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

<jats:p> Fibrosis severity is routinely inferred from collagen abundance, although whether collagen quantity determines pathological fibrosis remains unclear. In Duchenne muscular dystrophy (DMD), chronic muscle injury and inflammation drive extracellular matrix accumulation, making these processes difficult to disentangle. We exploit sarcospan overexpression in <jats:italic>mdx</jats:italic> mice, a model of DMD ( <jats:italic>mdx</jats:italic> <jats:sup>TG</jats:sup> ), which improves membrane integrity and muscle function despite persistent matrix remodeling. <jats:italic>mdx</jats:italic> <jats:sup>TG</jats:sup> muscle accumulates more collagen than <jats:italic>mdx</jats:italic> yet lacks its dense macrophage-rich scars. Matrisome proteomics and spatial transcriptomics reveal compositionally and spatially distinct matrix states, while decellularized <jats:italic>mdx</jats:italic> <jats:sup>TG</jats:sup> matrix protects myotubes from membrane damage relative to <jats:italic>mdx</jats:italic> matrix. Despite these differences, both dystrophic matrices remain stiff and induce nuclear YAP in fibro-adipogenic progenitors. Verteporfin suppresses collagen production and reduces fibrosis <jats:italic>in vivo</jats:italic> , while nuclear YAP is increased in FAPs from patients with DMD. Thus, collagen abundance alone does not define pathological fibrosis; matrix organization, biological activity, and mechanosignaling distinguish functionally distinct fibrotic states. </jats:p>