Treatment of muscle damage, induced by high intracellular Ca2+, with calmodulin antagonists.
1. Incubation of rat diaphragm muscles in the presence of Ca(2+)-ionophore A23187, which causes accumulation of free intracellular Ca2+, induced severe myofibrils damage. Electron microscopic studies have revealed that calmodulin (CaM) antagonists, trifluoperazine, thioridazine, pimozide and CGS 9343B, were most effective in preserving muscle structure. 2. The CaM antagonists raised the decreased glucose-1,6-bisphosphate levels, induced by high Ca2+, with a concomitant activation of the reduced cytosolic phosphofructokinase (the rate limiting enzyme of glycolysis) and thereby cytosolic glycolysis. 3. All four CaM inhibitors also prevented solubilization of cytoskeleton-bound glycolytic enzymes by high Ca2+. 4. The protective effect of these compounds on cytosolic and cytoskeletal glycolysis, was also expressed by their action in preserving muscle ATP levels. 5. The present experiments suggest that CaM antagonists may be effective drugs in treatment of muscle damage and various muscle diseases, which are characterized by a high pathological increase in intracellular Ca2+.
Beitner
R
R
Department of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Lilling
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000633:toxicity*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives*; D005958:Glucosephosphates / Q000378:metabolism; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D009135:Muscular Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D009210:Myofibrils / Q000187:drug effects / Q000201:enzymology; D010732:Phosphofructokinase-1 / Q000378:metabolism; D051381:Rats; D012132:Respiratory Muscles / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D002147:Calmodulin; D005958:Glucosephosphates; D000001:Calcimycin; D019298:Glucose-6-Phosphate; D000255:Adenosine Triphosphate; C016473:glucose-1,6-bisphosphate; D010732:Phosphofructokinase-1; D002118:Calcium