Ischemia and the Pathogenesis of Muscular Dystrophy

Project: Research project

Description

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD), the most common of the human muscular dystrophies, is a crippling, incurable disease caused by mutation of the gene encoding the sarcolemmal protein dystrophin. There currently is no effective treatment for DMD because the mechanism by which dystrophin deficiency produces the clinical phenotype is poorly understood. A characteristic histological feature of dystrophic muscle is the appearance of small random groups of necrotic muscle fibers surrounded by apparently normal fibers, a pattern that might be explained by microvascular ischemia. Whether muscle ischemia plays an important role in the pathogenesis of muscular dystrophy has not been studied. Therefore, the overall goal of this proposal is to determine if recurrent muscle ischemia plays a causal role in producing or accelerating the dystrophic phenotype and if early intervention with anti-ischemic therapy constitutes a viable countermeasure to slow progression of the disease. The mdx mouse, an animal model of DMD, will be studied at prenecrotic (12 wks old) phases of the disease to determine if (1) dystrophin-deficient skeletal muscle is abnormally sensitive to ischemic stress induced by acute mechanical occlusion or chronic pharmacological constriction of blood vessels; (2) ischemia enhances accumulation of reactive oxygen species (ROS) in dystrophin-deficient skeletal muscle, resulting in activation of the redox sensitive transcription factors NF-KappaB and AP-1; (3) sympathetic vasoconstriction is a proximate cause of ischemia in dystrophin-deficient skeletal muscle; and (4) the dystrophic phenotype is ameliorated by chronic treatment with vasodilators, antioxidants, or sympatholytics. A combination of histological and biochemical measurements will be used to evaluate skeletal muscle damage, ROS production, and transcription factor activation. Vascular function will be assessed in vivo by measuring changes in skeletal muscle blood flow in response to intra-arterial infusion of vasoconstrictor and vasodilator agents. Functional tests will be performed in conscious mice to measure grip strength and voluntary wheel running activity. Taken together, the proposed studies will provide a comprehensive assessment of the vulnerability of dystrophin-deficient skeletal muscle to ischemic stress, probing both a causal role for sympathetic vasoconstriction and an effector role for ROS in the dystrophic process. Additionally, these studies may identify potential new therapeutic targets to treat this devasting disease.
StatusFinished
Effective start/end date5/1/0410/31/09

Funding

  • National Institutes of Health: $342,160.00
  • National Institutes of Health: $311,903.00
  • National Institutes of Health: $319,410.00
  • National Institutes of Health: $296,801.00
  • National Institutes of Health: $302,858.00

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Dystrophin
Muscular Dystrophies
Skeletal Muscle
Ischemia
Duchenne Muscular Dystrophy
Reactive Oxygen Species
Muscles
Vasoconstriction
Vasodilator Agents
Phenotype
Blood Vessels
Transcription Factors
Sympatholytics
Inbred mdx Mouse
Intra Arterial Infusions
NF-kappa B
Transcription Factor AP-1
Hand Strength
Vasoconstrictor Agents
Constriction