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

线粒体在癌症化疗引起的骨骼肌疲劳中的作用

• 批准号: 8314261
• 负责人: Laura Ann Ashley Gilliam
• 金额: $ 5.29万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314261
• 关键词: Address; Adjuvant Chemotherapy; Adverse effects; Antioxidants; Bioenergetics; Buffers; Cancer Patient; Cell physiology; Chemotherapy-Oncologic Procedure; Complex; Data; Depressed mood; Development; Diagnosis; Doxorubicin; Electrons; Environment; Fatigue; Fiber; Functional disorder; Generations; Glutathione; Glutathione Disulfide; Human; Hydrogen Peroxide; Individual; Intervention; Laboratories; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Mentors; Metabolic; Mitochondria; Morbidity - disease rate; Mus; Muscle; Muscle Fatigue; Muscle Mitochondria; Muscle Weakness; Muscle function; Myocardium; Organelles; Outcome; Oxidants; Oxidation-Reduction; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Population; Positioning Attribute; Production; Proteins; Public Health; Quality of life; Reactive Oxygen Species; Recovery; Research; Research Project Grants; Respiration; Role; Site; Skeletal Muscle; Source; Striated Muscles; Symptoms; TNF gene; Testing; Time; Tissues; Training; Transgenic Organisms; Translational Research; Tumor Necrosis Factor Receptor; base; breast cancer diagnosis; career; catalase; chemotherapeutic agent; chemotherapy; design; falls; improved; malignant breast neoplasm; mitochondrial dysfunction; mouse model; overexpression; oxidation; post-doctoral training; prevent; programs; respiratory; response; therapy development; translational study; tumor

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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because fatigue is a universal symptom in cancer chemotherapy. This disabling symptom can persist for long periods of time in patients, limiting recovery and increasing overall morbidity. This project lays the groundwork for the development of therapies to alleviate or potentially eliminate this debilitating side effect, improving the quality of life for cancer patients.

描述(申请人提供)：衰弱的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，我发现服用化疗药物阿霉素的健康小鼠肌肉力量降低，疲劳率加快。缺乏肿瘤坏死因子受体亚型1(TNFR1)的小鼠可以免受肌肉力量下降的影响。然而，缺乏TNFR1并不能预防阿霉素诱导的加速疲劳。这些发现提供了证据，表明肿瘤坏死因子至少部分地调节了阿霉素引起的肌肉功能的下降，并提示持续性疲劳可能源于代谢。这个项目的重点是代谢，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可能会损害线粒体的呼吸，增加活性氧物种(ROS)，这是疲劳加速的潜在中介。这个项目的中心假设是，综合效应 癌症和化疗损害了线粒体的呼吸控制，增加了ROS的产生，将细胞内的氧化还原环境转变为更氧化的状态，并降低了肌肉收缩功能。为了解决这一假设，所有目标都将包括对渗透性纤维束进行的实时线粒体功能和细胞氧化还原状态的综合分析，以及整个肌肉疲劳的分析。该项目将在目标1和目标2中使用化疗药物阿霉素治疗荷瘤小鼠，然后在目标3中对乳腺癌患者进行翻译研究。具体目标1将确定效果 癌症化疗对骨骼肌线粒体功能、细胞氧化还原状态和收缩功能的影响。我们将确定癌症/化疗对肌肉线粒体功能的多个方面的单独和联合影响。具体目标2将确定线粒体ROS的产生是否代表癌症化疗引起的线粒体功能障碍和骨骼肌疲劳的潜在机制。我们将利用药理学和转基因线粒体靶向抗氧化策略来确定线粒体ROS产生在癌症和癌症化疗诱导的肌肉功能障碍中的作用。具体目标3将确定癌症化疗对接受阿霉素为主的化疗的乳腺癌患者骨骼肌线粒体功能的影响。该项目将确定线粒体ROS产量增加是否是骨骼肌功能障碍的潜在原因，潜在地建立了与肌肉功能障碍的机制联系。 公共卫生相关性：这项拟议的研究与公共健康相关，因为疲劳是癌症化疗的普遍症状。这种致残症状可能会在患者身上持续很长一段时间，限制康复并增加总体发病率。该项目为开发减轻或有可能消除这种衰弱副作用的疗法奠定了基础，从而提高了癌症患者的生活质量。