SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

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Malignant hyperthermia (MH) is a genetic disease in man and various animal species which predisposes to a life-threatening hypermetabolic syndrome. The acute onset MH syndrome is triggered unexpectedly by certain anesthetic agents. The primary defect occurs in skeletal muscle and experiments described in this project focus on the relationships between genetic defect and its phenotypic expression clinically in the patient, contracture response in biopsied skeletal muscle, calcium uptake and release by isolated membranes vesicles and a single protein molecule functioning as a calcium channel. These studies are based on a well founded hypothesis that MH is caused by anesthetic agent-induced loss in regulation of myoplasmic (Ca2+). A probable causal single amino acid substitution in the calcium release channel of MH pig muscle provides the model for characterizing phenotypic expression of this mutation at the animal, tissue, membrane and protein levels of organization. Also studied is a genetic canine MH model with an unknown mutation different from the MH pig. The MH canine model, studied in the same manner, will provide new, informative knowledge because the pig mutation occurs in less than 5% of MH human families. Animal models are phenotyped clinically by their response to anesthetic challenge and by in vitro by contracture sensitivity to caffeine, halothane, and ryanodine. Patients undergoing MH diagnostic muscle biopsies will provide muscle for studies parallel to those in the animal models. Similarities and dissimilarities among the contracture responses will be explored by investigation of calcium regulation by isolated sarcoplasmic reticulum membrane vesicles and by analysis of the single ryanodine receptor (RYR) calcium release channel in a planar lipid bilayer. The RYR calcium channel will be studied in biochemical and pharmacological detail to provide a basis for linking structure and function and the impact of mutations on this relationship. Such information will provide a basis for predicting the relationship between a specific mutation and susceptibility to anesthetic-induced malignant hyperthermia. This strategy will be essential for assessing the clinical relevance of newly discovered mutations in this major calcium release channel.