Sporadic Inclusion Body Myositis (IBM) is the most common muscle disease in adults over age 50, yet the cause of the disease is unknown, and there are no treatments. To better understand the pathogenesis of this disease and to identify therapeutic targets, we have developed two novel mouse models. First, by implanting human IBM biopsy tissue into immunocompromised mice, we have developed a human xenograft model that recapitulates key features of the disease including atrophy, endomysial inflammation, protein aggregates, and TDP-43 pathology. Second, by deleting TDP-43 specifically in skeletal muscle of mice, we replicated key IBM features including atrophy, rimmed vacuoles and protein aggregates. The goal of this proposal is to better understand the pathogenesis of IBM using these two mouse models and to validate therapeutic targets. We believe we have created the first clinically relevant mouse models of sporadic IBM. Such models have the potential to be useful for IBM studies including mechanistic studies and target validation. This project will independently and rigorously test both the role of the inflammatory response and the role of compromised TDP-43 splicing repression in IBM pathogenesis.
Since there is no accepted animal model of myositis (inflammation of muscle), this study aims to characterize and utilize the first mouse models. Importantly, we will use these models to help understand whether Inclusion Body Myositis (IBM), the most common late adult-onset muscle disease, is primarily a degenerative disease or an autoimmune disease. These 'personalized' and 'humanized' mouse models will be used to validate novel therapeutic targets for this devastating myodegenerative disease.