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New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD

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Abstract

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.

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Acknowledgements

This work was supported by the CNRS, the French Ministry of Research, and by “Association Française contre les Myopathies” (AFM). This review is partly based on a collaboration with Dr P. Gailly and Dr T. Ducret (Departement de Physiologie, Université Catholique de Louvain, Brussels B-1200, Belgium), and Dr O. Basset and Prof U. Ruegg (Laboratory of Pharmacology, University of Geneva, CH-1211 Geneva 4, Switzerland).

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  1. Institut de Physiologie et Biologie Cellulaires, CNRS, UMR-6187, University of Poitiers, 86022, Poitiers, France

    Bruno Constantin, Stéphane Sebille & Christian Cognard

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  1. Bruno Constantin
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Correspondence to Bruno Constantin.

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Constantin, B., Sebille, S. & Cognard, C. New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD. J Muscle Res Cell Motil 27, 375–386 (2006). https://doi.org/10.1007/s10974-006-9085-2

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