Investigator: Sachiko Homma Takayama PhD
Category: Research - Basic
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive, autosomal dominant disease caused by disrupted silencing of the transcription factor DUX4. Despite the overwhelming genetic evidence that DUX4 mRNA expression is necessary for FSHD, its primary role has been questioned because of the extremely low abundance of DUX4 mRNA in affected FSHD muscle cells and biopsies. Newly developed mouse models for FSHD identified that very low expression levels of DUX4 (even undetectable at protein levels) are enough to induce muscle damage and atrophic phenotypes. However, mechanisms of the atrophy are unknown. We found a gene that plays a role in degrading unwanted proteins and is associated with muscle atrophy was upregulated in an FSHD mouse model with very low expression of DUX4. Interestingly, DUX4 induces alternative splicing on the gene, and that could initiate atrophy process in FSHD. In this project, we will identify the roles of the gene and of DUX4-induced alternative splicing in muscle atrophy in FSHD. Results of this project may reveal therapeutic targets for DUX4-induced muscle atrophy.