Duchenne muscular dystrophy (DMD) is a recessive genetic disease resulting from mutation in the dystrophin gene that causes loss of the dystrophin protein, which is known to be found in muscle and brain tissue. In muscle, dystrophin is located in the dystrophin-glycoprotein complex (DGC), which has been shown to aid in force transduction across the sarcolemma (Turrina et al, 2013). DMD patients suffer from a progressive degeneration of muscles leading to loss of ambulation, and a shortened lifespan. Dystrophic muscle is characterized by cycles of degenerating fibers, fibrosis, increased fat deposition, split fibers, and hyaline fibers. Glucocorticoids (GC) are the most effective treatment of DMD, but these drugs only slow the progression of the disease and are known for their severe adverse effects. Skeletal muscle regeneration has been shown to be a spatio-temporally regulated process. Our laboratory has developed the theory that the cause for the failure of regeneration in dystrophic muscle is the result of inappropriate cross-talk between areas that are at different stages of regeneration. Furthermore, we hypothesize that glucocorticoids are effective due to their ability to resynchronize gene expression. In order to test our theory, we have developed a model of asynchronous regeneration in healthy muscle by creating cross-talk using multiple injuries with myotoxins. We found that placing injuries 10 days apart produced muscle histology with many of the features of dystrophic muscle. In the future, we can use this model to test the effectiveness of glucocorticoid treatment in resynchronization. As glucocorticoids are also an endogenous hormone, we sought to determine if their secretion was inherently altered in mdx mice. We found that mdx mice have a significantly dampened circadian endogenous glucocorticoid rhythm of secretion compared to wildtype mice. We also found that administering glucocorticoids in line with circadian rhythm of the endogenous hormone improves muscle histology. In the future, we could use more animals in a longer trial to determine if a chronotherapeutic approach to treatment of dystrophin-deficiency improves efficacy and decreases side effects of glucocorticoids. As dystrophin is expressed in regions of the brain responsible for glucocorticoid regulation, it is possible that lack of dystrophin is directly responsible for the change in endogenous glucocorticoid secretion. This is an important novel hypothesis that should be examined in the future.
|Advisor:||Hoffman, Eric P., Partridge, Terence A.|
|Commitee:||Chen, Yi-Wen, Freishtat, Robert, Nagaraju, Kanneboyina, Nazarian, Javad|
|School:||The George Washington University|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 75/12(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Pharmacology, Medicine|
|Keywords:||Circadian, Duchenne muscular dystrophy, Fibrosis, Glucocorticoids, Muscle, Regeneration|
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