权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8484739
负责人：
Laura Ann Ashley Gilliam
金额：
$ 5.56万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
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/8484739
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

项目摘要

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.