RyR1 Deficiency in Congenital Myopathies Disrupts Excitation–Contraction Coupling

Zhou, H. and Rokach, O. and Feng, L. and Munteanu, I. and Mamchaoui, K. and Wilmshurst, J. M. and Sewry, C. and Manzur, A. Y. and Pillay, K. and Mouly, V. and Duchen, M. and Jungbluth, H. and Treves, S. and Muntoni, F.. (2013) RyR1 Deficiency in Congenital Myopathies Disrupts Excitation–Contraction Coupling. Human Mutation, 34 (7). pp. 986-996.

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Official URL: http://edoc.unibas.ch/dok/A6174389

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In skeletal muscle, excitation-contraction (EC) coupling is the process whereby the voltage-gated dihydropyridine receptor (DHPR) located on the transverse tubules activates calcium release from the sarcoplasmic reticulum by activating ryanodine receptor (RyR1) Ca(2+) channels located on the terminal cisternae. This subcellular membrane specialization is necessary for proper intracellular signaling and any alterations in its architecture may lead to neuromuscular disorders. In this study, we present evidence that patients with recessive RYR1-related congenital myopathies due to primary RyR1 deficiency also exhibit downregulation of the alfa 1 subunit of the DHPR and show disruption of the spatial organization of the EC coupling machinery. We created a cellular RyR1 knockdown model using immortalized human myoblasts transfected with RyR1 siRNA and confirm that knocking down RyR1 concomitantly downregulates not only the DHPR but also the expression of other proteins involved in EC coupling. Unexpectedly, this was paralleled by the upregulation of inositol-1,4,5-triphosphate receptors; functionally however, upregulation of the latter Ca(2+) channels did not compensate for the lack of RyR1-mediated Ca(2+) release. These results indicate that in some patients, RyR1 deficiency concomitantly alters the expression pattern of several proteins involved in calcium homeostasis and that this may influence the manifestation of these diseases.
Faculties and Departments:03 Faculty of Medicine
03 Faculty of Medicine > Departement Biomedizin
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Perioperative Patient Safety (Girard/Treves)
UniBasel Contributors:Treves, Susan
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:31 May 2017 09:39
Deposited On:25 Oct 2013 08:33

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