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

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).