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 4

Batimastat treatment improves muscle phenotypes in iDUX4 mice.

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Batimastat treatment improves muscle phenotypes in iDUX4 mice. (A) H&amp...
(A) H&E staining of tibialis anterior (TA) muscle from WT, iDUX4 (Dox), and batimastat-treated iDUX4 mice (Dox+Bat). Immunofluorescence staining of TA muscle for collagen VI (white) and DAPI (blue). Scale bar: 50 μm. All mice were fed dox chow (62.5 mg/kg) for 20 days. Batimastat (2 mg/kg) was administered daily via intraperitoneal injection during the final 10 days of the induction period. (B) Distribution of myofiber cross-sectional area (CSA) in iDUX4 mice, with and without batimastat treatment (n = 4 per group). Data are shown as mean ± SEM. *P < 0.05 by multiple unpaired t tests. (C) Quantification of fibrosis based on collagen VI immunostaining in the samples shown in A. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01 by 1-way ANOVA followed by Tukey’s post hoc tests (n = 4). (D) Reverse transcription quantitative PCR (RT-qPCR) analysis of fibrotic markers (Mmp2, Mmp17, Col1a1, Col3a1, Tgfb1, Bmp4, and Pdgfra) in gastrocnemius muscle from WT (n = 3), Dox (n = 5), and Dox+Bat (n = 3). Gene expression was normalized to Gapdh. (E) RT-qPCR analysis of Mmp2 and Mmp17. (F) RT-qPCR analysis of DUX4 and its target gene Wfdc3. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by 1-way ANOVA followed by Tukey’s post hoc tests.