New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD
- 286 Downloads
Calcium mishandling in Duchenne muscular dystrophy (DMD) suggested that dystrophin, a membrane-associated cytoskeleton protein, may regulate calcium-signalling cascades such as calcium entries. Calcium overload in human DMD myotubes is dependent on their contractile activity suggesting the involvement of channels being activated during contraction and/or calcium release. Forced expression of mini-dystrophin in dystrophin-deficient myotubes, reactivates appropriate sarcolemmal expression of dystrophin-associated proteins and restores normal calcium handling in the cytosol. Furthermore, the recombinant mini-dystrophin reduced the store-operated calcium influx across the sarcolemma, and the mitochondrial calcium uptake during this influx. A slow component of calcium release dependent on IP3R, as well as the production of IP3, were also reduced to normal levels by expression of mini-dystrophin. Our studies provide a new model for the convergent regulation of transmembrane calcium influx and IP3-dependent calcium release by the dystrophin-based cytoskeleton (DBC). We also suggest molecular association of such channels with DBC which may provide the scaffold for assembling a multiprotein-signalling complex that modulates the channel activity. This suggests that the loss of this molecular association could participate in the alteration of calcium homeostasis observed in DMD muscle cells.
KeywordsSkeletal muscle Duchenne muscular dystrophy Dystrophine Calcium signalling Stone-operated calcium entries Inositol [1,3,5] triphosphate receptor Mitochondrial calcium uptake
Unable to display preview. Download preview PDF.
- Balghi H, Sebille S, Constantin B, Patri S, Thoreau V, Mondin L, Mok E, Kitzis A, Raymond G, Cognard C (2006) Mini-dystrophin expression down-regulates overactivation of G protein-mediated IP3 signalling pathway in dystrophin-deficient muscle cells. J Gen Physiol 127:171–182PubMedCrossRefGoogle Scholar
- Marchand E, Constantin B, Balghi H, Claudepierre MC, Cantereau A, Magaud C, Mouzou A, Raymond G, Braun S, Cognard C (2004) Improvement of calcium handling and changes in calcium-release properties after mini- or full-length dystrophin forced expression in cultured skeletal myotubes. Exp Cell Res 297:363–379PubMedCrossRefGoogle Scholar
- Rivet-Bastide M, Imbert N, Cognard C, Duport G, Rideau Y, Raymond G (1993) Changes in cytosolic resting ionized calcium level and in calcium transients during in vitro development of normal and Duchenne muscular dystrophy cultured skeletal muscle measured by laser cytofluorimetry using indo-1. Cell Calcium 14:563–571PubMedCrossRefGoogle Scholar
- Vandebrouck A, Ducret T, Basset O, Sebille S, Raymond G, Ruegg U, Gailly P, Cognard C, Constantin B (2005) Regulation of store-operated calcium entries and mitochondrial uptake by minidystrophin expression in cultured myotubes. FASEB J Epub 2005 Oct 27. short printed version 20: 136–138Google Scholar