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 Jun 23;23(13):6968. doi: 10.3390/ijms23136968.

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 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.

Keywords: ORAI1; STIM1; Stormorken syndrome; calcium; ion channel; mouse model; muscle disorder; shRNA; tubular aggregate myopathy.

MeSH terms

  • Animals
  • Blood Platelet Disorders* / genetics
  • Blood Platelet Disorders* / metabolism
  • Calcium / metabolism
  • Dyslexia* / genetics
  • Dyslexia* / metabolism
  • Erythrocytes, Abnormal
  • Ichthyosis* / genetics
  • Ichthyosis* / metabolism
  • Mice
  • Migraine Disorders / genetics
  • Migraine Disorders / metabolism
  • Miosis
  • Muscle Fatigue
  • Myopathies, Structural, Congenital* / genetics
  • Myopathies, Structural, Congenital* / metabolism
  • Myopathies, Structural, Congenital* / pathology
  • ORAI1 Protein* / genetics
  • ORAI1 Protein* / metabolism
  • Phenotype
  • Spleen / abnormalities
  • Spleen / metabolism
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism

Substances

  • ORAI1 Protein
  • Orai1 protein, mouse
  • Stromal Interaction Molecule 1
  • Calcium

Supplementary concepts

  • Stormorken Syndrome