Matrix metalloproteinases are hallmark early biomarkers and therapeutic targets in FSHD

Matrix remodeling by matrix metalloproteinases (MMPs) is essential formaintaining muscle homeostasis; however, MMP dysregulation can drivedegenerative processes. Interrogating biopsy RNA-seq data, we showthat MMP expression correlates with disease severity infacioscapulohumeral muscular dystrophy (FSHD). In the iDUX4pA FSHDmouse model, MMP expression progressively increases in response toDUX4-induced muscle degeneration. Single cell RNA-seq, furtheridentified fibroadipogenic progenitors (FAPs) and macrophages asprimary sources of MMPs, particularly MMP2, MMP14, and MMP19, indystrophic muscles. Treatment with the pan-MMP inhibitor Batimastatalleviated inflammation and fibrosis, improved muscle structure, anddecreased the numbers of FAPs and infiltrating macrophages. Thesefindings underscore the role of MMPs in driving muscle degeneration inFSHD, highlight MMPs as functional biomarkers of disease, and supportMMP inhibition as a DUX4-independent therapeutic strategy to limitfibroadipogenesis and promote muscle regeneration.