Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

Takako I. Jones; Guo-Liang Chew; Pamela Barraza-Flores; Spencer Schreier; Monique Ramirez; Ryan D. Wuebbles; Dean J. Burkin; Robert K. Bradley; Peter L. Jones

Although these mild mice appear outwardly healthy, the low-level recombination produces several assayable phenotypes. The mild phenotype manifests as increased expression of DUX4-FL target genes (Figure 3 ), decreased expression of Mstn ( Figure S7 ), 5-10% of myofibers with centralized nuclei at 10-12 weeks of age (Figures 7 and 8) , and 40% decreased capacity for muscle force generation in female (but not male) mice, assayed ex vivo (Figures 5, S4 and S5). There are also small but significant differences between males and females with respect to histology and centralized nuclei that need to be taken in to account. Overall, there is some low-level muscle pathology and new fiber regeneration, however, the mice do not exhibit increased apoptosis, immune cell infiltration, or increased fibrosis. The model is readily scalable, highly reproducible, and, considering that these mice live >1.5yrs (female n=43, male n=20), provides a DUX4-fl expression model that is amenable to longevity studies for efficacy of putative DUX4-targeted therapeutics. Thus, while the mild model is likely the easiest to work with and imposes no time limits on treatments, investigators should be careful in choosing which sex to use (or use a significant number of both sexes and analyze them separately), which age to use, and which muscles to assay or treat.