Aim: 

Malignant hyperthermia (MH) and environmental/exertional heat stroke (EHS) result in similar life threatening crises, with MH triggered by potent volatile anesthetics (e.g. halothane) and EHS by strenuous exercise and/or exposure to high environmental temperatures. MH episodes result from uncontrolled elevations in intracellular Ca²⁺ in skeletal muscle due to abnormalities in the sarcoplasmic reticulum (SR) Ca²⁺ release channel, or RYR1. However, not all confirmed MH families can be linked to mutations in RYR1, suggesting the possibility that alternative genes could be involved.

Methods: 

Here we determined the in vivo halothane and heat sensitivity of mice lacking CASQ1, the primary SR Ca²⁺ binding protein which regulates RYR1 channel activity.

Results: 

Surprisingly, both halothane and heat challenges trigger lethal MH/EHS-like episodes in male CASQ1-null mice, but not WT mice, characterized by difficulty in breathing and uncontrolled whole-body contractions. During heat-stress internal temperature of CASQ1-null mice increases more than in WT animals (hyperthermia) and skeletal fibers are severely damaged (rhabdomyolysis). Both heat- and halothane-induces episodes are prevented by prior dantrolene administration, the standard drug used to treat MH episodes in humans. In vitro studies indicate that CASQ1-null muscle exhibits increased contractile sensitivity to temperature and caffeine (in vitro contracture test, IVCT).

Conclusion: 

These results are consistent with lack of CASQ1 causing loss of a critical inhibitor influence on RYR1 function, which results in MH- and EHS-like episodes in mice under stress conditions, and support the need for CASQ1 gene linkage analysis in MH families that lack mutations in RYR1.