Orai1 tubular aggregate myopathy mice exhibit compromised muscle function, mitochondrial alterations, and postnatal adaptations

Tubular aggregate myopathy (TAM) is a heritable, myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates. Here, we generated a knock-in mouse model of TAM harboring a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice) that results in a severe, early-onset form of TAM in humans. By 8 months of age, OraiG100S/+ mice exhibit significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust presence of tubular aggregates. Unexpectedly, constitutive Ca2+ entry due to the Orai1 pore mutation is only observed in muscle during early development and is abolished in adult skeletal muscle, due in part to a reduction in ORAI1 expression. Consistent with proteomic analysis of GS mice, we demonstrated a robust mitochondrial damage using both morphological and functional approaches. GS mice represent a powerful model to investigate the pathophysiological mechanisms that underlie the muscle weakness, exercise intolerance and formation of tubular aggregates, as well as compensatory responses to limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.