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1 Department of Physiological Science, University of California - Los Angeles, Los Angeles, California, United States
2 Department of Physiological Science, University of California - Los Angeles, 90095, California, United States
* To whom correspondence should be addressed. E-mail: jtidball{at}physci.ucla.edu.
Null mutation of members of the dystrophin protein complex can cause progressive, and possibly fatal, muscle wasting. Although these muscular dystrophies arise from mutation of a single gene that is expressed primarily in muscle, the resulting pathology is complex and multi-systemic. Prior to the identification of the deficient proteins that underlie muscular dystrophies such as Duchenne muscular dystrophy (DMD), oxidative stress was proposed as a major cause of the disease. Now, current knowledge indicates that interactions between the primary genetic defect and disruptions in the production of free radicals contribute these diseases. In this review, we focus on the pathophysiology of dystrophin-deficiency in humans with DMD and the mdx mouse model of DMD. Current evidence indicates three routes through which free radical production can be disrupted in dystrophin-deficiency and promote pathology. First, constitutive differences in free radical production can disrupt signaling in muscle and other tissues and exacerbate pathology. Second, tissue responses to the pathology can shift free radical production to promote cellular injury and dysfunction. Finally, behavioral differences in the affected individual can cause changes in the production free radicals and contribute to disease. Unfortunately, the complexity of the free radical mediated processes that are perturbed in muscular dystrophy makes it difficult to develop therapies founded on systemic administration of anti-oxidants. More mechanistic knowledge of the specific disruptions of free radicals that underlie major features of muscular dystrophy is needed to develop more targeted therapeutic approaches.
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