title: Enhanced excitation-coupled Ca(2+) entry induces nuclear translocation of NFAT and contributes to IL-6 release from myotubes from patients with central core disease.
abstract: Prolonged depolarization of skeletal muscle cells induces entry of extracellular calcium into muscle cells, an event referred to as excitation-coupled calcium entry. Skeletal muscle excitation-coupled calcium entry relies on the interaction between the 1,4-dihydropyridine receptor on the sarcolemma and the ryanodine receptor on the sarcoplasmic reticulum membrane. In this study, we directly measured excitation-coupled calcium entry by total internal reflection fluorescence microscopy in human skeletal muscle myotubes harbouring mutations in the RYR1 gene linked to malignant hyperthermia (MH) and central core disease (CCD). We found that excitation-coupled calcium entry is strongly enhanced in cells from patients with CCD compared with individuals with MH and controls. Furthermore, excitation-coupled calcium entry induces generation of reactive nitrogen species and enhances nuclear localization of NFATc1, which in turn may be responsible for the increased IL-6 released by myotubes from patients with CCD.
authors.affiliation: Department of Anesthesia, Basel University Hospital, 4031 Basel, Switzerland. susan.treves@unibas.ch
authors.forename: Susan
authors.initials: S
authors.lastname: Treves
authors.forename: Mirko
authors.initials: M
authors.lastname: Vukcevic
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Jeannet
authors.forename: Soledad
authors.initials: S
authors.lastname: Levano
authors.forename: Thierry
authors.initials: T
authors.lastname: Girard
authors.forename: Albert
authors.initials: A
authors.lastname: Urwyler
authors.forename: Dirk
authors.initials: D
authors.lastname: Fischer
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
authors.forename: Sue
authors.initials: S
authors.lastname: Lillis
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Ros
authors.initials: R
authors.lastname: Quinlivan
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Francesco
authors.initials: F
authors.lastname: Zorzato
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008305:Malignant Hyperthermia / Q000235:genetics; D008856:Microscopy, Fluorescence; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D020512:Myopathy, Central Core / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D026361:Reactive Nitrogen Species / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D050778:NFATC Transcription Factors; D026361:Reactive Nitrogen Species; D002118:Calcium