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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F10B-S (20))
Program Officer
Boyce, Amanda T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
East Carolina University
Other Domestic Higher Education
United States
Zip Code
Gilliam, Laura A A; Lark, Daniel S; Reese, Lauren R et al. (2016) Targeted overexpression of mitochondrial catalase protects against cancer chemotherapy-induced skeletal muscle dysfunction. Am J Physiol Endocrinol Metab 311:E293-301
Fisher-Wellman, Kelsey H; Ryan, Terence E; Smith, Cody D et al. (2016) A Direct Comparison of Metabolic Responses to High-Fat Diet in C57BL/6J and C57BL/6NJ Mice. Diabetes 65:3249-3261
Gamboa, Jorge L; Billings 4th, Frederic T; Bojanowski, Matthew T et al. (2016) Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease. Physiol Rep 4:
Fisher-Wellman, Kelsey H; Lin, Chien-Te; Ryan, Terence E et al. (2015) Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit. Biochem J 467:271-80
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
Gilliam, Laura A A; Fisher-Wellman, Kelsey H; Lin, Chien-Te et al. (2013) The anticancer agent doxorubicin disrupts mitochondrial energy metabolism and redox balance in skeletal muscle. Free Radic Biol Med 65:988-996
Fisher-Wellman, Kelsey H; Gilliam, Laura A A; Lin, Chien-Te et al. (2013) Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload. Free Radic Biol Med 65:1201-1208