Discovery of heat-induced calcium release via ryanodine receptors and a novel mechanism of thermal runaway

Abstract

Regulation of thermogenesis in mammals is essential for maintaining body temperature homeostasis under fluctuating environmental temperature. Impairments in this regulation can lead to severe conditions, including fever or heatstroke. This review focuses on malignant hyperthermia (MH), a pathological escalation of thermogenesis in skeletal muscle. It highlights the role of type 1 ryanodine receptor (RYR1), a Ca²⁺ release channel, based on our recent studies. Previous studies have revealed that genetic mutations in RYR1 are associated with muscle disorders including MH, which are characterized by abnormal Ca²⁺-induced Ca²⁺ release (CICR). To test our hypothesis that RYR1 channel function is closely related to thermogenesis, we examined cultured cell lines expressing wild-type or MH-related mutants of RYR1, as well as muscle cells prepared from MH model mice. Using a local heating microscopy combined with fluorescence temperature imaging, we identified a novel phenomenon termed heat-induced Ca²⁺ release (HICR). Furthermore, our results indicate that anesthesia induces simultaneous increases in temperature and cytoplasmic Ca²⁺ concentration in muscle cells. Based on these findings, we propose a positive feedback loop where HICR drives further Ca²⁺ release during MH episodes, causing thermogenesis and further elevation of body temperature. This review summarizes our experimental results that were presented at the symposium, providing greater detail on the mechanisms underlying MH pathogenesis and the role of RYR1 in thermal regulation.