The role of mitochondria in skeletal muscle fatigue caused by cancer chemotherapy

描述（由申请人提供）：衰弱性肌肉无力和疲劳是癌症患者化疗的常见副作用，限制了治疗并增加了发病率。在我的论文研究中，我发现健康的老鼠服用了多柔比星（一种化疗药物），肌肉力量下降，疲劳速度加快。缺乏肿瘤坏死因子-受体亚型1 （TNFR1）的小鼠可以防止肌肉力量的下降。然而，TNFR1缺乏并不能防止阿霉素引起的加速疲劳。这些发现提供了证据，TNF至少部分介导了多柔比星引起的肌肉功能下降，并提示持续疲劳可能源于代谢。该项目侧重于代谢，更具体地说，是肌肉功能的线粒体方面。癌症和化疗的联合作用会损害线粒体呼吸，增加活性氧（ROS），这是加速疲劳速率的潜在介质。这个项目的中心假设是综合效应

DESCRIPTION (provided by applicant): Debilitating muscle weakness and fatigue are common side effects of chemotherapy in cancer patients, limiting treatment and increasing morbidity. In my dissertation research I found that healthy mice given doxorubicin, a chemotherapy drug, had decreased muscle force and an accelerated rate of fatigue. Mice deficient in tumor necrosis factor-¿ receptor subtype 1 (TNFR1) were protected against the fall in muscle force. However, TNFR1 deficiency did not protect against doxorubicin-induced accelerated fatigue. These findings provide evidence that TNF at least partially mediates the decline in muscle function in response to doxorubicin and suggest persistent fatigue may be metabolic in origin. This project focuses on the metabolic, and more specifically mitochondrial aspects of muscle function. The combined effect of cancer and chemotherapy can compromise mitochondrial respiration and increase reactive oxygen species (ROS), potential mediators of the accelerated rate of fatigue. The central hypothesis of this project is that the combined effect of cancer and chemotherapy compromises mitochondrial respiratory control and increases ROS production, shifting the intracellular redox environment to a more oxidized state and decreasing muscle contractile function. To address this hypothesis all aims will include a comprehensive analysis of real-time mitochondrial function and cellular redox state conducted on permeabilized fiber bundles in conjunction with whole muscle fatigue analysis. This project will use tumor-bearing mice treated with the chemotherapeutic agent doxorubicin in Aims 1 and 2, followed by a translational study in breast cancer patients in Aim 3. Specific Aim 1 will determine the effects of cancer chemotherapy on skeletal muscle mitochondrial function, cellular redox state, and contractile function. We will determine the individual and combined effects of cancer/chemotherapy on multiple aspects of mitochondrial function in muscle. Specific Aim 2 will determine whether mitochondrial ROS production represents an underlying mechanism for cancer chemotherapy induced mitochondrial dysfunction and skeletal muscle fatigue. We will utilize pharmacological and transgenic mitochondrial-targeted antioxidant strategies to determine the role of mitochondrial ROS production in cancer and cancer chemotherapy-induced muscle dysfunction. Specific Aim 3 will determine the effects of cancer chemotherapy on skeletal muscle mitochondrial function in breast cancer patients receiving doxorubicin-based chemotherapy. This project will determine whether elevated mitochondrial ROS production is an underlying cause of skeletal muscle dysfunction, potentially establishing a mechanistic link to muscle dysfunction.