Aagm. Benders et al., CA2- A STUDY IN SKELETAL-MUSCLE AND CULTURED MUSCLE-CELLS AND THE EFFECTS OF DANTROLENE AND VERAPAMIL( HOMEOSTASIS IN BRODYS DISEASE ), The Journal of clinical investigation, 94(2), 1994, pp. 741-748
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.