Muscular Dystrophy Specialized Research Center

Project 1 Project Summary Dystroglycanopathies are a group of congenital/limb-girdle muscular dystrophies that lead to progressive skeletal muscle weakness and a decline in respiratory function. Defects in the post-translational processing of the extracellular matrix (ECM) receptor, α-dystroglycan (α-DG), cause dystroglycanopathies. ECM proteins that contain laminin-G-like (LG) domains bind to α-DG via a unique heteropolysaccharide [-GlcA-β1,3-Xyl-α1,3-]n called matriglycan. Genetic studies show that mutations in many genes encoding enzymes required for the post-translational processing of α-DG result in the absence of matriglycan or a reduction in its length and impair α-DG receptor function. Although respiratory complications negatively affect patients with dystroglycanopathies, the causes of these conditions are understudied, and we have very little understanding of the mechanisms that regulate matriglycan synthesis in respiratory muscles or the mechanisms underlying the respiratory pathophysiology when matriglycan is absent or reduced in size. The overall objective of the proposed research is to elucidate the cellular and molecular mechanisms that underly respiratory complications in the dystroglycanopathies. The overarching hypothesis of our research is that a) regulation of matriglycan synthesis in respiratory muscles requires tissue-specific expression of dystroglycanopathy genes and enzyme-substrate complexes and b) defects in this process underly the respiratory pathophysiology observed in patients with dystroglycanopathies. Specific Aim 1 will define the biochemical regulation of matriglycan synthesis, the laminin-binding properties of matriglycan, and α-DG receptor function in respiratory muscles using dystroglycanopathy mouse models. Specific Aim 2 will determine the relationship between matriglycan length and α-DG receptor function and the resulting respiratory pathophysiology in various mouse models of dystroglycanopathy described in Specific Aim 1. These studies will use plethysmography to measure respiratory function (ventilation, tidal volume, respiratory rate, number of apneas, and response to hypercapnia and hypoxia) in order to determine the length and laminin-binding properties of matriglycan that are required to maintain normal respiratory function and the respiratory abnormalities in the absence or reduction of matriglycan. Specific Aim 3 will determine the ability of potential therapies in clinical trials to restore full-length matriglycan and normal respiratory function. These studies will determine the efficacy of current therapies in clinical trials (AAV FKRP and ribitol supplementation) to restore full-length matriglycan, α-DG receptor function, and normal respiratory function in dystroglycanopathy mouse models. Collectively, the expected outcome of these aims is a greater understanding of the pathological mechanisms underlying respiratory complications in the dystroglycanopathies. Moreover, this knowledge is critical for developing a scientific foundation for the design and validation of quantitative assays to determine target engagement as well as the development and improvement of therapeutic strategies to treat respiratory dysfunction in individuals with dystroglycanopathies.