Titre :
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Effect of ryanodine receptor 1 mutations on IL-6 release and intracellular calcium homeostasis in human myotubes from MHS individuals and patients affected by central core disease (abstract : congrès international de Myologie, 2005)
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contenu dans :
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Auteurs :
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Congrès international de myologie 2005 (International Congress of Myology 2005; 9-13 mai 2005; Nantes, France) ;
Treves S ;
Ducreux S ;
Muller C ;
Muntoni F ;
Sewry C ;
Quinlivan R ;
Girard T ;
Zorzato F
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Type de document :
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Article
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Année de publication :
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2005
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Pages :
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p. 160
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Langues:
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Anglais
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Mots-clés :
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biopsie musculaire
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calcium
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ciclosporine
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colloque
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cytokine
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dantrolène
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diagnostic
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ELISA
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gène RYR1
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homéostasie
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humain
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hyperthermie maligne
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IL-6
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muscle squelettique
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mutation génétique
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myopathie à central core
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myotube
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récepteur à la ryanodine
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Résumé :
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Communication n° 12. Introduction and objectives : More than 60 mutations in the skeletal muscle RYR1 gene have been identified and associated with Malignant Hyperthermia (MH) and Central Core Disease (CCD). Most MH-linked mutations are localised at the N-terminal while CCD-linked mutations are mainly localised in the C-terminal transmembrane domain. Functional studies have revealed that RYR1 mutations affect myoplasmic calcium homeostasis. Since calcium regulates many aspects of cell physiology, including cytokine release, we investigated whether activation of the RYR stimulates IL-6 release from cultured human myotubes. We also studied [Ca2+]i of human myotubes obtained from patients carrying RYR1-mutations linked to CCD and compared it to that observed in cells from control or MHS individuals. Methods : Human myotubes were established from muscle biopsies of patients undergoing the in vitro contracture test and from 2 patients affected by CCD, after obtaining informed consent. [Ca2+]i measurements were carried out using the fluorescent indicator fura-2. Release of cytokines from myotubes was determined using the CLB PeliKine Compact indirect ELISA Kit. Results : Pharmacological activation of the RYR induces release of IL-6 from cultured myotubes; release depends on de novo protein synthesis and is blocked by dantrolene and cyclosporine Myotubes from the two patients affected CCD show an increase in the release of IL-6, compared to cells derived from control or MHS individuals. The functional impact on calcium release of RYR1 mutations linked to CCD or MH is different: human myotubes carrying an MH-linked RYR1 mutation show a shift in their sensitivity to RYR agonists, whereas human myotubes harbouring C-terminal mutations linked to CCD exhibit reduced [Ca2+]i increase in response to RYR activation. Conclusions : Our results suggest that abnormal release of calcium via mutated RYR enhance the production of the inflammatory cytokine IL-6 which may in turn affect signalling pathways responsible for the trophic status of muscle fibres.
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