Porcine malignant hyperthermia susceptibility: increased calcium-sequestering activity of skeletal muscle sarcoplasmic reticulum

Abstract

This study tested the hypothesis that calcium-sequestration by isolated sarcoplasmic reticulum was abnormal in skeletal muscle of malignant hyperthermia-susceptible swine. A heavy sarcoplasmic reticulum fraction was isolated from malignant hyperthermia and control muscle using differential and density-gradient centrifugation. Prior to onset of malignant hyperthermia, calcium-sequestering activity (Vmax at 37 degrees C, mumol calcium/mg/min) was twofold increased in malignant hyperthermia sarcoplasmic reticulum compared to control sarcoplasmic reticulum (1.96 +/- 0.50 versus 4.00 +/- 0.87, P less than 0.01), although thermodynamic and kinetic properties of this activity were otherwise indistinguishable between groups. This increased activity of the malignant hyperthermia sarcoplasmic reticulum fraction was associated with twofold increased concentration of Ca-ATPase and calsequestrin protein. When a malignant hyperthermia-reaction developed, calcium-uptake was depressed to less than 5% of control values. These data indicate that malignant hyperthermia is not initiated due to a defect in the calcium-sequestration mechanism, however, loss of calcium-uptake activity occurring after the onset of malignant hyperthermia might result in the propagation and irreversibility of the malignant hyperthermia reaction.