14 system regulates ER stress- induced unfolded protein response (UPR) in skeletal muscle of tumor-bearing mice. In addition, our experiments demonstrate that targeted inhibition of the PERK and/or IRE1/XBP1 arms of the UPR improves protein synthesis in skeletal muscle of mice. However, the role of the TWEAK-Fn14 system and UPR pathways in the regulation of skeletal muscle mass and function during cancer cachexia and aging remains completely unknown. In this project, we will investigate the role of TWEAK/Fn14/UPR signaling axis in skeletal muscle atrophy and whether targeted genetic ablation of Fn14 or components of the UPR attenuate muscle wasting in preclinical mouse models of cancer cachexia and during aging. Based on our preliminary results, we hypothesize that the TWEAK/Fn14 system causes skeletal muscle wasting through the activation of the PERK and the IRE1α/XBP1 arms of the UPR during aging and cancer cachexia. Our specific aims are to: (I) Investigate the role of the TWEAK/Fn14 system in skeletal muscle wasting during aging and cancer cachexia, and (II) Investigate the mechanisms by which TWEAK/Fn14-induced activation of the UPR pathways cause skeletal muscle wasting during aging and cancer cachexia. Our proposed studies will identify key mechanisms responsible for the loss of skeletal muscle mass. Successful completion of this project will provide strong basis for the development of new therapies for sarcopenia and cancer cachexia.