Lethal Exertional Strokes in RYR1Y522S/WT and CASQ1-Null Mice are Prevented by Drugs used to Treat Malignant Hyperthermia in Humans

Abstract

In humans, lethal over-heating episodes are triggered by administration of halogenated anesthetics (a disorder known as Malignant Hyperthermia Susceptibility, MHS) and by high temperature and/or strenuous exercise (crises identified as Environmental/Exertional Heat Strokes, EHSs). Whereas MH crises are successfully treated by intravenous administration of dantrolene, to date no pharmacological interventions are available to prevent or reverse EHS.We previously demonstrated that ryanodine receptor type-1 (RYR1) Y522S/WT (carrying a mutation linked to MHS in humans) and Calsequestrin-1 knockout (CASQ1-null) mice trigger lethal crises when exposed to both halothane and heat. Here we tested the following hypotheses: a) strenuous exercise in challenging environmental conditions is a stress capable of triggering EHS-lethal episodes in both mouse models; b) drugs used to treat MH crises in humans (dantrolene or its analog azumolene) can prevent such exertion-induced strokes. When RYR1Y522S/WT (n=10) and CASQ1-null (n=14) mice were subjected to an exertional-stress protocol (executed on a treadmill at 34°C, 30-40% of humidity) which was tolerated by WT animals (n=10), their mortality was dramatically increased (80% and 79%, respectively). During the exertional protocol RYR1Y522S/WT and CASQ1-null mice showed: a) rise in core temperature (respectively 5.35±0.25°C and 4.92±0.26°C) significantly higher than WT mice (2.57±0.2°C); b) high percentage of skeletal fibers presenting severe structural damage (respectively 99% and ∼64%); and c) elevated blood levels of creatine-kinase, K+, and Ca2+ (suggestive of rhabdomyolysis). Interestingly, pre-treatment of animals with dantrolene or azumolene prevented completely exertional-strokes in both RYR1Y522S/WT (n=7) and CASQ1-null (n=8) mice, strongly suggesting that: a) exertional-crises may share common molecular mechanisms with anesthetic-induced MH; b) drugs used in the operating room to treat acutely MH crises should be considered for treatment of environmental/exertional heat strokes.