CA2- A STUDY IN SKELETAL-MUSCLE AND CULTURED MUSCLE-CELLS AND THE EFFECTS OF DANTROLENE AND VERAPAMIL( HOMEOSTASIS IN BRODYS DISEASE )

Brody's disease, i.e., sarcoplasmic reticulum (SR) Ca2+-dependent Mg2-ATPase (Ca2+-ATPase) deficiency, is a rare inherited disorder of skel etal muscle function. Pseuda-myotonia is the most important clinical f eature. SR Ca2+-ATPase and Ca2+ homeostasis are examined in m. quadric eps and/or cultured muscle cells of controls and 10 patients suffering from Brody's disease. In both m. quadriceps and cultured muscle cells of patients, the SR Ca2+-ATPase activity is decreased by similar to 5 0%. However, the concentration of SR Ca2+-ATPase and SERCA1 are normal . SERCA1 accounts for 83 and 100% of total SR Ca2+-ATPase in m. quadri ceps and cultured muscle cells, respectively. This implies a reduction of the molecular activity of SERCA1 in Brody's disease. The cytosolic Ca2+ concentration ([Ca2+](i)) at rest and the increase of [Ca2+](i) after addition of acetylcholine are the same in cultured muscle cells of controls and patients. The half-life of the maximal response, howev er, is raised three times in the pathological muscle cells. Addition o f dantrolene or verapamil after the maximal response accelerates the r estoration of the [Ca2+](i) in these muscle cells. The differences in Ca2+ handling disappear by administration of dantrolene or verapamil c oncomitantly with acetylcholine. The reduced Ca2+ re-uptake from the c ytosol presumably due to structural modification(s) of SERCA1 may expl ain the pseudo-myotonia in Brody's disease. Single cell measurements s uggest a beneficial effect of dantrolene or verapamil in treating pati ents suffering from Brody's disease.