{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T05:59:07Z","timestamp":1792735147257,"version":"4.5.0"},"reference-count":32,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01 AR055685"],"award-info":[{"award-number":["R01 AR055685"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012644","name":"Friends of FSH Research","doi-asserted-by":"publisher","award":["na"],"award-info":[{"award-number":["na"]}],"id":[{"id":"10.13039\/100012644","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>FSHD is caused by loss of silencing of the DUX4 gene, but the DUX4 protein has not yet been directly detected immunohistologically in affected muscle, raising the possibility that DUX4 expression may occur at time points prior to obtaining adult biopsies for analysis, with consequent perturbations of muscle being responsible for disease progression. To test the extent to which muscle can regenerate following DUX4-mediated degeneration, we employed an animal model with reversible DUX4 expression, the iDUX4pA;HSA mouse. We find that muscle histology does recover substantially after DUX4 expression is switched off, with the extent of recovery correlating inversely with the duration of prior DUX4 expression. However, despite fairly normal muscle histology, and recovery of most cytological parameters, the fibroadipogenic progenitor compartment, which is significantly elevated during bouts of fiber-specific DUX4 expression, does not return to basal levels, even many weeks after a single burst of DUX4 expression. We find that muscle that has recovered from a DUX4 burst acquires a propensity for severe fibrosis, which can be revealed by subsequent cardiotoxin injuries. These results suggest that a past history of DUX4 expression leads to maintained pro-fibrotic alterations in the cellular physiology of muscle, with potential implications for therapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms23041983","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T05:14:43Z","timestamp":1644556483000},"page":"1983","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD"],"prefix":"10.3390","volume":"23","author":[{"given":"Darko","family":"Bosnakovski","sequence":"first","affiliation":[{"name":"Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA"},{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Oyler","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA"},{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Mitanoska","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA"},{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1291-1560","authenticated-orcid":false,"given":"Madison","family":"Douglas","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA"},{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4147-1146","authenticated-orcid":false,"given":"Elizabeth T.","family":"Ener","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA"},{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1504-4367","authenticated-orcid":false,"given":"Ahmed S.","family":"Shams","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA"},{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Human Anatomy and Embryology Program, Faculty of Medicine, Suez Canal University, Ismailia 41111, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5579-7534","authenticated-orcid":false,"given":"Michael","family":"Kyba","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA"},{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1212\/WNL.0000000000000797","article-title":"Population-based incidence and prevalence of facioscapulohumeral dystrophy","volume":"83","author":"Deenen","year":"2014","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0378-1119(99)00267-X","article-title":"Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element","volume":"236","author":"Gabriels","year":"1999","journal-title":"Gene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1093\/hmg\/2.12.2037","article-title":"FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit","volume":"2","author":"Wijmenga","year":"1993","journal-title":"Hum. 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