Elevated subsarcolemmal Ca2+ in mdx mouse skeletal muscle fibers detected with Ca2+-activated K+ channels

AUTOR(ES)

Mallouk, Nora

FONTE

The National Academy of Sciences

RESUMO

Duchenne muscular dystrophy results from the lack of dystrophin, a cytoskeletal protein associated with the inner surface membrane, in skeletal muscle. The cellular mechanisms responsible for the progressive skeletal muscle degeneration that characterizes the disease are still debated. One hypothesis suggests that the resting sarcolemmal permeability for Ca2+ is increased in dystrophic muscle, leading to Ca2+ accumulation in the cytosol and eventually to protein degradation. However, more recently, this hypothesis was challenged seriously by several groups that did not find any significant increase in the global intracellular Ca2+ in muscle from mdx mice, an animal model of the human disease. In the present study, using plasma membrane Ca2+-activated K+ channels as subsarcolemmal Ca2+ probe, we tested the possibility of a Ca2+ accumulation at the restricted subsarcolemmal level in mdx skeletal muscle fibers. Using the cell-attached configuration of the patch-clamp technique, we demonstrated that the voltage threshold for activation of high conductance Ca2+-activated K+ channels is significantly lower in mdx than in control muscle, suggesting a higher subsarcolemmal [Ca2+]. In inside-out patches, we showed that this shift in the voltage threshold for high conductance Ca2+-activated K+ channel activation could correspond to a ≈3-fold increase in the subsarcolemmal Ca2+ concentration in mdx muscle. These data favor the hypothesis according to which an increased calcium entry is associated with the absence of dystrophin in mdx skeletal muscle, leading to Ca2+ overload at the subsarcolemmal level.

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