Anti-oxidant treatment of muscle wasting and fatigue in tumor-bearing mice

描述（申请人提供）：疲劳是癌症患者在抗肿瘤治疗期间和之后最常见和最痛苦的症状。癌症相关疲劳（CRF）没有有效的治疗方法，为了开发和测试新的治疗方法，需要更多关于其原因的信息。大量证据表明，肿瘤生长会增加血清中促炎细胞因子的水平，从而增加骨骼肌萎缩相关分解代谢途径的表达和活性。肿瘤生长和促炎细胞因子也增加了肌肉细胞中活性氧（ROS）的产生，这也可以激活肌肉萎缩的这些相同的分解代谢途径。肌肉量的减少会导致肌肉无力，而氧化应激会降低肌肉细胞的收缩力。有初步证据表明，在荷瘤啮齿动物中，氧化应激和收缩功能障碍也发生在心肌中。有一些证据表明，预处理抗氧化剂可以防止细胞因子诱导的分解代谢和肌肉细胞的收缩功能障碍。辅酶Q10 （coQ10）是细胞线粒体中天然存在的抗氧化剂，在炎症反应中被耗尽。本研究的目的是验证CoQ10治疗可减少荷瘤小鼠肌肉萎缩，改善骨骼肌和心肌收缩功能的假设。申请人将使用ELISA， PCR和超声心动图的实验室技术来评估荷瘤小鼠的肌肉萎缩和肌肉功能，并测量车轮跑步活动和握力来模拟疲劳和虚弱的行为。症状管理是国家癌症研究中心的一个重点研究领域，本研究的发现将有助于测试临床干预措施以减少癌症患者的疲劳所需的知识基础。在这种肿瘤诱导的疲劳动物模型中，心肌功能障碍的证明将影响临床医生如何评估和治疗慢性肾功能衰竭患者。申请人将在肌肉萎缩和肌肉功能障碍的生物标志物以及临床试验研究方面接受强有力的实验室培训，为她在大型学术医疗中心担任护士科学家做好准备。

DESCRIPTION (provided by applicant): Fatigue is the most common and the most distressing symptom reported by cancer patients during and after anti-tumor treatments. There are no effective treatments for cancer related fatigue (CRF) and more information about its causes are needed in order to develop and test new treatments. A large body of evidence has shown that tumor growth increases serum levels of pro-inflammatory cytokines that increase expression and activity of catabolic pathways implicated in skeletal muscle wasting. Tumor growth and pro-inflammatory cytokines also increase production of reactive oxygen species (ROS) in muscle cells, which can also activate these same catabolic pathways of muscle wasting. The loss of muscle mass contributes to muscle weakness, while oxidative stress reduces contraction force in muscle cells. There is preliminary evidence in tumor-bearing rodents that oxidative stress and contractile dysfunction also occur in the myocardium. There is some evidence that pretreatment with an anti-oxidant prevents cytokine-induced catabolism and contractile dysfunction in muscle cells. Coenzyme Q10 (coQ10) is a naturally occurring anti-oxidant in mitochondria of cells that is depleted during the inflammatory response. The purpose of this study is to test the hypothesis that treatment with CoQ10 will reduce muscle wasting and improve contractile function of skeletal and heart muscle of tumor-bearing mice. The applicant will use laboratory techniques of ELISA, PCR, and echocardiography to evaluate muscle wasting and muscle function in tumor-bearing mice, and measures of wheel running activity and grip strength to model behaviors of fatigue and weakness. Symptom management is a research emphasis area of the NINR, and the findings of this study will contribute to the knowledge base needed to test clinical interventions to reduce fatigue in cancer patients. Demonstration of myocardial dysfunction in this animal model of tumor-induced fatigue will impact how clinicians evaluate and treat patients with CRF. The applicant will receive strong laboratory training in biomarkers of muscle wasting and muscle dysfunction, as well as clinical trials research to prepare her for a career as a nurse scientist in a large academic medical center. PUBLIC HEALTH RELEVANCE: Fatigue is the most common and most distressing symptom reported by cancer patients before and after treatment, negatively affecting their quality of life. Fatigue also increases the social and financial burden of health care for cancer patients. This study will examine the role of cardiac dysfunction, and the effect of anti-oxidant treatment in an animal model of cancer- related fatigue.