Tubular aggregate myopathy may be due to overactivation of Store Operated Ca2+ Entry (SOCE) as a result of a gain-of-function variant in the STIM1 or ORAI1 genes. ORAI1 is a T-tubule membrane calcium channel that is activated by STIM1, a sarcoplasmic reticulum membrane protein that senses depletion of intracellular calcium stores.
- KO mice for ORAI1 show reduced lifespan and weight, exercise intolerance, reduced muscle strength and an increased number of structurally altered mitochondria.
- Electron microscopy revealed no increase in tubular aggregates with age, and more sarcoplasmic reticulum cisternae without adjacent T-tubules.
- Although the improvement of STIM1-linked congenital myopathy mouse models by inhibiting ORAI1 was demonstrated in March 2024, no selective molecules existed until now. Chemists have now identified compounds in the indazole or pyrazole class that completely block capacitive calcium entry (SOCE) by selectively inhibiting the ORAI1 calcium channel.
