Increased calcium influx in dystrophic muscle.
We examined pathways which might result in the elevated resting free calcium [( Ca2+]i) levels observed in dystrophic mouse (mdx) skeletal muscle fibers and myotubes and human Duchenne muscular dystrophy myotubes. We found that mdx fibers, loaded with the calcium indicator fura-2, were less able to regulate [Ca2+]i levels in the region near the sarcolemma. Increased calcium influx or decreased efflux could lead to elevated [Ca2+]i levels. Calcium transient decay times were identical in normal and mdx fibers if resting [Ca2+]i levels were similar, suggesting that calcium-sequestering mechanisms are not altered in dystrophic muscle, but are slowed by the higher resting [Ca2+]i. The defect appears to be specific for calcium since resting free sodium levels and sodium influx rates in the absence of Na+/K(+)-ATPase activity were identical in normal and dystrophic cells when measured with sodium-binding benzofuran isophthalate. Calcium leak channels, whose opening probabilities (Po) were voltage independent, could be the major calcium influx pathway at rest. We have shown previously that calcium leak channel Po is significantly higher in dystrophic myotubes. These leak channels were selective for calcium over sodium under physiological conditions. Agents that increased leak channel activity also increased [Ca2+]i in fibers and myotubes. These results suggest that increased calcium influx, as a result of increased leak channel activity, could result in the elevated [Ca2+]i in dystrophic muscle.
Turner
P R
PR
Department of Molecular and Cell Biology, University of California, Berkeley 94720.
Fong
P Y
PY
Denetclaw
W F
WF
Steinhardt
R A
RA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D012964:Sodium / Q000378:metabolism
D015220:Calcium Channels; D012964:Sodium; D002118:Calcium