An in silico FSHD muscle fibre for modelling DUX4 dynamics and predicting the impact of therapy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an incurable myopathy linked to over‐expression of the myotoxic transcription factor DUX4. Targeting DUX4 is the leading therapeutic approach, however it is only detectable in 0.1‐3.8% of FSHD myonuclei. How rare DUX4 drives FSHD and the optimal anti‐DUX4 strategy is unclear. We combine stochastic gene expression with compartment models of cell states, building a simulation of DUX4 expression and consequences in FSHD muscle fibres. Investigating iDUX4 myoblasts, scRNAseq and snRNAseq of FSHD muscle we estimate parameters including DUX4 mRNA degradation, transcription and translation rates and DUX4 target gene activation rates. Our model accurately recreates the distribution of DUX4 and target gene positive cells seen in scRNAseq of FSHD myocytes. Importantly we show DUX4 drives significant cell death despite expression in only 0.8% of live cells. Comparing scRNAseq of unfused FSHD myocytes to snRNAseq of fused FSHD myonuclei, we find evidence of DUX4 protein syncytial diffusion and estimate its rate via genetic algorithms. We package our model into freely available tools, to rapidly investigate consequences of anti‐DUX4 therapy.