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

Prolonged depolarisation 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 TIRF microscopy in human skeletal muscle myotubes harbouring mutation in the RYR1 gene linked to malignant hyperthermia and central core disease. We found that excitation-coupled calcium entry is strongly enhanced in cells from patients with central core disease compared to individuals with malignant hyperthermia and controls. Furthermore, excitation-coupled calcium entry induces generation of reactive nitrogen species and causes the nuclear translocation of NFATc1, which in turn may be responsible for increased of IL6 released by myotubes from patients with central core disease.