{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:55:13Z","timestamp":1791507313825,"version":"4.3.4"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007380","name":"Fondation de l'Avenir pour la Recherche M\u00e9dicale Appliqu\u00e9e","doi-asserted-by":"publisher","award":["EQU201903007784"],"award-info":[{"award-number":["EQU201903007784"]}],"id":[{"id":"10.13039\/100007380","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013465","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","award":["eOPMD 17110"],"award-info":[{"award-number":["eOPMD 17110"]}],"id":[{"id":"10.13039\/100013465","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019125","name":"Sorbonne Universit\u00e9","doi-asserted-by":"publisher","award":["SU\u201016\u2010R\u2010EMR\u201060 Fib\u2010Cell"],"award-info":[{"award-number":["SU\u201016\u2010R\u2010EMR\u201060 Fib\u2010Cell"]}],"id":[{"id":"10.13039\/501100019125","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Fibrosis is defined as an excessive accumulation of extracellular matrix (ECM) components. Many organs are subjected to fibrosis including the lung, liver, heart, skin, kidney, and muscle. Muscle fibrosis occurs in response to trauma, aging, or dystrophies and impairs muscle function. Fibrosis represents a hurdle for the treatment of human muscular dystrophies. While data on the mechanisms of fibrosis have mostly been investigated in mice, dystrophic mouse models often do not recapitulate fibrosis as observed in human patients. Consequently, the cellular and molecular mechanisms that lead to fibrosis in human muscle still need to be identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Combining mass cytometry, transcriptome profiling, <jats:italic>in vitro<\/jats:italic> co\u2010culture experiments, and <jats:italic>in vivo<\/jats:italic> transplantation in immunodeficient mice, we investigated the role and nature of nonmyogenic cells (fibroadipogenic progenitors, FAPs) from human fibrotic muscles of healthy individuals (FibM<jats:sup>CT<\/jats:sup>) and individuals with oculopharyngeal muscular dystrophy (OPMD; FibM<jats:sup>OP<\/jats:sup>), as compared with nonmyogenic cells from human nonfibrotic muscle (M<jats:sup>CT<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that the proliferation rate of FAPs from fibrotic muscle is 3\u20134 times higher than those of FAPs from nonfibrotic muscle (population doubling per day: M<jats:sup>CT<\/jats:sup> 0.2\u00a0\u00b1\u00a00.1, FibM<jats:sup>CT<\/jats:sup> 0.7\u00a0\u00b1\u00a00.1, and FibM<jats:sup>OP<\/jats:sup> 0.8\u00a0\u00b1\u00a00.3). When cocultured with muscle cells, FAPs from fibrotic muscle impair the fusion index unlike M<jats:sup>CT<\/jats:sup> FAPs (myoblasts alone 57.3\u00a0\u00b1\u00a011.1%, coculture with M<jats:sup>CT<\/jats:sup> 43.1\u00a0\u00b1\u00a08.9%, with FibM<jats:sup>CT<\/jats:sup> 31.7\u00a0\u00b1\u00a08.2%, and with FibM<jats:sup>OP<\/jats:sup> 36.06\u00a0\u00b1\u00a010.29%). We also observed an increased proliferation of FAPs from fibrotic muscles in these co\u2010cultures in differentiation conditions (FibM<jats:sup>CT<\/jats:sup> +17.4%, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.01 and FibM<jats:sup>OP<\/jats:sup> +15.1%, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.01). This effect is likely linked to the increased activation of the canonical TGF\u03b2\u2010SMAD pathway in FAPs from fibrotic muscles evidenced by pSMAD3 immunostaining (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). In addition to the profibrogenic TGF\u03b2 pathway, we identified endothelin as a new actor implicated in the altered cross\u2010talk between muscle cells and fibrotic FAPs, confirmed by an improvement of the fusion index in the presence of bosentan, an endothelin receptor antagonist (from 33.8\u00a0\u00b1\u00a010.9% to 52.9\u00a0\u00b1\u00a010.1%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data demonstrate the key role of FAPs and their cross\u2010talk with muscle cells through a paracrine signalling pathway in fibrosis of human skeletal muscle and identify endothelin as a new druggable target to counteract human muscle fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12974","type":"journal-article","created":{"date-parts":[[2022,3,23]],"date-time":"2022-03-23T06:55:37Z","timestamp":1648018537000},"page":"1771-1784","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["A negative feedback loop between fibroadipogenic progenitors and muscle fibres involving endothelin promotes human muscle fibrosis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2589-8657","authenticated-orcid":false,"given":"Mona","family":"Bensalah","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9 Inserm, Institut de Myologie, Centre de Recherche en Myologie  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Muraine","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9 Inserm, Institut de Myologie, Centre de Recherche en Myologie  Paris 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