Fig. 7. Potential mechanism of bupivacaine-induced myotoxicity and N -acetylcysteine (NAC) cytoprotection in skeletal muscle. Bupivacaine increases the production of reactive oxygen species (ROS) which induce sarcoplasmic reticulum (SR) stress and the unfolded protein response and may cause SR calcium depletion. Bupivacaine sequentially induces ROS production and SR stress leading to apoptosis mediated by the mitochondrial death pathway. Blocking ROS production, the antioxidant NAC protects against bupivacaine-induced myotoxicity. ATF-6 = activating transcription factor 6; CHOP = C/EBP homologous protein; RyR = channel ryanodine receptors; SERCA = sarcoplasmic reticulum Ca2+ATPase; XBP-1 = X-box-binding protein 1.