CELLULAR-DAMAGE IN MOUSE SKELETAL-MUSCLE CAUSED BY MENADIONE

Exposure of the isolated mouse soleus muscle preparation to 10, 25 or 50 mu M menadione for 30 min causes subsequent release of creatine kin ase (CK) and ultrastructural damage to the myofilament apparatus. CK r elease was slightly reduced under hypoxia (p < 0.01), but radical scav engers catalase (150,000 U/l) desferrioxamine (0.8 mM) or dimethylthio urea (10 mM) were without significant effect. Mannitol at high concent ration (50 mM) reduced CK efflux (p < 0.05). CK efflux with menadione (10 or 25 mu M) was approximately doubled when external Ca2+ was remov ed; under these conditions, hypoxia provided complete production. The ultrastructural damage of the myofilament apparatus and cell organelle s was characteristic of that triggered by a raised [Ca2+](i) and was u naffected by external conditions. It is concluded that (1) CK release and myofilament damage are independent pathways; (2) menadione causes the release of Ca2+ from intracellular sites and so causes cell damage ; (3) O-2 radicals do not play a major part in this Ca2+ release; (4) removal of extracellular Ca2+ activates the CK release mechanism and a lso switches it so that it operates via an O-2-dependent mechanism, an d (5) raised [Ca2+](i) interacts synergistically with the activated CK release mechanism.