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

The goal in this study was to generate three levels of FSHD-like severity using our FLExDUX4 mouse model and characterize the progression of pathology in ways useful to those performing preclinical testing of candidate DUX4-targeted therapeutics. We have provided an initial molecular, phenotypic, physiological, and histological characterization of three severity levels of inducible FSHD-like model mice. A key feature of these models is that the ACTA1-MCM;FLExD bi-transgenic mice express chronic low-level mosaic and skeletal muscle-specific DUX4-fl mRNA and protein. Thus, the moderate and severe models are not introducing DUX4 expression to a naive system, instead providing a situation similar to the bursts of DUX4 expression seen in FSHD myocytes [19] . It is well-documented that cells from asymptomatic FSHD subjects express DUX4, and cells from relatively healthy muscle biopsies from clinically . CC-BY-NC 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/471094 doi: bioRxiv preprint affected FSHD patients express significant levels of DUX4 [9, 16, 17] . Thus, these models are recapitulating how we envision the DUX4 situation in FSHD, whereby genetically FSHD patients express a low level of DUX4 in their skeletal muscles and at some point, DUX4 levels significantly increase, along with muscle pathology. These bi-transgenic FSHD-like models allow investigators to recapitulate the chronic, low-levels of DUX4, followed by an investigatorcontrolled increase in DUX4 expression, and accompanying pathology, to whatever degree is desired.