Duchenne muscular dystrophy (DMD) is a devastating type of muscular dystrophy, with an incidence of 1 in every 3500 males. DMD is an X-linked, muscle-wasting disease caused by mutations in the cytoskeletal protein dystrophin. Young DMD patients experience muscle damage that is followed by regeneration; however, as the disease progresses regeneration is impeded and muscle fibers are progressively replaced by connective tissue and fatty deposits. Profound muscle weakness results in decreased mobility by 10 to 12 year of age and eventually death by the age of 20 to 30 due to respiratory and/or cardiac failure. While there is currently no treatment for the disease, many different therapeutic approaches for DMD are entering clinical trials. Accumulating evidence supports the idea that the elevated susceptibility to damage in mdx muscles correlates with the presence of increased sarcolemmal Ca2+ influx and increased production of reactive oxygen species (ROS). Impaired autophagy, a cellular process to clear damaged constituents, has recently been implicated in the disease process. Ongoing work by our group has found that increased ROS generation from Nox2 contributes to altered redox balance and Ca2+ homeostasis in skeletal muscle from the mouse model of muscular dystrophy (Mdx). We have recently shown that Src, a non-receptor tyrosine kinase, acts as a redox switch to activate Nox2. Genetic inhibition of Nox2 decreases the exuberant ROS generation, decreases Src kinase activity, and rescues the defective autophagy in skeletal muscle from Mdx mice. Furthermore, we have shown that inhibiting Src kinase in-vitro decreases oxidative stress and improves autophagy. In preliminary data we have recently found that treating Mdx mice with the Src kinase inhibitor dasatinib improves autophagic flux and skeletal muscle function. The overall goal of this proposal is to test whether inhibition of Src kinase can prevent oxidative stress, impaired autophagic flux, and muscle pathology in Mdx mice. If successful, the proposed research will provide a novel therapeutic target, Src kinase, for DMD. Given that Src kinase inhibitors are in clinical development for the treatment of cancer, results from these studies will be valuable for future clinical trials for the treatment of DMD.

Public Health Relevance

Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, making skeletal muscle more fragile during activities performed by patients in everyday life (e.g. walking). No cures exist and current treatments that slow muscle degeneration are largely ineffective. We have strong evidence that Src tyrosine kinase plays a key role in the disease process. We propose testing Src kinase inhibitors, which are already in clinical trials for the treatment of cancer, as therapeutic agents for the treatment of muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR061370-07S1
Application #
9677800
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2012-08-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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