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The aim of the present study was twofold: (1) to determine whether RyR1 content is also decreased in other myopathies and (2) to investigate the mechanisms by which decreased RyR1 protein triggers muscular disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used publicly available datasets, muscles from human inflammatory and mitochondrial myopathies, an inducible muscle\u2010specific <jats:italic>RYR1<\/jats:italic> recessive mouse model and RyR1 knockdown in C2C12 muscle cells to measure RyR1 content and endoplasmic reticulum (ER) stress markers. Proteomics, lipidomics, molecular biology and transmission electron microscopy approaches were used to decipher the alterations associated with the reduction of RyR1 protein levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>RYR1<\/jats:italic> transcripts were reduced in muscle samples of patients suffering from necrotizing myopathy (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.026), inclusion body myopathy (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.003), polymyositis (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and juvenile dermatomyositis (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and in muscle samples of myotonic dystrophy type 2 (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), presymptomatic (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and symptomatic (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) Duchenne muscular dystrophy, Becker muscular dystrophy (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.004) and limb\u2010girdle muscular dystrophy type 2A (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.004). RyR1 protein content was also significantly decreased in inflammatory myopathy (\u221275%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and mitochondrial myopathy (\u221271%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) muscles. Proteomics data showed that depletion of RyR1 protein in C2C12 myoblasts leads to myotubes recapitulating the common molecular alterations observed in myopathies. Mechanistically, RyR1 protein depletion reduces ER\u2013mitochondria contact length (\u221226%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), Ca<jats:sup>2+<\/jats:sup> transfer to mitochondria (\u221248%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.002) and the mitophagy gene Parkinson protein 2 transcripts (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.037) and induces mitochondrial accumulation (+99%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.005) and dysfunction (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). This was associated to the accumulation of deleterious sphingolipid species. Our data showed increased levels of the ER stress marker chaperone\u2010binding protein\/glucose regulated protein 78, GRP78\u2010Bip, in RyR1 knockdown myotubes (+45%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.046), in mouse RyR1 recessive muscles (+58%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.001) and in human inflammatory (+96%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.006) and mitochondrial (+64%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.049) myopathy muscles. This was accompanied by increased protein levels of the pro\u2010apoptotic protein CCAAT\u2010enhancer\u2010binding protein homologous protein, CHOP\u2010DDIT3, in RyR1 knockdown myotubes (+27%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), mouse RyR1 recessive muscles (+63%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.009), human inflammatory (+50%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.038) and mitochondrial (+51%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.035) myopathy muscles. In publicly available datasets, the decrease in <jats:italic>RYR1<\/jats:italic> content in myopathies was also associated to increased ER stress markers and <jats:italic>RYR1<\/jats:italic> transcript levels are inversely correlated with ER stress markers in the control population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Decreased RyR1 is commonly observed in myopathies and associated to ER stress in vitro, in mouse muscle and in human myopathy muscles, suggesting a potent role of RyR1 depletion\u2010induced ER stress in the pathogenesis of myopathies.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13349","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T21:02:50Z","timestamp":1700082170000},"page":"2882-2897","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Ryanodine receptor type 1 content decrease\u2010induced endoplasmic reticulum stress is a hallmark of myopathies"],"prefix":"10.1002","volume":"14","author":[{"given":"Jeremy","family":"Vidal","sequence":"first","affiliation":[{"name":"Institute of Sport Sciences and Department of Biomedical Sciences University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Center for Integrative Genomics University of Lausanne  Lausanne Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Wohlwend","sequence":"additional","affiliation":[{"name":"Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pirkka\u2010Pekka","family":"Laurila","sequence":"additional","affiliation":[{"name":"Helsinki University Central Hospital  Helsinki 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