Cachexia in ApcMin/+ mice: The role of IL-6

描述（由申请人提供）：恶病质是一种全身消瘦的病症，占所有癌症相关死亡的20-40%，特别是胃肠道和肺癌。炎性细胞因子是骨骼肌损失的重要效应物，并且细胞因子IL-6作为参与恶病质的信号分子而声名狼借。突变Apc基因（ApcMin/+）杂合子小鼠在10周龄时产生显著的肠息肉负担，并在18至26周龄之间出现恶病质。使用这种小鼠研究恶病质的调节是新颖的，并且与其他恶病质动物模型相比具有优势，包括消耗速度较慢和缺乏厌食症。PI显示炎性细胞因子IL-6是ApcMin/+小鼠中恶病质的调节剂。IL-6的敲除防止恶病质，而IL-6的过表达加速恶病质。目前尚不清楚IL-6是通过影响肿瘤生长或肿瘤源性恶病质介质的分泌对肌肉产生直接作用还是间接作用。然而，了解IL-6消融的有益作用将清楚地提供对癌症期间炎症和恶病质之间关系的洞察。本申请的总体目的是解决ApcMin/+小鼠恶病质的潜在机制。这些机制将在初始和严重阶段的浪费和肌肉的氧化代谢能力进行检查。目的1将描述在恶病质ApcMin/+小鼠的早期和严重消瘦阶段肌肉蛋白质合成和蛋白酶体降解的调节。在恶病质的进展过程中，糖酵解和氧化肌肉中这些过程的差异调节将被检查。实验还将检查循环IL-6对肌肉蛋白质合成和降解的分级增加。目的2将描述ApcMin/+小鼠在早期和严重消瘦阶段肌肉线粒体功能和肌细胞凋亡的调节。将在恶病质进展期间和分级IL-6过表达情况下评估肌肉氧化应激、蛋白质化学修饰、线粒体解偶联、线粒体数量以及糖酵解和氧化肌肉中的细胞凋亡指数的生物标志物。目的3将确定通过肌肉gp 130受体的直接信号传导是否调节ApcMin/+小鼠中的肌肉蛋白质周转、线粒体功能和细胞凋亡。这些研究将使用肌肉特异性cre-lox系统以组织特异性方式降低gp 130受体表达，以确定IL-6对恶病质的容许作用是对肌肉代谢的直接作用还是通常由肿瘤生长或炎症引起的间接作用。 公共卫生相关性。这项工作的完成将导致更好地理解系统性IL-6信号传导在调节恶病质严重肌肉萎缩中的作用。确定治疗和预防严重消瘦阶段的治疗对策的潜在靶点应使患者更好地耐受和响应潜在癌症病症的治疗，从而改善死亡率和发病率

DESCRIPTION (provided by applicant): Cachexia is a condition of whole body wasting that accounts for 20-40% of all cancer-related deaths, particularly GI tract and lung cancers. Inflammatory cytokines are significant effectors of skeletal muscle loss, and the cytokine IL-6 has gained notoriety as a signaling molecule involved in cachexia. Mice heterozygous for a mutated Apc gene (ApcMin/+) develop a significant intestinal polyp burden by 10 weeks of age and become cachexic between 18 and 26 weeks of age. The use of this mouse for studying the regulation of cachexia is novel, and has advantages compared to other animal models of cachexia, including a slower rate of wasting and lack of anorexia. The PI has shown that the inflammatory cytokine IL-6 is a modulator of cachexia in the ApcMin/+ mouse. Knockout of IL-6 prevents cachexia, while over-expression of IL-6 accelerates cachexia. It is not yet clear whether IL-6 exerts a direct effect on muscle or an indirect affect, by affecting tumor growth or secretion of a cachexic mediator of tumor origin. However, understanding the beneficial effects of IL-6 ablation will clearly provide insight into the relationships between inflammation and cachexia during cancer. The overall purpose of this application is to address mechanisms underlying cachexia in the ApcMin/+ mouse. These mechanisms will be examined in respect to the initial and severe stages of wasting and the muscle's oxidative metabolism capacity. Aim 1 will characterize the regulation of muscle protein synthesis and proteasomal degradation during the early and severe stages of wasting in the cachexic ApcMin/+ mouse. Differential regulation of these processes in glycolytic and oxidative muscle during the progression of cachexia will be examined. Experiments also will examine graded increases in circulating IL-6 on muscle protein synthesis and degradation. Aim 2 will characterize the regulation of muscle mitochondrial function, and myonuclear apoptosis during the early and severe stages of wasting in the ApcMin/+ mouse. Biomarkers of muscle oxidative stress, protein chemical modification, mitochondria uncoupling, mitochondrial number, and indices of apoptosis in glycolytic and oxidative muscle will be assessed during the progression of cachexia and with graded IL-6 over- expression. Aim 3 will determine if direct signaling through the muscle gp130 receptor regulates muscle protein turnover, mitochondrial function and apoptosis in the ApcMin/+ mouse. These studies will use a muscle-specific cre-lox system to decrease gp130 receptor expression in a tissue-specific manner in order to determine whether the permissive effect of IL-6 on cachexia is a direct effect on muscle metabolism or an indirect effect resulting from tumor growth or inflammation, in general. PUBLIC HEALTH RELEVANCE. Completion of this work will lead to a better understanding of the role of systemic IL-6 signaling for the regulation of severe muscle wasting with cachexia. The identification of potential targets for therapeutic countermeasures to both treat and prevent the severe stages of wasting should allow patients to better tolerate and respond to treatments for the underlying cancer condition, thus improving mortality and morbidity