Inositol trisphosphate receptor-mediated Ca2+ signalling stimulates mitochondrial function and gene expression in core myopathy patients

Abstract

Coremyopathies are a group of childhoodmuscle disorders caused bymutations of the ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum. Thesemutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletalmusclemyotubes derived from patients. However, the functional relevance and the relationship of IP3Rmediated Ca2+ signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffusemulti-mini-cores, devoid ofmitochondrial activity, which is a key pathological consequence of RyR1mutations. Here we usedmuscle biopsies of central core andmultiminicore disease patientswith RyR1mutations, aswell as cellular and in vivomousemodels of the disease to characterize global cellular andmitochondrial Ca2+ signalling,mitochondrial function and gene expression associated with the disease. We show that RyR1mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear andmitochondrial Ca2+ signals and increasedmitochondrial activity. Moreover, western blot andmicroarray analysis indicated enhancedmitochondrial biogenesis at the transcriptional and protein levels and was reflected in increasedmitochondrial DNA content. The phenotype was recapitulated by RYR1 silencing inmouse cellularmyotubemodels. Altogether, these data indicate that remodelling of skeletalmuscle Ca2+ signalling following loss of functional RyR1mediates bioenergetic adaptation.