ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome
Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both of which regulate Ca2+ homeostasis through the ubiquitous store-operated Ca2+ entry (SOCE) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here, we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology; an increase of thrombocytes; and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes in Stim1R304W/+ muscle and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multisystemic TAM/STRMK signs, and we identified myostatin as a promising biomarker for TAM/STRMK in humans and mice.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
JCI insight - 9(2024), 6 vom: 05. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Silva-Rojas, Roberto [VerfasserIn] |
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| Links: |
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| Themen: |
Calcium |
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| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 04.04.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.174866 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both of which regulate Ca2+ homeostasis through the ubiquitous store-operated Ca2+ entry (SOCE) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here, we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology; an increase of thrombocytes; and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes in Stim1R304W/+ muscle and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multisystemic TAM/STRMK signs, and we identified myostatin as a promising biomarker for TAM/STRMK in humans and mice | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Calcium channels | |
| 650 | 4 | |a Genetic diseases | |
| 650 | 4 | |a Muscle biology | |
| 650 | 4 | |a Skeletal muscle | |
| 650 | 4 | |a Therapeutics | |
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| 700 | 1 | |a Pérez-Guàrdia, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Simon, Alix |e verfasserin |4 aut | |
| 700 | 1 | |a Djeddi, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Treves, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Ribes, Agnès |e verfasserin |4 aut | |
| 700 | 1 | |a Silva-Hernández, Lorenzo |e verfasserin |4 aut | |
| 700 | 1 | |a Tard, Céline |e verfasserin |4 aut | |
| 700 | 1 | |a Laporte, Jocelyn |e verfasserin |4 aut | |
| 700 | 1 | |a Böhm, Johann |e verfasserin |4 aut | |
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