{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:57:50Z","timestamp":1790877470512,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014055","name":"U.S. Army Medical Research Acquisition Activity","doi-asserted-by":"publisher","award":["W81XWH\u201021\u20102\u20100014"],"award-info":[{"award-number":["W81XWH\u201021\u20102\u20100014"]}],"id":[{"id":"10.13039\/100014055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Repurposing clinically approved antifibrotic agents presents a potential near\u2010term therapeutic strategy to mitigate the extensive fibrotic scarring that follows severe volumetric muscle loss (VML) injury and inhibits functional recovery. We hypothesized that daily oral administration of pirfenidone, an FDA\u2010approved antifibrotic, would mitigate the overwhelming fibrotic response and facilitate functional recovery in a clinically relevant porcine VML model. Yorkshire\u2010cross pigs (\n                    <jats:italic>n<\/jats:italic>\n                    \u00a0=\u00a012) underwent VML or sham surgery in the peroneus tertius muscle and were subsequently allocated to pirfenidone treatment or untreated controls. At the 4\u2010week study endpoint, the affected muscles underwent comprehensive histological, biochemical, transcriptional and neuromuscular functional assessments. Transcription profiling demonstrated that pirfenidone downregulated key pro\u2010inflammatory cytokine and chemokine regulators involved in excessive fibrosis, including TNF, CCL3L1 and CCL2. While pirfenidone treatment failed to reduce total collagen deposition, evidenced by picrosirius red quantification and hydroxyproline content, it did result in a less dense collagen fibre architecture, suggestive of altered tissue remodelling. However, pirfenidone treatment impaired functional recovery through reduced contractile output and resulted in stagnant weight gain compared to the untreated cohort. This work demonstrates that systemic pirfenidone administration failed to meaningfully reduce fibrosis and subsequently worsened functional capacity following VML, similar to previous antifibrotic studies. The functional deficits and stagnant weight gains observed here\u00a0underscore a critical knowledge gap regarding the impact of systemic antifibrotics on contractile recovery, necessitating a rigorous re\u2010evaluation of delivery routes, dosages and administration timelines to ensure that future therapies for fibrotic scarring do not inadvertently hinder the physiological recovery of VML\u2010injured muscle.\n                  <\/jats:p>","DOI":"10.1113\/ep093693","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:50:17Z","timestamp":1785430217000},"page":"4286-4295","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic pirfenidone treatment fails to mitigate fibrosis and compromises functional recovery in a porcine model of volumetric muscle loss"],"prefix":"10.1113","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2752-3832","authenticated-orcid":false,"given":"Jessica M.","family":"Motherwell","sequence":"first","affiliation":[{"name":"Extremity Trauma and Amputation Center of Excellence Defense Health Agency  Falls Church Virginia USA"},{"name":"Department of Surgery Uniformed Services University of the Health Sciences  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0155-1131","authenticated-orcid":false,"given":"Ondine","family":"Eken","sequence":"additional","affiliation":[{"name":"Extremity Trauma and Amputation Center of Excellence Defense Health Agency  Falls Church Virginia USA"},{"name":"Department of Surgery Uniformed Services University of the Health Sciences  Bethesda Maryland USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc.  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6641-4356","authenticated-orcid":false,"given":"Claudia E.","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Extremity Trauma and Amputation Center of Excellence Defense Health Agency  Falls Church Virginia USA"},{"name":"Department of Surgery Uniformed Services University of the Health Sciences  Bethesda Maryland USA"},{"name":"C2 Alaska LLC  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3701-0950","authenticated-orcid":false,"given":"Christopher L.","family":"Dearth","sequence":"additional","affiliation":[{"name":"Extremity Trauma and Amputation Center of Excellence Defense Health Agency  Falls Church Virginia USA"},{"name":"Department of Surgery Uniformed Services University of the Health Sciences  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2244-1443","authenticated-orcid":false,"given":"Stephen M.","family":"Goldman","sequence":"additional","affiliation":[{"name":"Extremity Trauma and Amputation Center of Excellence Defense Health Agency  Falls Church Virginia USA"},{"name":"Department of Surgery Uniformed Services University of the Health Sciences  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-018-0027-8"},{"issue":"23","key":"e_1_2_10_3_1","first-page":"7409","article-title":"Engineering the immune and fibrotic response in VML","volume":"603","author":"Altamirano D. 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