Molecular, Histological, and Functional Changes in Acta1-MCM;FLExDUX4/+ Mice.

Abstract

DUX4 is the major gene responsible for facioscapulohumeral dystrophy (FSHD). Several mouse models expressing DUX4 have been developed, the most commonly used by academic laboratories being ACTA1-MCM/FLExDUX4. In this study, molecular and histological modifications in the tibialis anterior and quadriceps muscles were investigated in this model at different time points. We investigated several changes that could be used as markers of therapeutic efficacy. Our results confirm the progressive muscular dystrophy previously described but also highlight biases associated with tamoxifen injections and the complexity of choosing the genes used to calculate a DUX4-pathway gene composite score. We also developed a comprehensive force test that better reflects the movements made in everyday life. This functional force-velocity-endurance model, which describes the force production capacities at all velocity and fatigue levels, was applied on 12-13-week-old animals without tamoxifen. Our data highlight that previously unsuspected muscle properties are also affected by the expression of DUX4, leading to a weaker muscle with a lower initial muscle force but with preserved power and endurance capacity. Importantly, this force-velocity-endurance approach can be used in humans for clinical evaluations.