Failed Regeneration in the Muscular Dystrophies: Inflammation, Fibrosis and Fat: Project 2

Project: Research project

Project Details

Description

Muscular dystrophy arises from defects in many different single genes. Mutations in the genes encoding dystrophin or the sarcoglycans elicit a similar phenotype of progressive muscle weakness accompanied by dilated cardiomyopathy. The relationship between dystrophin and sarcoglycan loss is further reinforced by the assembly of these proteins into the dystrophin glycoprotein complex (DGC). The DGC plays a key role in stabilizes the plasma membrane against the forces associated with repetitive contraction. As both cardiac and skeletal muscle face repeated contraction, both heart and muscle are damaged by loss of the DGC. Mutations in γ-sarcoglycan lead to a recessive form of muscular dystrophy, similar to what occurs in Duchenne Muscular Dystrophy (DMD). There is a single mutation responsible for γ-sarcoglycan, 521ΔT, that has been described in LGMD patients from around the world. Despite the presence of the identical gene mutation, there is considerable phenotypic variability with this mutation. Similarly, in DMD, brothers sharing the same mutation may have a discrepant disease process. We sought to identify genes that modify the outcome of muscular dystrophy using a mouse model of γ-sarcoglycan mutations, Sgcg null. We selected this model because of the strong evidence for genetic modifiers in the corresponding human disease and because we reasoned that such modifiers could point to pathways that may be useful for therapeutic intervention. Using the Sgcg null model, we recently identified LTBP4, a TGFβ binding protein, as a modifier of muscle disease. We mapped modifiers of muscular dystrophy by identifying two distinct background strains, D2 and 129, that lead to severe and mild forms of muscle disease, respectively. We now propose to use a similar strategy to understand modifiers of cardiac function in muscular dystrophy.

Aim 1. Map modifiers of cardiac function in muscular dystrophy. Rationale: Our prior data relied on mapping fibrosis, or hydroxyproline content, as well as mapping Evans blue dye uptake as a reflection of the muscle pathology in muscular dystrophy. We found that for skeletal muscle, these pathological features correlated with muscle strength and muscle function. However, as cardiac function can be established using less invasive in vivo methods, we propose to generate a cohort of animals for mapping modifiers of cardiac function as assessed by echocardiography. We will conduct this study in Sgcg null mice as this model displays cardiomyopathy that is variable and can be measured early than in the mdx mouse. Hypothesis: We hypothesize that the same genetic modifiers will also be applicable to dystrophin-mediated pathology given the mechanistic overlap of dystrophin and sarcoglycan.

Aim 2. Map modifiers of cardiac muscle pathology in muscular dystrophy. Rationale: Our prior analysis focused on limb skeletal muscle, as this is a primary target in muscular dystrophy. We now have an additional cohort, which demonstrate a range of cardiac pathology, measured as hydroxyproline content. We propose to conduct a genomewide screen on this cohort to identify genetic loci that modify cardiac fibrosis in muscular dystrophy. These loci identified from this screen may differ from those identified in Aim 1. If the loci overlap, this will provide additional information to help refine the loci identified in Aim 1. If they differ, this will demonstrate that fibrosis and function are regulated by different genetic pathways. Hypothesis: Loci that regulate fibrosis will also regulate cardiac functi
StatusFinished
Effective start/end date10/1/147/31/15

Funding

  • University of Pennsylvania (554991//5U54AR052646)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (554991//5U54AR052646)

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