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

描述(申请人提供)：癌症恶病质，无意中体重和肌肉质量的减少，直接影响患者的生存和生活质量。对于癌症患者和健康人来说，骨骼肌在维持健康方面的作用涉及肌肉质量的数量和肌肉的质量，因为它关系到代谢能力和底物利用的灵活性。虽然了解肌肉质量下降是恶病质研究的一个主要焦点，但肌肉质量下降可能在恶病质进展和质量下降中都起着作用。了解癌症患者的全身环境如何扰乱肌肉代谢和蛋白质周转调节仍然是一个巨大的挑战，足以阻碍癌症恶病质的治疗。炎性细胞因子IL-6和肌肉STAT信号是荷瘤小鼠肌肉萎缩的明显调节因素。恶病质肌肉中通过mTOR合成的肌肉蛋白质也受到抑制。然而，在我们对IL-6调节抑制的肌肉合成代谢信号与癌症恶病质的理解上仍然存在显著的差距。这一建议机械地扩展了我们已发表的初步数据，该数据检测了IL-6对恶病质进展过程中肌肉蛋白质周转的调节。我们的长期目标是通过了解炎症、代谢和激素信号通路的相互作用来扰乱肌肉蛋白质的合成，从而提高癌症患者的存活率。我们研究的总体目标是从机制上了解在ApcMin/和Lewis肺癌(LLC)移植小鼠恶病质的发生和发展过程中，IL-6细胞因子家族如何调节营养、激素和肌肉蛋白质周转的机械控制。我们的中心假设是，通过mTOR信号抑制肌肉蛋白质合成是恶病质诱导的肌肉质量下降的基础。这项拟议研究的基本原理是，识别代谢信号通路和这些过程的炎症调节因子将允许采取治疗对策，阻止或逆转癌症导致的肌肉萎缩的进展。在我们之前的研究和使用ApcMin/和LLC小鼠恶病质模型的初步数据的指导下，我们计划检验我们的中心假设，并实现这一应用的三个特定目标：1)确定恶病质进展过程中IL-6对蛋白质合成和运动抵抗所必需的IL-6调节蛋白质合成和mTOR信号；2)确定在恶病质进展过程中肌肉氧化代谢的变化是否调节mTOR信号和蛋白质合成；以及3)确定在恶病质进展过程中是否抑制睾酮和雄激素相关信号调节mTOR信号和蛋白质周转。这项研究具有创新性，因为它将检查由慢性全身炎症调节的机械、代谢和激素信号通路，并控制恶病质肌肉蛋白质合成的mTOR信号调节。这一结果具有重要意义，因为它将导致发展体育活动和药物干预，可以干预癌症导致的肌肉萎缩的进展。

DESCRIPTION (provided by applicant): Cancer cachexia, the unintentional loss of bodyweight and muscle mass, directly impacts patient survival and quality of life. The role of skeletal muscle in maintaining health, for cancer patients and healthy individuals, involves both the amount of muscle mass and the quality of the muscle, as it relates to metabolic capacity and substrate utilization flexibility. Although understanding muscle mass loss is a major focus of cachexia research, reduced muscle quality likely plays a role in both cachexia progression and mass loss. Understanding how the cancer patient's systemic environment disrupts both muscle metabolism and protein turnover regulation remains a challenge that is substantial enough to have impeded cancer cachexia treatment. Inflammatory cytokine IL-6 and muscle STAT signaling are clear regulators of muscle wasting in tumor-bearing mice. Muscle protein synthesis through mTOR is also suppressed in cachectic muscle. However, significant gaps remain in our understanding of the IL-6 regulation of suppressed muscle anabolic signaling with cancer cachexia. This proposal mechanistically extends our published and preliminary data examining IL-6 regulation of muscle protein turnover during the progression of cachexia. Our long-term goal is to improve cancer patient survival through understanding inflammatory, metabolic and hormonal signaling pathway interactions that disrupt muscle protein synthesis. Our study's overall objective is to mechanistically understand how the IL-6 family of cytokines can regulate nutrient, hormonal, and mechanical control of muscle protein turnover during the initiation and progression of cachexia in ApcMin/+ and Lewis Lung Carcinoma (LLC) implanted mice. Our central hypothesis is that muscle protein synthesis suppression through mTOR signaling is fundamental for cachexia- induced muscle mass loss. The rationale for this proposed research is that the identification of metabolic signaling pathways and the inflammatory regulators of these processes will allow therapeutic countermeasures that can block or reverse the progression of muscle wasting with cancer. Guided by our prior research and preliminary data using ApcMin/+ and LLC mouse cachexia models, we plan to test our central hypothesis and accomplish the objectives of this application with three specific aims: 1) Identify the IL-6 regulation of protein synthesis and mTOR signaling necessary for anabolic resistance to feeding and exercise during the progression of cachexia; 2) Determine if alterations in muscle oxidative metabolism regulate mTOR signaling and protein synthesis during the progression of cachexia; and 3) Determine if suppressed testosterone and androgen-associated signaling regulate mTOR signaling and protein turnover during the progression of cachexia. This research is innovative because it will examine mechanical, metabolic, and hormonal signaling pathways that are regulated by chronic systemic inflammation and control mTOR-signaling regulation of muscle protein synthesis with cachexia. It is significant because the results will lead to developing physical activity and pharmaceutical interventions that can intervene in the progression of muscle wasting with cancer.