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治疗后报告的最常见和最令人痛苦的症状。目前还没有有效的治疗癌症相关性疲劳(CRF)的方法，需要更多关于其原因的信息，以开发和测试新的治疗方法。大量证据表明，肿瘤生长增加了促炎症细胞因子的血清水平，从而增加了与骨骼肌萎缩有关的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物种(ROS)的产生，这也可以激活这些相同的肌肉萎缩的分解代谢途径。肌肉质量的丧失会导致肌肉无力，而氧化应激则会降低肌肉细胞的收缩力量。在携带肿瘤的啮齿动物身上有初步证据表明，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，用抗氧化剂预处理可以防止细胞因子诱导的肌肉细胞分解代谢和收缩功能障碍。辅酶Q10(CoQ10)是一种天然存在于细胞线粒体中的抗氧化剂，在炎症反应中耗尽。本研究的目的是验证辅酶Q10治疗能减少荷瘤小鼠肌肉损耗和改善骨骼肌和心肌收缩功能的假说。申请者将使用实验室技术如酶联免疫吸附试验、聚合酶链式反应和超声心动图来评估荷瘤小鼠的肌肉消耗和肌肉功能，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NINR的一个研究重点领域，这项研究的结果将有助于建立所需的知识库，以测试临床干预措施，以减少癌症患者的疲劳。在这种肿瘤诱导疲劳的动物模型中，心肌功能障碍的演示将影响临床医生评估和治疗CRF患者的方式。申请者将接受关于肌肉萎缩和肌肉功能障碍的生物标记物的强有力的实验室培训，以及临床试验研究，为她在大型学术医学中心担任护士科学家做好准备。 公共卫生相关性：疲倦是癌症患者在治疗前后报告的最常见和最令人痛苦的症状，对他们的生活质量产生负面影响。疲劳还增加了癌症患者医疗保健的社会和经济负担。这项研究将在癌症相关疲劳的动物模型中检测心脏功能障碍的作用以及抗氧化剂治疗的效果。

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.