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Fibrosis in muscle is associated with decreased contractile forces and increased passive stiffness that limits joint mobility leading to contractures. However, the assumption that more fibrotic material is directly related to decreased function has not held true. Here we utilize novel measurement of extracellular matrix (ECM) and collagen architecture to relate ECM form to muscle function. We used <jats:italic>mdx<\/jats:italic> mice, a model for Duchenne muscular dystrophy that becomes fibrotic, and wildtype mice. In this model, extensor digitorum longus (EDL) muscle was significantly stiffer, but with similar total collagen, while the soleus muscle did not change stiffness, but increased collagen. The stiffness of the EDL was associated with increased collagen crosslinking as determined by collagen solubility. Measurement of ECM alignment using polarized light microscopy showed a robust relationship between stiffness and alignment for wildtype muscle that broke down in <jats:italic>mdx<\/jats:italic> muscles. Direct visualization of large collagen fibres with second harmonic generation imaging revealed their relative abundance in stiff muscles. Collagen fibre alignment was linked to stiffness across all muscles investigated and the most significant factor in a multiple linear regression\u2010based model of muscle stiffness from ECM parameters. This work establishes novel characteristics of skeletal muscle ECM architecture and provides evidence for a mechanical function of collagen fibres in muscle. This finding suggests that anti\u2010fibrotic strategies to enhance muscle function and excessive stiffness should target large collagen fibres and their alignment rather than total collagen.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp280656","type":"journal-article","created":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T17:25:17Z","timestamp":1606584317000},"page":"943-962","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Passive stiffness of fibrotic skeletal muscle in <i>mdx<\/i> mice relates to collagen architecture"],"prefix":"10.1113","volume":"599","author":[{"given":"Sarah E.","family":"Brashear","sequence":"first","affiliation":[{"name":"Department of Neurobiology Physiology, and Behavior, University of California Davis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1841-2148","authenticated-orcid":false,"given":"Ross 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