Secondary dystroglycanopathies are a form of muscular dystrophy caused by a failure in the glycosylation (a process of adding sugars) of the protein dystroglycan. Dystroglycan is located at the surface of cells where it tightly binds to extracellular matrix proteins when it is properly glycosylated, forming an important structural and signaling link from the outside to the inside of cells. In secondary dystroglycanopathies, the dystroglycan link outside of cells is disrupted, causing progressive muscle weakness and wasting and possible heart, brain and eye disease. Dystroglycanopathy muscular dystrophies encompass a wide spectrum of disease phenotypes ranging from neonatal onset of severe disease with early death, to late onset disease (teens) with milder symptoms. Mutations in the gene encoding fukutin, FKTN, cause the most common severe form of dystroglycanopathy (Fukuyama congenital muscular dystrophy). Using a novel mouse model of fukutin-dystroglycanopathy, it has recently been shown that dystroglycan abnormalities during muscle development, regeneration and differentiation are required for severe muscular dystrophy in mice. The proposed research aims to address the defects in muscle regeneration following developmental or post-development loss of dystroglycan function. The objectives of the proposed research are to address the role of dystroglycan function in the timing and cell source of muscle regeneration defects using the fukutin-dystroglycanopathy mouse model. To meet these objectives, the proposed specific aims use genetic, histological, biochemical, and imaging methods to track muscle fiber regrowth following muscle injury. This research is directly relevant to human health because abnormalities in muscle regeneration are a key target for developing therapeutics to improve the lives of dystroglycanopathy muscular dystrophy patients. Currently, there is no therapy for dystroglycanopathy muscular dystrophy;therefore, the expected research advances are necessary and relevant to the mission of the NIH.
The proposed research is relevant to public health because identifying the fundamental defects in muscle fiber regeneration caused by abnormal dystroglycan function is critical for devising appropriate strategies to rebuild healthy muscle fibers and for evaluating the degree with which new therapies can be expected to improve patient lives. As such, the proposed study is relevant to the NIH mission to support research into the causes of and treatments for neuromuscular disorders, aiming to ultimately reduce the burden of disease.