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J. Biol. Chem., Vol. 279, Issue 42, 43838-43846, October 15, 2004

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Effect of Ryanodine Receptor Mutations on Interleukin-6 Release and Intracellular Calcium Homeostasis in Human Myotubes from Malignant Hyperthermia-susceptible Individuals and Patients Affected by Central Core Disease^*

Sylvie Ducreux, Francesco Zorzato, Clemens Müller¶, Caroline Sewry||**, Francesco Muntoni||, Ros Quinlivan**, Gabriella Restagno, Thierry Girard, and Susan Treves

From the Departments of Anaesthesia and Research, Kantonsspital Basel, 4031 Basel, Switzerland, the Dipartimento di Medicina Sperimentale e Diagnostica, Universitá di Ferrara, 44100 Ferrara, Italy, the ^¶Institut für Humangenetik, Biozentrum der Universität Würzburg, 97074 Würzburg, Germany, ^||The Dubowitz Neuromuscular Centre, London W120NN, United Kingdom, the ^**Neuromuscular Centre, Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry SY10 7AG, United Kingdom, and the Dipartimento di Patologia Clinica, S.C. Genetica Molecolare, Azienda Ospedaliera S.Anna, 10126 Torino, Italy

In this study we report for the first time the functional properties of human myotubes isolated from patients harboring the native RYR1 I4898T and R4893W mutations linked to central core disease. We examined two aspects of myotube physiology, namely excitation-contraction and excitation-secretion coupling. Our results show that upon activation of the ryanodine receptor (RYR), myotubes release interleukin-6 (IL-6); this was dependent on de novo protein synthesis and could be blocked by dantrolene and cyclosporine. Myotubes from the two patients affected by central core disease showed a 4-fold increase in the release of the inflammatory cytokine IL-6, compared with cells derived from control or malignant hyperthermia susceptible individuals. All tested myotubes released calcium from intracellular stores upon stimulation via surface membrane depolarization or direct RYR activation by 4-chloro-m-cresol. The functional impact on calcium release of RYR1 mutations linked to central core disease or malignant hyperthermia is different: human myotubes carrying the malignant hyperthermia-linked RYR1 mutation V2168M had a shift in their sensitivity to the RYR agonist 4-chloro-m-cresol to lower concentrations, whereas human myotubes harboring C-terminal mutations linked to central core disease exhibited reduced [Ca²⁺]_i increase in response to 4-chloro-m-cresol, caffeine, and KCl. Taken together, these results suggest that abnormal release of calcium via mutated RYR enhances the production of the inflammatory cytokine IL-6, which may in turn affect signaling pathways responsible for the trophic status of muscle fibers.

Received for publication, April 1, 2004 , and in revised form, August 7, 2004.

^* This work was supported by Swiss National Science Foundation (Grants 3200-063959.00 and 3200-067820.02, by Association Française contre les Myopathies, by the European Union Grant HPRN-CT-2002-00331, and by the Department of Anesthesia, Kantonsspital Basel. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 41-61-265-2373; Fax: 41-61-265-3702; E-mail: susan.treves{at}unibas.ch.

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