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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AR061946-03
Application #
8664738
Study Section
Special Emphasis Panel (ZRG1-F10B-S (20))
Program Officer
Boyce, Amanda T
Project Start
2012-06-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$58,618
Indirect Cost
Name
East Carolina University
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Hinkley, J Matthew; Ferey, Jeremie L; Brault, Jeffrey J et al. (2014) Constitutively active CaMKK* stimulates skeletal muscle glucose uptake in insulin-resistant mice in vivo. Diabetes 63:142-51