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Article

Silencing of the Ca2+ Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice

1
IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France
2
Institut Clinique de la Souris (ICS), 67404 Illkirch, France
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Olga Karpicheva and Yurii Borovikov
Int. J. Mol. Sci. 2022, 23(13), 6968; https://doi.org/10.3390/ijms23136968
Received: 6 May 2022 / Revised: 17 June 2022 / Accepted: 20 June 2022 / Published: 23 June 2022
(This article belongs to the Special Issue Molecular Research on Muscle Protein and Myopathies 2.0)
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 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+/− mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1R304W/+Orai1+/− 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. View Full-Text
Keywords: tubular aggregate myopathy; Stormorken syndrome; muscle disorder; calcium; STIM1; ORAI1; mouse model; ion channel; shRNA tubular aggregate myopathy; Stormorken syndrome; muscle disorder; calcium; STIM1; ORAI1; mouse model; ion channel; shRNA
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MDPI and ACS Style

Silva-Rojas, R.; Pérez-Guàrdia, L.; Lafabrie, E.; Moulaert, D.; Laporte, J.; Böhm, J. Silencing of the Ca2+ Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice. Int. J. Mol. Sci. 2022, 23, 6968. https://doi.org/10.3390/ijms23136968

AMA Style

Silva-Rojas R, Pérez-Guàrdia L, Lafabrie E, Moulaert D, Laporte J, Böhm J. Silencing of the Ca2+ Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice. International Journal of Molecular Sciences. 2022; 23(13):6968. https://doi.org/10.3390/ijms23136968

Chicago/Turabian Style

Silva-Rojas, Roberto, Laura Pérez-Guàrdia, Emma Lafabrie, David Moulaert, Jocelyn Laporte, and Johann Böhm. 2022. "Silencing of the Ca2+ Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice" International Journal of Molecular Sciences 23, no. 13: 6968. https://doi.org/10.3390/ijms23136968

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