Pathogenic Mechanisms in Facioscapulohumeral Muscular Dystrophy

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PROJECT SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent myopathy afflicting males and females, children and adults. In the majority of clinical FSHD cases, muscle weakness is not noticeable until the second or third decade of life followed by a progressive pathology impacting many facets of everyday life, ranging from being unable to comb one's own hair or walk the dog to including having to change or abandon careers, loss of independence and, in ~20% of FSHD patients, becoming wheelchair bound and/or require aid in breathing. Currently there are no treatments to slow down, stop, or reverse disease progression. Recent advances have identified the aberrant expression of the DUX4 transcription factor as the primary initiator of the FSHD pathogenic cascade of events. In vitro studies have identified numerous DUX4-mediated events that have adverse effects on cell viability and function and could conceivably lead to muscle disease if they were to happen in the context of an actual person. However, due to the complexities of FSHD and the lack of any valid animal model for FSHD, which, if any, of these pathways actually has pathogenic relevance. We have successfully generated and validated a phenotypic FSHD-like mouse model based on DUX4 expression. This allows, for the first time, the interrogation of downstream effects of DUX4 expression as to potential roles in pathophysiology and validation as therapeutic targets. We will initially focus on the innate immune response. The major gene expression signature from FSHD muscle biopsies indicates the immune response is highly activated in FSHD muscle. Many other muscular dystrophies have immune system components and there are many available ameliorative treatments for these muscular dystrophies that target the inflammatory response. Identifying the inflammatory response as a key mechanism in developing FSHD pathology would be a significant advance and open many new avenues for therapeutic intervention. In addition, the design of the model allows us to initiate DUX4 expression in adult animals. Therefore, we will use our FSHD-like mouse model to identify potential biomarkers of disease progression and compare with what has been found in human biospecimens. Importantly, in our mice we will be able to distinguish early, initiating events from those due to long-term cumulative effects and this may help determine which biomarkers correlate more directly with DUX4 expression and are the best to follow as the field moves to clinical trials.