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

Abstract

Core myopathies are a group of childhood muscle disorders caused by mutations of the ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum. These mutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletal muscle myotubes derived from patients. However, the functional relevance and the relationship of IP3R mediated Ca2+ signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffuse multi-mini-cores, devoid of mitochondrial activity, which is a key pathological consequence of RyR1 mutations. Here we used muscle biopsies of central core and multi-minicore disease patients with RyR1 mutations, as well as cellular and in vivo mouse models of the disease to characterize global cellular and mitochondrial Ca2+ signalling, mitochondrial function and gene expression associated with the disease. We show that RyR1 mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear and mitochondrial Ca2+ signals and increased mitochondrial activity. Moreover, western blot and microarray analysis indicated enhanced mitochondrial biogenesis at the transcriptional and protein levels and was reflected in increased mitochondrial DNA content. The phenotype was recapitulated by RYR1 silencing in mouse cellular myotube models. Altogether, these data indicate that remodelling of skeletal muscle Ca2+ signalling following loss of functional RyR1 mediates bioenergetic adaptation.

Correlation of phenotype with genotype and protein structure in RYR1-related disorders

“…In recent years, functional studies have shed light on the mechanistic consequence of specific RYR1 variants, although these constitute < 10% of almost 700 known RYR1 variants [28, 40]. Variants associated with RYR1 -RD have been identified throughout the RYR1 coding and intronic regions and can lead to chronic SR Ca 2+ leak, decreased RyR1 protein levels, and RyR1 hyper- or hypo-sensitivity to agonists such as 4-chloro- m -cresol and caffeine [71, 72, 83, 95]. …”

Differential Effects of 25-Hydroxyvitamin D3 versus 1α 25-Dihydroxyvitamin D3 on Adipose Tissue Browning in CKD-Associated Cachexia

“…The functional significance of these differentially expressed muscle genes were summarized in Table 6 . Decreased muscle expression of Csrp3, Fhl1, Myl2 and Tnnc1 and increased expression of Itpr1stimulate muscle regeneration and improve muscle function [ 26 , 27 , 30 , 31 , 32 , 33 , 34 , 38 ]. Decreased expression of Cyfip2 improves remodeling of extracellular matrix and leads to accelerated muscle regeneration [ 28 , 29 ].…”

“…Moreover, repletion of 25(OH)D3 in CKD mice significantly decreased expression of pro-fibrotic genes (PAI-1, IL-1α, IL-1β, Agt, Ctgf, Akt1 and Smad3) and increased the expression of anti-fibrotic genes (Bmp7 and IL-13Rα2) the repletion of 1,25(OH)2D3. Itpr1 impairs glucose transport in muscle [37] associated with decreased muscle regeneration and mitochondrial dysfunction in myopathy patients [38]…”

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

“…This evidence confirms that only little is known about this channel, particularly in cardiac and vascular homeostasis or metabolism. The recent findings of the physical link between ER and mitochondria, mediated by a protein complex including ITPR, suggest a potential role of the receptor in the regulation of calcium-dependent mitochondrial metabolism [118][119][120][121][122][123][124][125][126][127][128][129][130]. The ability of ITPR to indirectly regulate mitochondrial energetic metabolism could have a significant impact on the health and homeostasis of the tissues strongly dependent on mitochondrial energetic production, such as cardiac and skeletal muscle.…”