Exercise is one of the most powerful tools to prevent muscle loss and aging-related diseases. Reactive oxygen species (ROS) and inflammation, long-thought to contribute to tissue damage, have recently been recognized to function as signaling molecules necessary for the benefits of exercise. My preliminary data demonstrate that improved glucose tolerance and exercise capacity, two hallmarks of exercise-induced muscle adaptation, are attenuated in mice deficient in NADPH oxidase 4 (Nox4), an ROS-producing enzyme. My data indicate that Nox4 drives an Nlrp3 muscle cytokine response that leads to improved muscle metabolism. In this proposal, I will investigate the role of redox-mediated adaptation to exercise using state-of-the art techniques in immunology and muscle physiology (e.g., Amnis/Immagestream, RNA-seq, and ex vivo muscle stimulation). To aid me in completion of this project, I have established a strong mentoring team comprised of experts in the fields of inflammation and immunology (Dr. Katherine Fitzgerald), muscle molecular biology and regeneration (Dr. Charles Emerson), skeletal muscle adaptation to exercise and redox signaling (Dr. Zhen Yan) and immunometabolism (Dr. Michael Czech), all of whom are top leaders in their respective fields and have lengthy track records of mentoring success. My career goal is to lead a successful research program dedicated to the investigation of redox and inflammatory signaling in angiogenesis and skeletal muscle adaptation. I believe that the knowledge gained by understanding the details of ROS signaling in adaptation to exercise will lead to the development of better therapeutic strategies to combat frailty, diabetes, obesity, and musculoskeletal diseases.

Public Health Relevance

Regular physical activity is among the most effective ways to prevent obesity, diabetes, cardiovascular disease, and age- related muscle decline. Muscle adaptation in response to exercise contributes to the beneficial effect of physical activity and overall health. This proposal seeks to understand the signals for adaptation to exercise that lead to improved muscle and whole body metabolism. The work contained in this proposal will provide the insight needed to design new therapies for improving muscle metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AR073332-01A1
Application #
9666583
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Boyce, Amanda T
Project Start
2019-03-25
Project End
2024-02-29
Budget Start
2019-03-25
Budget End
2020-02-29
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Type
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061