Calcitonin gene-related peptide restores disrupted excitation–contraction coupling in myotubes expressing central core disease mutations in RyR1

摘要

Non-technical summaryCentral core disease (CCD) is linked to mutations in the skeletal muscle ryanodine receptor (RyR1) gene that are believed to disrupt excitation–contraction (EC) coupling. EC coupling requires activation of RyR1s to release Ca²⁺ from the sarcoplasmic reticulum (SR). Subsequently, the SR Ca²⁺-ATPase (SERCA) returns cytoplasmic Ca²⁺ to intracellular stores. Here, we have investigated the effects of two CCD RyR1 mutants (I4897T and Y523S) in C2C12 myotubes. Both mutations significantly altered myogenesis and SERCA gene expression – inhibition by I4897T and stimulation by Y523S. They are thought to behave differently (‘Ca²⁺-impermeable’ and ‘leaky’, respectively), but disrupted EC coupling through the same mechanism (store depletion). It is conceivable that reduced SERCA expression by I4897T could explain this paradox. In both cases, the neuropeptide CGRP restored EC coupling by increasing SR Ca²⁺ content. We propose that CGRP and its corresponding signalling pathway exert beneficial effects in myotubes expressing CCD mutants.