Posted by Friends of FSH Research on Sep 19, 2023
Update by Matthew Cowley
See also An in-silico approach to understanding DUX4 expression
With the valuable support of Friends of FSH Research, we have developed a computational cellular model of facioscapulohumeral muscular dystrophy (FSHD), based on a mechanism where expression of DUX4 (currently the main target for FSHD therapy) leads to muscle cell death. DUX4 is a transcription factor, which means it can control the expression of other genes (termed DUX4 targets). In FSHD, these targets likely cause muscle wasting.
We classified cells in FSHD muscle into 5 different categories by measuring DUX4 and its targets: (1) healthy cells, (2) cells expressing only DUX4, (3) cells expressing both DUX4 and DUX4 targets, (4) cells expressing only DUX4 targets and (5) dead cells (Figure 1). These groups of cells can be identified in FSHD patient muscle using a technique called single cell RNA-sequencing. By building a bespoke mathematical model and performing careful lab experiments investigating DUX4 and its targets, we estimated the rates at which FSHD muscle cells moved across the 5 categories, from healthy to dead. This allowed us to create a simulation of the life of an FSHD muscle fibre, describing how the therapeutic target DUX4 impacts on the course of the disease.
Using our new model, we found that despite a very low number of cells expressing DUX4 at any given time, DUX4 targets drive significant cell death. We also found strong evidence that DUX4 spreads along FSHD muscle fibres, causing additional damage on its path. Our simulation allows investigators to ‘test-out’ different ways of targeting DUX4 for FSHD therapy, rapidly and for free, to see how likely they are to help patients, saving time and money in vital research projects. We have packaged our model into freely available, user-friendly tools to accelerate research into FSHD therapies. The full results of the project can be seen in our published journal article.