Identification and Efficacy of Anti-Fibrotic Treatments for Duchenne Muscular Dystrophy Mouse Models
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Date
2012-06
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The Ohio State University
Abstract
Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disease caused by the absence of dystrophin at the muscle membrane. Duchenne Muscular Dystrophy patients suffer from progressive muscle deterioration, including respiratory muscles, and, until more recent advancements, died from skeletal muscle disease at a young age. Today, many patients live long enough to experience cardiomyopathy due to increased cardiac muscle damage and subsequent fibrosis. These patients often die in their late teens or twenties from complications due to heart failure rather than skeletal muscle disease. Through long-term treatment of 4 week and 8 week dystrophin-deficient, utrophin-haploinsufficient (het) mice with antifibrotic medications, we determined whether current standard-of-care drug treatment can be preventative of cardiac dysfunction if started prior to initial signs of damage. Spironolactone and lisinopril drug treatments were applied via water bottles three times per week until the mice reached the age of 20 weeks. Following treatment, cardiac magnetic resonance images (MRI) and both skeletal and cardiac muscle physiology data, along with histological data were obtained. The results of the project indicated that the combinatorial antifibrotic treatment significantly reduces cardiac damage and nearly restores cardiac function in the mouse models that begin treatment at 4 weeks of age. This project has direct implications for the treatment of Duchenne Muscular Dystrophy patients. After concluding the first project, a second project was started in which we tested the efficacy of spironolactone and lisinopril individually in comparison to the combination treatment.
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Keywords
Duchenne Muscular Dystrophy, Cardiomyopathy, Spironolactone, Lisinopril, Mouse model