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Distinct extracellular matrix states uncouple collagen accumulation from pathological fibrosis in Duchenne muscular dystrophy

ABSTRACT: Collagen accumulation is the most widely used measure of fibrosis and is often assumed to reflect pathological severity. Whether collagen quantity itself determines the biological consequences of fibrosis has been difficult to test because tissue injury, inflammation, and extracellular matrix deposition usually occur simultaneously. Using sarcospan-transgenic mdx muscle (mdxTG), in which membrane integrity is improved and muscle function is restored despite persistent extracellular matrix accumulation, we find that collagen accumulates beyond levels in mdx muscle (model of Duchenne muscular dystrophy, DMD) while dense macrophage-rich inflammatory lesions are markedly reduced. Quantitative matrisome proteomics demonstrates broad extracellular matrix expansion, whereas spatial transcriptomics reveals that fibrotic and inflammatory gene programs exhibit reduced focal clustering compared to mdx muscle. Despite this spatial reorganization, decellularized mdx and mdxTG extracellular matrices are mechanically and compositionally remodeled and both induce nuclear YAP localization in wild-type fibro-adipogenic progenitors (FAPs). FAPs remain the principal source of fibrillar collagen in both dystrophic models, without a corresponding increase in their proportion among total muscle-resident cells. Verteporfin reduces collagen production by mdx FAPs in vitro and attenuates collagen accumulation and scarring in mdx muscle. Consistently, FAPs from patients with DMD exhibit increased nuclear YAP localization. Together, these findings demonstrate that extracellular matrix organization and mechanosignaling activity are separable: a dystrophic matrix devoid of dense fibrotic and inflammatory scars can remain mechanically instructive, indicating that collagen abundance alone does not define pathological fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE343269 | GEO | 2026/08/21

REPOSITORIES: GEO

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Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration - is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an "HDAC-myomiR-BAF60 variant network" regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) miR-1.2, miR-133 and miR-206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. miRNA modulation upon Histone Deacetylase inhibition in Fibro-Adipogenic Progenitors (FAPs) derived from young mdx mice was evaluated by small RNA-sequencing in 2 controls and 2 treated samples

Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration M-bM-^@M-^S is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an M-bM-^@M-^\HDAC-myomiR-BAF60 variant networkM-bM-^@M-^] regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a M-bM-^@M-^\latentM-bM-^@M-^] myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) 1.2, 133 and 206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. Genome-wide chromatin accessibility patterns in FAPs cells derived from mdx mice at different ages treated either with HDAC inhibitor Trichostatin A (TSA) or with vehicle (saline solution) were assessed using NA-seq (PMID: 19289091)

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Distinct extracellular matrix states uncouple collagen accumulation from pathological fibrosis in Duchenne muscular dystrophy

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