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Enhanced excitation-coupled Ca2+ entry induces nuclear translocation of NFAT and contributes to IL-6 release from myotubes from patients with central core disease

Lookup NU author(s): Dr Anna Sarkozy, Emerita Professor Katherine Bushby

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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.

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Author(s): Treves S, Vukcevic M, Jeannet PY, Levano S, Girard T, Urwyler A, Fischer D, Voit T, Jungbluth H, Lillis S, Muntoni F, Quinlivan R, Sarkozy A, Bushby K, Zorzato F

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2011

Volume: 20

Issue: 3

Pages: 589-600

Print publication date: 18/11/2010

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/hmg/ddq506

DOI: 10.1093/hmg/ddq506

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