Ca2+ homeostasis in Brody's disease. A study in skeletal muscle and cultured muscle cells and the effects of dantrolene an verapamil.
Brody's disease, i.e., sarcoplasmic reticulum (SR) Ca(2+)-dependent Mg(2+)-ATPase (Ca(2+)-ATPase) deficiency, is a rare inherited disorder of skeletal muscle function. Pseudo-myotonia is the most important clinical feature. SR Ca(2+)-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 Ca(2+)-ATPase activity is decreased by approximately 50%. However, the concentration of SR Ca(2+)-ATPase and SERCA1 are normal. SERCA1 accounts for 83 and 100% of total SR Ca(2+)-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.
Benders
A A
AA
Department of Biochemistry, University of Nijmegen, The Netherlands.
Veerkamp
J H
JH
Oosterhof
A
A
Jongen
P J
PJ
Bindels
R J
RJ
Smit
L M
LM
Busch
H F
HF
Wevers
R A
RA
D000109:Acetylcholine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000172:deficiency*; D002478:Cells, Cultured; D002648:Child; D003620:Dantrolene / Q000494:pharmacology*; D005260:Female; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009132:Muscles / Q000378:metabolism*; D009222:Myotonia / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology*
D014700:Verapamil; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D003620:Dantrolene; D000109:Acetylcholine; D002118:Calcium