Progress Update: Testing the effects of antifibrotic drugs on an FSHD mouse model and FSHD fibroadipoprogenitors: the first step toward antifibrotic therapy for FSHD

Posted by Friends of FSH Research on Oct 11, 2022

Report by Darko Bosnakovski
See grant Testing the effects of antifibrotic drugs on an FSHD mouse model and FSHD fibroadipoprogenitors: the first step toward antifibrotic therapy for FSHD

Emerging evidence suggests a crucial role of fibroadipogenic progenitors (FAPs) in muscle homeostasis. Fibrosis is one of the most predominant pathological features of the affected muscles in FSHD patients. The substitution of the muscle tissue with fibrous and fatty tissue progresses over time and directly impacts muscle physiology and skeletal mobility. Thus, controlling or reverting fibrosis may decrease progressive muscle damage and promote muscle regeneration. We know very little about FAPs and muscle fibrosis in FSHD patients. Therefore, we conducted a project that aimed to better understand the fibroadipogenic process in FSHD and test the effectiveness of various antifibrotic drugs in reducing muscle degeneration in an FSHD mouse model. We found that transient expression of DUX4 provokes long-lasting muscle aberration in the FSHD animal model, the iDUX4pA mouse. An increased FAPs infiltration, excess extracellular matrix deposition, alteration in the myofiber size distribution, and impaired regeneration have been detected long after a short pulse or even a single burst of DUX4. Based on our study, we proposed that transient DUX4 expression might prime the muscle for degenerative processes mediated by external factors like injuries. This project also allowed us to test the effectiveness of the different antifibrotic drugs in preventing and reducing muscle fibrosis and degeneration in the FSHD animal model, iDUX4pA. Finally, we had an opportunity to explore the fibrotic status of the FSHD FAPs, which is a crucial first step in understanding the role of these cells in the pathogenesis of diseases. This study helped us to obtain preliminary data used in our successful NIH application, and part of the results was incorporated into two recent publications. We want to thank Friends of FSH Research for funding our project and making this study possible.