Agonist-induced myopathy at the neuromuscular junction is mediated by calcium.
Inactivation of cholinesterases at mammalian neuromuscular junctions (nmj) produces extensive muscle "necrosis." Fine-structurally, this myopathy begins near the nmj with an increase in large-diameter vesicles in the soleplasm, the dissolution of Z-disks, dilation of mitochondria, destruction of sarcoplasmic reticulum, and often a highly specific contracture of the muscle under the endplate. Since a Ca++-activated protease which specifically removes Z-disks is known to exist in mammalian skeletal muscle, we tested the possibility that the myopathy after esterase inactivation is due to the prolongation of acetylcholine lifetime and thus of Ca++ influx. We first produced the myopathy near endplates by inactivating esterases with diisopropylfluorophosphate (DFP) followed by nerve stimulation for 1--2 h in vitro. The myopathy was later mimicked by bath application of carbamylcholine without esterase inhibitors. This myopathy could be prevented by inactivating the acetylcholine receptors (AChR) with alpha-bungarotoxin (alpha-BGT) or by removing Ca++ from the bath with EGTA. These results favor the hypothesis that esterase inhibition leads to an agonist-induced myopathy, which is mediated by Ca++ and requires an intact AChR.
D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors; D066298:In Vitro Techniques; D007531:Isoflurophate / Q000494:pharmacology; D051379:Mice; D008931:Mitochondria, Muscle / Q000648:ultrastructure; D009132:Muscles / Q000187:drug effects* / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced; D009210:Myofibrils / Q000648:ultrastructure; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000648:ultrastructure
D002038:Bungarotoxins; D002800:Cholinesterase Inhibitors; D007531:Isoflurophate; D002217:Carbachol; D002118:Calcium