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DMD patients also develop dilated cardiomyopathy (DCM). We have previously shown that DMD (<jats:italic>mdx<\/jats:italic>) mice and a canine DMD model (GRMD) exhibit abnormal intracellular calcium (Ca<jats:sup>2+<\/jats:sup>) cycling related to early\u2010stage pathological remodelling of the ryanodine receptor intracellular calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) contributing to age\u2010dependent DCM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we used hiPSC\u2010CMs from DMD patients selected by Speckle\u2010tracking echocardiography and canine DMD cardiac biopsies to assess key early\u2010stage Duchenne DCM features.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Dystrophin deficiency was associated with RyR2 remodelling and SR Ca<jats:sup>2+<\/jats:sup> leak (RyR2 Po of 0.03\u00a0\u00b1\u00a00.01 for HC vs. 0.16\u00a0\u00b1\u00a00.01 for DMD, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), which led to early\u2010stage defects including senescence. We observed higher levels of senescence markers including p15 (2.03\u00a0\u00b1\u00a00.75 for HC vs. 13.67\u00a0\u00b1\u00a05.49 for DMD, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and p16 (1.86\u00a0\u00b1\u00a00.83 for HC vs. 10.71\u00a0\u00b1\u00a03.00 for DMD, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) in DMD hiPSC\u2010CMs and in the canine DMD model. The fibrosis was increased in DMD hiPSC\u2010CMs. We observed cardiac hypocontractility in DMD hiPSC\u2010CMs. Stabilizing RyR2 pharmacologically by S107 prevented most of these pathological features, including the rescue of the contraction amplitude (1.65\u00a0\u00b1\u00a00.06\u00a0\u03bcm for DMD vs. 2.26\u00a0\u00b1\u00a00.08\u00a0\u03bcm for DMD\u00a0+\u00a0S107, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). These data were confirmed by proteomic analyses, in particular ECM remodelling and fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified key cellular damages that are established earlier than cardiac clinical pathology in DMD patients, with major perturbation of the cardiac ECC. Our results demonstrated that cardiac fibrosis and premature senescence are induced by RyR2 mediated SR Ca<jats:sup>2+<\/jats:sup> leak in DMD cardiomyocytes. We revealed that RyR2 is an early biomarker of DMD\u2010associated cardiac damages in DMD patients. The progressive and later DCM onset could be linked with the RyR2\u2010mediated increased fibrosis and premature senescence, eventually causing cell death and further cardiac fibrosis in a vicious cycle leading to further hypocontractility as a major feature of DCM. The present study provides a novel understanding of the pathophysiological mechanisms of the DMD\u2010induced DCM. By targeting RyR2 channels, it provides a potential pharmacological treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13411","type":"journal-article","created":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T03:41:22Z","timestamp":1705290082000},"page":"536-551","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy"],"prefix":"10.1002","volume":"15","author":[{"given":"Monia","family":"Souidi","sequence":"first","affiliation":[{"name":"PhyMedExp University of Montpellier, INSERM, CNRS  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Resta","sequence":"additional","affiliation":[{"name":"Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM University of Toulouse  Toulouse 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Biology of the neuromuscular system, INSERM, UPEC, EFS, EnvA  Maisons\u2010Alfort France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Rivier","sequence":"additional","affiliation":[{"name":"PhyMedExp University of Montpellier, INSERM, CNRS  Montpellier France"},{"name":"Department of Pediatric Neurology, Reference Center for Neuromuscular Diseases AOC, Clinical Investigation Centre Montpellier University Hospital  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Cazorla","sequence":"additional","affiliation":[{"name":"PhyMedExp University of Montpellier, INSERM, CNRS  Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Parini","sequence":"additional","affiliation":[{"name":"Institute of Metabolic and Cardiovascular Diseases (I2MC), INSERM University of Toulouse  Toulouse 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of Cachexia, Sarcopenia and 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