Low-dose Simvastatin Increases Skeletal Muscle Sensitivity to Caffeine and Halothane

Objective To determine whether the myotoxic side effects of statin simvastatin affect skeletal muscle's sensitivity to caffeine and halothane.Methods Primary cultured neonate rat skeletal myotubes were treated with 0.01-5.0 μmol/L simvastatin for 48 hours. MTT was used to evaluate cellular viability. The gross morphology and microstructure of the myotubes were observed with a light and electron microscope, respectively. The intracellular calcium concentrations ([Ca²⁺]i) at rest and in response to caffeine and halothane were investigated by fluorescence calcium imaging. Data were analyzed by analysis of variance (ANOVA) test.Results Simvastatin (0.01-5.0 μmol/L) decreased myotube viability, changed their morphological features and microstructure, and increased the resting [Ca²⁺]i in a dose-dependent manner. Simvastatin did not change myotube's sensitivity to low doses of caffeine (0.625-2.5 mmol/L) or halothane (1.0-5.0 mmol/L). In response to high-dose caffeine (10.0 mmol/L, 20.0 mmol/L) and halothane (20.0 mmol/L, 40.0 mmol/L), myotubes treated with 0.01 μmol/L simvastatin showed a significant increase in sensitivity, but those treated with 1.0 μmol/L and 5.0 μmol/L simvastatin showed a significant decrease. The sarcoplasmic reticulum Ca²⁺ storage peaked in the myotubes treated with 0.01 μmol/L simvastatin, but it decreased when cells were treated with higher doses of simvastatin (0.1-5.0 μmol/L).Conclusions The myotoxic side effect of simvastatin was found to change the sensitivity of myotubes in response to high-dose caffeine and halothane. When dose was low, sensitivity increased mainly because of increased Ca²⁺ content in the sarcoplasmic reticulum, which might explain why some individuals with statin-induced myotoxic symptoms may show positive caffeine-halothane contracture test results. However, when the dose was high and the damage to the myotubes was severer, sensitivity was lower. It is here supposed that the damage itself might put individuals with statin-induced myotoxic symptoms at greater risks of presenting with rhabdomyolysis during surgery or while under anesthesia.