{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T09:48:08Z","timestamp":1788601688611,"version":"build-2803163510"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G056521N"],"award-info":[{"award-number":["G056521N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G026522N"],"award-info":[{"award-number":["G026522N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G058924N"],"award-info":[{"award-number":["G058924N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009315","name":"Cystinosis Ireland","doi-asserted-by":"publisher","award":["HRCI\u2010HRB\u20102022\u2010014"],"award-info":[{"award-number":["HRCI\u2010HRB\u20102022\u2010014"]}],"id":[{"id":"10.13039\/501100009315","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021081","name":"European Rare Kidney Disease Reference Network","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021081","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":[[2025,12]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n Cystinosis is a rare multisystem, autosomal recessive disease caused by dysfunction or loss of cystinosin (CTNS), which results in lysosomal cystine accumulation, primarily affecting the kidneys. Advances in renal transplantation, cysteamine treatment and improved medical care have increased life expectancy, revealing additional systemic phenotypes like myopathy later in life. Muscle weakness is a major concern leading to life\u2010threatening events in patients, and yet the aetiology of cystinosis myopathy remains to be elucidated.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We generated human muscle cell\u2010based models using CRISPR technology to explore the pathophysiology of cystinosis myopathy with the potential to develop new therapies. We used a 4\u2010day differentiation protocol of myoblasts into myotubes to study the effect of CTNS loss in key regulators of myogenic differentiation using western blot analysis. Afterwards, we used lentiviral (LV)\u2010mediated\n CTNS<\/jats:italic>\n \n WT<\/jats:italic>\n <\/jats:sup>\n cDNA addition in\n CTNS<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n cells to corroborate the CTNS\u2010specific effect. As a next step, we performed multiomic analysis (proteomics, transcriptomics and metabolomics) to gain in\u2010depth knowledge of affected mechanisms.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The polyclonal, isogenic human\n CTNS<\/jats:italic>\n knock\u2010out (KO;\n CTNS<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n ) myoblasts exhibited unaltered growth characteristics and accumulated cystine. Early\u2010stage differentiation of myoblasts into myotubes showed a mild reduction in the fusion index of\n CTNS<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n myotubes. Upon examination of several key regulators of myogenic differentiation, we observed significantly decreased myosin heavy chain (MyHC) and ryanodine receptor (RyR) protein levels in\n CTNS<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n myotubes compared to WT cells. Complementation with\n CTNS<\/jats:italic>\n \n WT<\/jats:italic>\n <\/jats:sup>\n cDNA addition in\n CTNS<\/jats:italic>\n \n \u2212\/\u2212<\/jats:italic>\n <\/jats:sup>\n cells rescued the fusion index, cystine and altered protein levels to WT. In addition, proteomic analysis showed no differences at myoblast level upon the loss of CTNS, but following myotube differentiation,\n CTNS<\/jats:italic>\n deletion led to an increase of five protein groups mainly involved in oxidative stress pathways, and a decrease of 18 protein groups biologically connected in myofibril assembly and muscle cell differentiation processes. Importantly, LV\u2010mediated\n CTNS<\/jats:italic>\n addback reverted protein levels to WT levels. Moreover, metabolomics revealed a distinct clustering resulting from CTNS loss.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Muscle\u2010specific complications are often overlooked in systemic cystinosis treatment. We show that defective CTNS function impairs effective cystine mobilization from lysosomes, thereby affecting the protein levels of myogenic regulators. A deeper understanding of the molecular mechanisms underlying cystinosis myopathy holds promise for the development of targeted, personalized therapies to improve the quality of life for patients living with cystinosis.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.70116","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T09:24:55Z","timestamp":1762766695000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["An Isogenic Human Myoblast Cell Model for Cystinosis Myopathy Reveals Alteration of Key Myogenic Regulatory Proteins"],"prefix":"10.1002","volume":"16","author":[{"given":"Louise","family":"Medaer","sequence":"first","affiliation":[{"name":"Advanced Disease Modelling, Targeted Drug Discovery and Gene Therapy (ADVANTAGE), Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6392-7755","authenticated-orcid":false,"given":"Roger","family":"Mora","sequence":"additional","affiliation":[{"name":"Advanced Disease Modelling, Targeted Drug Discovery and Gene Therapy (ADVANTAGE), Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Vrije Universiteit Brussel (VUB) Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nefele","family":"Giarratana","sequence":"additional","affiliation":[{"name":"Stem Cell and Developmental Biology Unit, Department of Development and Regeneration, Faculty of Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Yedigaryan","sequence":"additional","affiliation":[{"name":"Stem Cell and Developmental Biology Unit, Department of Development and Regeneration, Faculty of Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"La\u00a0Rovere","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Faculty of Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Levtchenko","sequence":"additional","affiliation":[{"name":"Emma Children Hospital Amsterdam UMC Amsterdam AZ the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Mouly","sequence":"additional","affiliation":[{"name":"Myoline Platform, Sorbonne Universit\u00e9, Inserm Institut de Myologie, Centre de Recherche en Myologie Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Els","family":"Verhoeyen","sequence":"additional","affiliation":[{"name":"Universit\u00e9 C\u00f4te D'azur, Institute for health and medical research (INSERM), Mediterranean Centre for Molecular Medicine (C3M) Nice France"},{"name":"International Center for Infectiology Research (CIRI) Universit\u00e9 de Lyon Lyon France"},{"name":"INSERM U1111; Ecole normale sup\u00e9rieure (ENS) de Lyon Universit\u00e9 de Lyon Lyon France"},{"name":"Centre national de la recherche scientifique (CNRS), UMR5308 Lyon France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan","family":"Eeltink","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Vrije Universiteit Brussel (VUB) Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim","family":"Treumann","sequence":"additional","affiliation":[{"name":"Cystinosis Ireland Dublin 2 Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Vervliet","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Faculty of Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurilio","family":"Sampaolesi","sequence":"additional","affiliation":[{"name":"Stem Cell and Developmental Biology Unit, Department of Development and Regeneration, Faculty of Medicine KU Leuven Leuven Belgium"},{"name":"Histology and Medical Embryology Unit, Department of Anatomy, Histology, Forensic Medicine and Orthopedics Sapienza University of Rome Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0191-3904","authenticated-orcid":false,"given":"Rik","family":"Gijsbers","sequence":"additional","affiliation":[{"name":"Advanced Disease Modelling, Targeted Drug Discovery and Gene Therapy (ADVANTAGE), Department of Pharmacological and Pharmaceutical Sciences, Faculty of Medicine KU Leuven Leuven Belgium"},{"name":"Leuven Viral Vector Core, Group Biomedical Sciences, Faculty of Medicine KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0498-319"},{"issue":"3","key":"e_1_2_8_3_1","first-page":"535","article-title":"High\u2010Resolution Mapping of the Gene for Cystinosis, Using Combined Biochemical and Linkage Analysis","volume":"58","author":"Jean G.","year":"1996","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.47.6.979"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-020-04487-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-012-2242-5"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26726"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410350209"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-021-05343-x"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/1752-1947-2-235"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12464"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2430841"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-147-4-200708210-00006"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004670050467"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27039"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.119.2.394"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.277"},{"key":"e_1_2_8_18_1","unstructured":"(ACE) C.A.C.E.A.I.W.G.C.A.C.E. 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