Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers

Malignant hyperthermia (MH) is associated with abnormal regulation of intracellular calcium in skeletal muscle fibers. Cyclic adenosine diphosphate-ribose (cADPR) is an endogenous metabolite of β-NAD⁺ that induces Ca²⁺ release from intracellular stores in many tissues. Microinjection of cADPR (0.5 or 1 μM) increased the intracellular resting Ca²⁺ concentration ([Ca²⁺](i)) in intact swine skeletal muscle in a dose- dependent manner. However, the increase in [Ca²⁺](i) was greater in malignant-hyperthermia-susceptible (MHS) fibers than in non-susceptible (MHN) fibers. Incubation of muscle fibers in low external Ca²⁺ solution or in the presence of L-type Ca²⁺ channel entry blockers, or intracellular microinjection of heparin or ruthenium red did not modify the effect of cADPR on [Ca²⁺](i). Dantrolene (50 μM), a known inhibitor of intracellular Ca²⁺ release, decreased resting [Ca²⁺](i) and prevented the cADPR-induced increase in [Ca²⁺](i). These results provide evidence: (1) for the existence of Ca²⁺ release mechanisms occurring via non-ryanodine or inositol 1,4,5-trisphosphate (InsP₃) receptor mechanisms; (2) that MHS skeletal muscles exhibit a higher responsiveness to cADP-ribose-induced release of Ca²⁺ and (3) that the ability of dantrolene to block cADP- ribose-induced release of Ca²⁺ could be related to its pharmacologic effect on resting [Ca²⁺](i).