# Matrix metalloproteinases are hallmark early biomarkers and therapeutic targets in FSHD

## TL;DR

This study shows that matrix metalloproteinases (MMPs) play a key role in muscle degeneration in FSHD and that inhibiting them can reduce disease symptoms.

## Contribution

The study identifies MMPs as early biomarkers and therapeutic targets in FSHD, independent of DUX4 activity.

## Key findings

- MMP levels increase with disease severity in FSHD and are primarily produced by FAPs and macrophages.
- Inhibiting MMPs with batimastat reduces inflammation, fibrosis, and muscle degeneration in FSHD models.
- MMPs are proposed as functional biomarkers and potential therapeutic targets for FSHD.

## Abstract

Matrix remodeling by metalloproteinases (MMPs) is essential for maintaining muscle homeostasis; however, their dysregulation can drive degenerative processes. By interrogating biopsy RNA-Seq data, we showed that MMP expression correlated with disease severity in facioscapulohumeral muscular dystrophy (FSHD). In the iDUX4pA FSHD mouse model, MMP levels also progressively increased in response to double homeobox 4–induced (DUX4-induced) muscle degeneration. Single-cell RNA-Seq further identified fibroadipogenic progenitors (FAPs) and macrophages as the primary sources of MMPs, particularly MMP2, MMP14, and MMP19, in dystrophic muscle. Treatment with the pan-MMP inhibitor batimastat alleviated inflammation and fibrosis, improved muscle structure, and decreased the number of FAPs and infiltrating macrophages. These findings underscore the role of MMPs in driving muscle degeneration in FSHD, highlight MMPs as functional biomarkers of disease, and support MMP inhibitors as a DUX4-independent therapeutic approach to limit fibroadipogenesis and promote muscle regeneration.

Matrix metalloproteinases (MMPs) are early and progressive drivers of FSHD muscle degeneration, and their inhibition alleviates pathology, offering a DUX4-independent therapeutic strategy.