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 1

Elevated MMP and MMP-associated genes in FSHD patient biopsies.

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Elevated MMP and MMP-associated genes in FSHD patient biopsies. (A) GSEA...
(A) GSEA shows enrichment of 23 MMPs and 79 MMP-associated genes in biopsy samples from healthy donors (controls) and patients with FSHD across 3 independent studies (38–40). Asterisks indicate significant enrichment (FDR < 0.25). (B and C) Volcano plots display differential expression MMP family and MMP-associated genes in STIR− (uninflamed) (B) and STIR+ (inflamed) (C) FSHD biopsies compared with healthy controls from the Banerji dataset. (D) Heatmaps illustrating MMP gene expression patterns in STIR− and STIR+ samples from the Banerji dataset. Cross marks indicate statistical significance compared with control. †P < 0.05 by Student’s 2-tailed t test. Asterisks indicate significant differences between STIR− and STIR+. *P < 0.05 by Student’s 2-tailed t test. (E and F) Heatmaps showing the correlation between clinical severity score (E) and pathological score (F) and MMP expression in initial visit biopsy samples from the Wang dataset. Asterisks indicate statistical significance. *P < 0.05, **P < 0.01, and ***P < 0.001 by 1-way ANOVA. (G) Heatmaps depicting the increased MMP levels in line with the expression of DUX4-associated biomarker genes in Wang dataset. Cross marks indicate statistical significance compared with control. †P < 0.05 by Student’s 2-tailed t test. Asterisks indicate significant differences across DUX4 score groups 1, 2, 3, and 4. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 by 1-way ANOVA. (H) Summary of MMP expression across various muscular dystrophies. Expression in each disease cohort was compared with the corresponding healthy control within each study.