Matrix metalloproteinases are hallmark early biomarkers and therapeutic targets in FSHD
Usuk Jung, Erdong Wei, Haseeb Ahsan, Ana Mitanoska, Kenric Chen, Michael Kyba, Darko Bosnakovski
Usuk Jung, Erdong Wei, Haseeb Ahsan, Ana Mitanoska, Kenric Chen, Michael Kyba, Darko Bosnakovski
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Research Article Cell biology Muscle biology

Matrix metalloproteinases are hallmark early biomarkers and therapeutic targets in 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.

Authors

Usuk Jung, Erdong Wei, Haseeb Ahsan, Ana Mitanoska, Kenric Chen, Michael Kyba, Darko Bosnakovski

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Figure 2

MMP expression correlates with disease stage in iDUX4 mice.

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MMP expression correlates with disease stage in iDUX4 mice. (A) Represen...
(A) Representative H&E-stained images of muscle tissues from uninduced iDUX4 mice (control) and at 1 day, 10 days, and 16 weeks following DUX4 induction (100 mg/kg/d dox). Scale bar: 50 μm. (B) GSEA reveals progressive enrichment of MMPs and MMP-related genes at 1 day, 10 days, and 16 weeks following DUX4 induction, compared with uninduced, age-matched iDUX4 control mice. Asterisks denote statistically significant enrichment (FDR < 0.25). Each induced group includes 4 mice; control groups consist of 6 mice for the 1- and 10-day time points and 4 mice for the 16-week time point. (C) Volcano plots display differential expression of MMP and MMP-associated genes at 1 day, 10 days, and 16 weeks after DUX4 induction, compared with control uninduced iDUX4 mice. (D) Bar graph showing fold changes in MMP gene expression at various time points following DUX4 induction, normalized to age-matched, uninduced iDUX4 mice. Data are presented as mean ± SEM. Red asterisks indicate statistically significant differences between each DUX4-induced group and its respective time-matched control (*P < 0.05, Student’s 2-tailed t test). Black asterisks indicate significant differences among DUX4-induced time points (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; 1-way ANOVA with Tukey’s post hoc test).