Hypersensitive response of malignant hyperthermia-susceptible skeletal muscle to inositol 1,4,5-trisphosphate induced release of calcium

Abstract

Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Besides a mutation in the ryanodine receptor gene, an increase in inositol, 1,4,5-trisphosphate (InsP₃) levels could be a possible candidate for the abnormal regulation of intracellular calcium. However, the effect of InsP₃ on [Ca²⁺]i in MH is not known. Microinjection of InsP₃ increased intracellular Ca²⁺ in intact skeletal muscle from malignant hyperthermia susceptible swines (MHS) with a higher potency and efficacy than in muscles from nonsusceptible (MHN) swines. Omission of extracellular Ca²⁺ or incubation of muscle fibers with Ca²⁺ channel blockers did not modify the response to InsP₃. However, dantrolene (50 μM) a known blocker of intracellular Ca²⁺ release, decreased resting intracellular Ca²⁺ concentration and prevented the InsP₃-induced increase in intracellular Ca²⁺. This suggests (i) that MHS skeletal muscles exhibit a higher responsiveness to InsP₃-induced release of Ca²⁺, which could implicate InsP₃ in the pathophysiology of MH, and (ii) that the beneficial effect of dantrolene in MHS could be related to its ability to prevent the InsP₃-induced release of Ca²⁺.