Advances in malignant hyperthermia: novel insights into heat-induced Ca²⁺ release as a thermal signaling

Thermoregulation is essential for maintaining homeostasis in mammals under various environmental conditions. Impairment of this function can result in severe conditions, such as fever, heat stroke, and malignant hyperthermia (MH). In this review, we will focus on the role of the type 1 ryanodine receptor (RYR1), a Ca²⁺ release channel that is crucial for excitation-contraction coupling in skeletal muscles. Mutations in RYR1 are associated with muscle disorders, including MH, which is characterized by dysregulated Ca²⁺-induced Ca²⁺ release (CICR). Recent advances from genetically engineered mouse models of MH have provided new insights into the pathophysiological mechanisms underlying anesthetic- and heat-induced episodes, and revealed a heat-induced Ca²⁺ release (HICR) mechanism mediated by RYR1. Experimental evidences demonstrate that anesthetics induce simultaneous increases in cellular temperature and cytosolic Ca²⁺ concentration. Therefore, this review proposes that an increase in cellular temperature triggers further Ca²⁺ release via HICR, establishing a positive feedback loop that sustains excessive heat production during MH crises.