Silencing of the Ca<sup>2+</sup> Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice
Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca<sup>2+</sup> entry due t...
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MDPI AG
2022-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/13/6968 |
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| author | Roberto Silva-Rojas Laura Pérez-Guàrdia Emma Lafabrie David Moulaert Jocelyn Laporte Johann Böhm |
| author_facet | Roberto Silva-Rojas Laura Pérez-Guàrdia Emma Lafabrie David Moulaert Jocelyn Laporte Johann Böhm |
| author_sort | Roberto Silva-Rojas |
| collection | DOAJ |
| description | Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca<sup>2+</sup> entry due to gain-of-function mutations in the Ca<sup>2+</sup> sensor STIM1 or the Ca<sup>2+</sup> 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 <i>Stim1<sup>R304W/+</sup></i> mice with <i>Orai1<sup>+/−</sup></i> mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the <i>Stim1<sup>R304W/+</sup>Orai1<sup>+/−</sup></i> mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their <i>Stim1<sup>R304W/+</sup></i> littermates. We also produced AAV particles containing <i>Orai1</i>-specific shRNAs, and intramuscular injections of <i>Stim1<sup>R304W/+</sup></i> mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that <i>Orai1</i> silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target <i>Orai1</i> expression in postnatal tissues. |
| first_indexed | 2024-03-09T21:52:12Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:52:12Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c98d4c68960542b790f296ceb7b4c10e2023-11-23T20:05:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012313696810.3390/ijms23136968Silencing of the Ca<sup>2+</sup> Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in MiceRoberto Silva-Rojas0Laura Pérez-Guàrdia1Emma Lafabrie2David Moulaert3Jocelyn Laporte4Johann Böhm5IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceIGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceIGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceInstitut Clinique de la Souris (ICS), 67404 Illkirch, FranceIGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceIGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceTubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca<sup>2+</sup> entry due to gain-of-function mutations in the Ca<sup>2+</sup> sensor STIM1 or the Ca<sup>2+</sup> 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 <i>Stim1<sup>R304W/+</sup></i> mice with <i>Orai1<sup>+/−</sup></i> mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the <i>Stim1<sup>R304W/+</sup>Orai1<sup>+/−</sup></i> mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their <i>Stim1<sup>R304W/+</sup></i> littermates. We also produced AAV particles containing <i>Orai1</i>-specific shRNAs, and intramuscular injections of <i>Stim1<sup>R304W/+</sup></i> mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that <i>Orai1</i> silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target <i>Orai1</i> expression in postnatal tissues.https://www.mdpi.com/1422-0067/23/13/6968tubular aggregate myopathyStormorken syndromemuscle disordercalciumSTIM1ORAI1 |
| spellingShingle | Roberto Silva-Rojas Laura Pérez-Guàrdia Emma Lafabrie David Moulaert Jocelyn Laporte Johann Böhm Silencing of the Ca<sup>2+</sup> Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice International Journal of Molecular Sciences tubular aggregate myopathy Stormorken syndrome muscle disorder calcium STIM1 ORAI1 |
| title | Silencing of the Ca<sup>2+</sup> Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice |
| title_full | Silencing of the Ca<sup>2+</sup> Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice |
| title_fullStr | Silencing of the Ca<sup>2+</sup> Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice |
| title_full_unstemmed | Silencing of the Ca<sup>2+</sup> Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice |
| title_short | Silencing of the Ca<sup>2+</sup> Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice |
| title_sort | silencing of the ca sup 2 sup channel orai1 improves the multi systemic phenotype of tubular aggregate myopathy tam and stormorken syndrome strmk in mice |
| topic | tubular aggregate myopathy Stormorken syndrome muscle disorder calcium STIM1 ORAI1 |
| url | https://www.mdpi.com/1422-0067/23/13/6968 |
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