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

Silva-Rojas, Roberto; Pérez-Guàrdia, Laura; Lafabrie, Emma; Moulaert, David; Laporte, Jocelyn; Böhm, Johann

doi:10.3390/ijms23136968

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

¹,

²,

^1,*,†

and

Johann Böhm

^1,*,†

IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France

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)

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Abstract

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 Stim1^R304W/+ mice with Orai1^+/− mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the Stim1^R304W/+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 Stim1^R304W/+ littermates. We also produced AAV particles containing Orai1-specific shRNAs, and intramuscular injections of Stim1^R304W/+ 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

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

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