Myotonic dystrophy (DM1) is the most common form of muscular dystrophy in adults and children. Though there are a variety of other multi-systemic effects, DM1 is mainly characterized by myotonia and progressive muscle wasting. Muscle weakness, wasting, and fatigue have also been reported as the most impactful adverse outcomes by patients. RNA splicing defects have been identified as key effects of the toxic RNA produced in DM1 patients, and using myoblast cells from mice and DM1 patients, we and others have previously demonstrated the deleterious effects of the toxic RNA on myogenic differentiation. But little is known about the regenerative process in DM1 or the effects of RNA toxicity on this. Addressing this key issue is hampered without a model in which we can develop a thorough understanding of the effects of RNA toxicity on muscle regeneration and one in which to test therapies targeting this process. Satellite cells are key cellular mediators of muscle regeneration in response to damage. Here, we have developed the first RNA toxicity mouse model with demonstrated expression of the toxic RNA in satellite cells. We will use this model to characterize the effects of RNA toxicity on satellite cells and muscle regeneration. We will also study the expression of various key proteins implicated in DM1 such as MBNL1 and CUGBP1 in satellite cells, especially in response to damage. We will also use this model to study the effects of therapeutics on satellite cell function in RNA toxicity. Our goal is to understand the role of RNA toxicity in the process of muscle regeneration in order to provide a platform for developing therapies to treat muscular dystrophy in DM1. .
Myotonic dystrophy (DM1) is the most common form of muscular dystrophy in adults and children. It is caused by the expression of a toxic RNA from the mutant DM1 gene. Progressive muscle wasting and weakness are a hallmark of DM1 and cause significant morbidity and adversely affect the quality of life for patients with DM1. Muscle maintenance and regeneration is critically dependent upon muscle stem cells (known as satellite cells). Though this is a crucial component of muscle, very little is known about the effects of RNA toxicity on satellite cells or their ability to repair muscle in the context of RNA toxicity. Currently, there are no mouse models of RNA toxicity in satellite cells. We have developed new mouse models of RNA toxicity, as well as new mouse models to study the satellite cell niche in the context of RNA toxicity. Our goal is to use these models to characterize and understand the effects of the toxic RNA on these cells and the process of muscle regeneration in order to provide a better understanding of muscular dystrophy in DM1, and to develop novel mouse models and techniques which can be used to study the effects of new therapies on muscle regeneration and the satellite cells niche.
