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TAM\/STRMK arises from excessive extracellular Ca2+ entry due to gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1. Currently, no treatment is available. Here we assessed the therapeutic potential of ORAI1 downregulation to anticipate and reverse disease development in a faithful mouse model carrying the most common TAM\/STRMK mutation and recapitulating the main signs of the human disorder. To this aim, we crossed Stim1R304W\/+ mice with Orai1+\/\u2212 mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1R304W\/+Orai1+\/\u2212 mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their Stim1R304W\/+ littermates. We also produced AAV particles containing Orai1-specific shRNAs, and intramuscular injections of Stim1R304W\/+ mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that Orai1 silencing partially prevents the development of the multi-systemic TAM\/STRMK phenotype in mice, and we also established an approach to target Orai1 expression in postnatal tissues.<\/jats:p>","DOI":"10.3390\/ijms23136968","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T21:25:00Z","timestamp":1656019500000},"page":"6968","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Silencing of the Ca2+ Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0349-4283","authenticated-orcid":false,"given":"Roberto","family":"Silva-Rojas","sequence":"first","affiliation":[{"name":"IGBMC (Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire), Inserm U1258, CNRS UMR7104, Universit\u00e9 de Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7668-4651","authenticated-orcid":false,"given":"Laura","family":"P\u00e9rez-Gu\u00e0rdia","sequence":"additional","affiliation":[{"name":"IGBMC (Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire), Inserm U1258, CNRS UMR7104, Universit\u00e9 de Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Lafabrie","sequence":"additional","affiliation":[{"name":"IGBMC (Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire), Inserm U1258, CNRS UMR7104, Universit\u00e9 de Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Moulaert","sequence":"additional","affiliation":[{"name":"Institut Clinique de la Souris (ICS), 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8256-5862","authenticated-orcid":false,"given":"Jocelyn","family":"Laporte","sequence":"additional","affiliation":[{"name":"IGBMC (Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire), Inserm U1258, CNRS UMR7104, Universit\u00e9 de Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8019-9504","authenticated-orcid":false,"given":"Johann","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"IGBMC (Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire), Inserm U1258, CNRS UMR7104, Universit\u00e9 de Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature04702","article-title":"A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function","volume":"441","author":"Feske","year":"2006","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm1155","article-title":"Calcium signalling: Dynamics, homeostasis and remodelling","volume":"4","author":"Berridge","year":"2003","journal-title":"Nat. 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