{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:07:44Z","timestamp":1790518064914,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T00:00:00Z","timestamp":1638489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014865","name":"Fondation Maladies Rares","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013465","name":"French Muscular Dystrophy Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013465","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":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Facioscapulohumeral dystrophy (FSHD) is a late\u2010onset autosomal dominant form of muscular dystrophy involving specific groups of muscles with variable weakness that precedes inflammatory response, fat infiltration, and muscle atrophy. As there is currently no cure for this disease, understanding and modelling the typical muscle weakness in FSHD remains a major milestone towards deciphering the disease pathogenesis as it will pave the way to therapeutic strategies aimed at correcting the functional muscular defect in patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To gain further insights into the specificity of the muscle alteration in this disease, we derived induced pluripotent stem cells from patients affected with Types 1 and 2 FSHD but also from patients affected with Bosma arhinia and microphthalmia. We differentiated these cells into contractile innervated muscle fibres and analysed their transcriptome by RNA Seq in comparison with cells derived from healthy donors. To uncover biological pathways altered in the disease, we applied MOGAMUN, a multi\u2010objective genetic algorithm that integrates multiplex complex networks of biological interactions (protein\u2013protein interactions, co\u2010expression, and biological pathways) and RNA Seq expression data to identify active modules.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 132 differentially expressed genes that are specific to FSHD cells (false discovery rate\u00a0&lt;\u00a00.05). In FSHD, the vast majority of active modules retrieved with MOGAMUN converges towards a decreased expression of genes encoding proteins involved in sarcomere organization (<jats:italic>P<\/jats:italic> value 2.63e<jats:sup>\u221212<\/jats:sup>), actin cytoskeleton (<jats:italic>P<\/jats:italic> value 9.4e<jats:sup>\u22125<\/jats:sup>), myofibril (<jats:italic>P<\/jats:italic> value 2.19e<jats:sup>\u221212<\/jats:sup>), actin\u2013myosin sliding, and calcium handling (with <jats:italic>P<\/jats:italic> values ranging from 7.9e<jats:sup>\u221235<\/jats:sup> to 7.9e<jats:sup>\u221221<\/jats:sup>). Combined with <jats:italic>in vivo<\/jats:italic> validations and functional investigations, our data emphasize a reduction in fibre contraction (<jats:italic>P<\/jats:italic> value\u00a0&lt;\u00a00.0001) indicating that the muscle weakness that is typical of FSHD clinical spectrum might be associated with dysfunction of calcium release (<jats:italic>P<\/jats:italic> value\u00a0&lt;\u00a00.0001), actin\u2013myosin interactions, motor activity, mechano\u2010transduction, and dysfunctional sarcomere contractility.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Identification of biomarkers of FSHD muscle remain critical for understanding the process leading to the pathology but also for the definition of readouts to be used for drug design, outcome measures, and monitoring of therapies. The different pathways identified through a system biology approach have been largely overlooked in the disease. Overall, our work opens new perspectives in the definition of biomarkers able to define the muscle alteration but also in the development of novel strategies to improve muscle function as it provides functional parameters for active molecule screening.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12835","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T08:55:43Z","timestamp":1638521743000},"page":"621-635","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Facioscapulohumeral dystrophy weakened sarcomeric contractility is mimicked in induced pluripotent stem cells\u2010derived innervated muscle fibres"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4474-9887","authenticated-orcid":false,"given":"Camille","family":"Laberthonni\u00e8re","sequence":"first","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elva\u2010Maria","family":"Novoa\u2010del\u2010Toro","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9gane","family":"Delourme","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rapha\u00ebl","family":"Chevalier","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natacha","family":"Broucqsault","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kilian","family":"Mazaleyrat","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Streichenberger","sequence":"additional","affiliation":[{"name":"Neuropathology Lyon Civil Hospices  Lyon France"},{"name":"Neuromyog\u00e8ne Institute, CNRS\u2013UMR 5310, INSERM 1217 Claude Bernard University Lyon 1, University of Lyon  Lyon France"},{"name":"Reference Centre for Neuromuscular Diseases Hospital for Woman Mother Child  Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Manel","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Timone Infant Hospital  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafa\u00eblle","family":"Bernard","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"},{"name":"Reference Centre for Neuromuscular Diseases and ALS Timone Adult Hospital  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Salort Campana","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahram","family":"Attarian","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Aix Marseille Univ, INSERM, Marseille Medical Genetics, MMG  Marseille 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