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Regulation of store‐operated calcium entries and mitochondrial uptake by minidystrophin expression in cultured myotubes
Author(s) -
Vandebrouck A.,
Ducret T.,
Basset O.,
Sebille S.,
Raymond G.,
Ruegg U.,
Gailly P.,
Cognard C.,
Constantin B.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-3633fje
Subject(s) - myogenesis , calcium , dystrophin , microbiology and biotechnology , serca , utrophin , calcium in biology , sarcolemma , t type calcium channel , myocyte , chemistry , calcium atpase , duchenne muscular dystrophy , voltage dependent calcium channel , sarcoplasm , biology , endocrinology , biochemistry , skeletal muscle , atpase , genetics , organic chemistry , enzyme
Defective expression of dystrophin in muscle cells is the primary feature of Duchenne muscular dystrophy (DMD), which is accompanied by fiber necrosis and intracellular calcium mishandling. These features led to the hypothesis that dystrophin could control calcium movements. Calcium mishandling in human DMD myotubes is dependent on contraction and/or calcium release activity, suggesting the involvement of channels being activated during these processes. Forced expression of minidystrophin at the plasma membrane of dystrophin‐deficient Sol8 myotubes reactivates appropriate sarcolemmal expression of dystrophin‐associated proteins and results in normal calcium homeostasis. In active dystrophic myotubes, store‐operated calcium channels could be responsible for a sustained calcium influx in muscle cells. We show here that depletion of calcium stores (sarcoplasmic reticulum) by repetitive activation of calcium release and blockade of SERCA leads to a calcium influx. In myotubes expressing recombinant minidystrophin, these store‐dependent influxes were reduced to a level similar to that observed in myotubes expressing native dystrophin. High store‐dependent calcium influxes in dystrophindeficient myotubes were associated with sustained cytosolic calcium transients and high intramitochondrial entries, while lower store‐dependent calcium influx in myotubes expressing minidystrophin resulted in shorter calcium transients and reduced calcium uptake into mitochondria. We propose that minidystrophin negatively regulates sarcolemmal store‐dependent calcium channels, which reduces store‐dependent calcium influx, as well as its mitochondrial uptake. Forced expression of minidystrophin in dystrophic cells might restore the regulation of sarcolemmal store‐dependent channels, which could protect against calcium mishandling.