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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/13/6968 |
| Summary: | 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. |
|---|---|
| ISSN: | 1661-6596 1422-0067 |