Exacerbated Skeletal Muscle Phenotype in Mice with 'Homotypic' Expression of the Tubular Aggregate Myopathy ORAI1 G100S Mutation.

Background: Tubular aggregate myopathy (TAM) is an autosomal dominant myopathy that results from gain-of-function mutations in the STIM1 and ORAI1 genes, which encode the two key proteins that coordinate store-operated Ca2+ entry in skeletal muscle and other cell types. Knock-in mice heterozygous for a glycine-to-serine point mutation in the ORAI1 pore (ORAI1G100S/+ or GS mice) phenocopy several key aspects of TAM in humans with the analogous mutation including muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and the presence of tubular aggregates. Methods: Since homozygous inheritance of the ORAI1-G100S mutation is embryonic lethal, we assessed the impact of homotypic ORAI1-G100S expression in skeletal muscle by crossing GS mice with constitutive, muscle-specific ORAI1 knock-in mice (cORAI1-KO). Results: Compound cORAI1-KO/GS mice exhibit only one active ORAI1 (GS) allele, and thus only express ORAI1-G100S monomers in skeletal muscle ('homotypic' GS mice). Homotypic GS mice exhibit an earlier onset and more severe muscle phenotype than age-matched heterotypic GS mice with both WT and GS alleles. Specifically, homotypic GS mice exhibit TAs at an earlier age, as well as significantly reduced in vivo muscle performance (grip strength, treadmill endurance, and rotarod endurance), maximal specific force production, and respiratory function, compared to those observed for both WT and heterotypic GS mice. Conclusions: These findings indicate that homotypic expression of the ORAI1-G100S mutation in skeletal muscle results in an earlier-onset and more severe muscle phenotype.