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

Treadmill assays indicated that muscle use and/or function was impaired by induction of DUX4-fl expression in the moderate and severe mouse models. Ex vivo muscle contractile studies using the isolated extensor digitorum longus (EDL) were then performed on these mice to assess changes in muscle strength [52, 53, 69] . Muscle forces from isometric contractions (twitch and tetanic) and tetanic force changes with increased frequencies of electric stimulation (force frequency) were measured and muscle stiffness was calculated from analysis of eccentric . CC-BY-NC 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.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 contractions ( Figures 5 and S4 ). EDL muscles isolated from the mild model bi-transgenic mice (no TMX) were initially compared with age-matched ACTA1-MCM mice (control) treated with the appropriate dose of TMX for the respective group isolated at TMX D14 or TMX D10 from the first injection. Interestingly, despite having similar treadmill endurance profiles as controls ( Figure 4 ), the female bi-transgenic mice (no TMX) consistently showed significantly lower maximum absolute force and specific force measurements (maximum force normalized by cross sectional area: CSA) compared with controls ( Figure 5 and S4). Male bi-transgenic mice, however, were less affected and only showed a significant strength difference from controls with respect to maximum twitch force and maximum force frequency ( Figure S4D -F), and no significant change in specific force measurements. However, both male and female bi-transgenic mild models were significantly less responsive to mid-level and high stimulation frequencies (65-180 Hz) compared with controls ( Figure 5C and S4). We conclude that chronic, low, mosaic DUX4-FL expression in even a few myofibers reproducibly produced a measurable decrease in isometric contractile strength of muscle that does not appear to affect treadmill fitness. Thus, this data suggests that these mild bi-transgenic (no TMX) mice may present a model of presymptomatic FSHD or an early symptomatic mild FSHD.