Duchenne muscular dystrophy (DMD) is the most common lethal X-linked genetic disease affecting boys caused by mutations in the dystrophin gene that lead to a non functional dystrophin protein product. The loss of dystrophin results in extensive muscle damage, muscle wasting, reduced muscle function, and death in the mid to late 20's. Additional pathologic features that exacerbate the muscle damage are inflammation and oxidative stress. ATP production, particularly oxidative metabolism, is also compromised with this disease further reducing muscle function. Resveratrol reduces inflammation, oxidative stress, enhances oxidative metabolism, and activates the utrophin promoter; a gene whose protein product reduces dystrophic muscle damage. Therefore resveratrol treatment would likely benefit dystrophic muscle by reducing muscle pathology and increasing muscle function. The primary purpose of this study was to determine the effect of resveratrol treatment on muscle function, muscle pathology, oxidative capacity, and utrophin protein expression in the mdx mouse model of DMD. Specific aim 1 examined the effect of resveratrol treatment on in-vivo and in-situ muscle function. Resveratrol treatment significantly increased rotarod performance, increased specific peak tension of the triceps surae muscle complex, and reduced the rate of tension decline of the triceps surae muscle complex. Specific aim 2 examined the effect of resveratrol on muscle pathology. Muscle damage and oxidative stress were reduced in 12 week old mdx mice after 8 weeks of resveratrol treatment while total inflammation was reduced in 5 week old mdx mice after 10 days of resveratrol treatment. Specific aim 3 examined the effect of resveratrol on oxidative capacity and utrophin protein content in type I and type II muscles. Resveratrol did not increase the protein expression or activity of metabolic proteins nor was utrophin protein increased in either type I or type II muscles. In summary, resveratrol increased muscle function while decreasing inflammation and oxidative stress in dystrophic muscle, but resveratrol did not increase the expression or activity of oxidative metabolic proteins or utrophin. We conclude that resveratrol may be a likely therapy for patients with DMD by decreasing many pathological features associated with the disease improving muscle function.
|Advisor:||Kostek, Matthew C.|
|Commitee:||Carson, James A., Fayad, Raja, Murphy, Angela E.|
|School:||University of South Carolina|
|School Location:||United States -- South Carolina|
|Source:||DAI-B 73/10(E), Dissertation Abstracts International|
|Subjects:||Genetics, Cellular biology, Physiology|
|Keywords:||Duchenne muscular dystrophy, Genetic diseases, Inflammation, Oxidative capacity, Oxidative stress, Resveratrol, Utrophin|
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