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

Brody's disease, i.e., sarcoplasmic reticulum (SR) Ca2+-dependent Mg2+-ATPase (Ca2+-ATPase) deficiency, is a rare inherited disorder of skeletal muscle function. Pseuda-myotonia is the most important clinical feature. SR Ca2+-ATPase and Ca2+ homeostasis are examined in m. quadriceps 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 50%. However, the concentration of SR Ca2+-ATPase and SERCA1 are normal. SERCA1 accounts for 83 and 100% of total SR Ca2+-ATPase in m. quadriceps 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, however, is raised three times in the pathological muscle cells. Addition of dantrolene or verapamil after the maximal response accelerates the restoration of the [Ca2+](i) in these muscle cells. The differences in Ca2+ handling disappear by administration of dantrolene or verapamil concomitantly with acetylcholine. The reduced Ca2+ re-uptake from the cytosol presumably due to structural modification(s) of SERCA1 may explain the pseudo-myotonia in Brody's disease. Single cell measurements suggest a beneficial effect of dantrolene or verapamil in treating patients suffering from Brody's disease.