Inositol Trisphosphate Receptor Mediated Ca2+ Signalling Stimulates Mitochondrial Function and Gene Expression in Core Myopathy Patients
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PROVIDER: PRJNA407299 | ENA |
REPOSITORIES: ENA
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Project description:Elevated inositol trisphosphate receptor (IP3R) levels have been previously reported in skeletal muscle myotubes derived from patients with ryanodine receptor 1 (RyR1) mutation related core myopathies. 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, 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 characterise whole genome and mitochondrial gene expression to assess if remodeling of skeletal muscle following loss of functional RyR1 mediates bioenergetic adaptation.
2020-09-15 | GSE103854 | GEO
Project description:Elevated inositol trisphosphate receptor (IP3R) levels have been previously reported in skeletal muscle myotubes derived from patients with ryanodine receptor 1 (RyR1) mutation related core myopathies. 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, 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 characterise whole genome and mitochondrial gene expression to assess if remodeling of skeletal muscle following loss of functional RyR1 mediates bioenergetic adaptation.
2020-09-15 | GSE103853 | GEO
Project description: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.
| S-EPMC6005141 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-09-15 | GSE103855 | GEO
Project description:Activated Foxp3+ regulatory T (Treg) cells differentiate into effector Treg (eTreg) cells to maintain peripheral immune homeostasis and tolerance. T cell receptor (TCR)-mediated induction and regulation of store-operated Ca2+ entry (SOCE) is essential for eTreg cell differentiation and function. However, SOCE regulation in Treg cells remains unclear. Here we show that inositol polyphosphate multikinase (IPMK), which generates inositol tetrakisphosphate and inositol pentakisphosphate, is a pivotal regulator of Treg cell differentiation downstream of TCR signaling. IPMK is highly expressed in TCR-stimulated Treg cells and promotes a TCR-induced Treg cell program. IPMK-deficient Treg cells display aberrant T cell activation and impaired differentiation into RORγt+ Treg cells, and tissue-resident Treg cells. Mechanistically, IPMK controls the generation of higher-order inositol phosphates, thereby promoting Ca2+ mobilization and Treg cell effector functions. Our findings identify IPMK as a critical regulator of TCR-mediated Ca2+ influx and highlight the importance of IPMK in Treg cell-mediated immune homeostasis.
2023-05-18 | GSE198960 | GEO
Project description:Differentiation and homeostasis of effector Treg cells are regulated by inositol polyphosphates modulating Ca2+ influx
| PRJNA817570 | ENA
Project description:Inositol Trisphosphate Receptor Mediated Ca2+ Signalling Stimulates Mitochondrial Function and Gene Expression in Core Myopathy Patients [Mouse arrays]
| PRJNA407300 | ENA
Project description:Inositol Trisphosphate Receptor Mediated Ca2+ Signalling Stimulates Mitochondrial Function and Gene Expression in Core Myopathy Patients [Human arrays]
| PRJNA407301 | ENA
Project description:The nephrotoxic ifosfamide-metabolite chloroacetaldehyde (CAA) induces changes in intracellular Ca2+-concentration of human RPTEC. This effect is due to a PKA-dependent inhibition of Na+/Ca2+ exchange (Benesic, A., Schwerdt, G. at. al. (2005) Kidney Int 68, 2029-2041). Thus, possible effects of CAA-exposure on cAMP and Ca2+ regulated genes as well the Ca2+/NFAT pathway were investigated by cDNA-microarray analysis. Both microarrays (cAMP/Ca2+ and Ca2+(NFAT) were performed twice. After 24 h CAA exposure a marked downregulation of c-fos and junB was observed in all arrays performed. In the cAMP/Ca2+-arrays downregulation of FOS, ADRB1, INHBA, CDK5, IL2, PLN, SRF, GCG, SGK, JUNB, BDNF, S100A6, CCNA1, MIF, HK2, SST and EGR2 by CAA was observed in two independent experiments. From the AP-1 family expression of junD and fosB were not altered. Overexpression by CAA of CREB and DDIT3 were only observed in one of two experiments. JUND, FOSB, FOSL1, CREM and CREBBP expression was not influenced in reproducible manner, as well as all members of the NFAT-family. In the Ca2+/NFAT-Arrays, PPP3CB, VAV3, NFATC1, IL8, IL6, FASLG, IL3, IFNB1, FOS, BCL2, EGR3, CD3G, HRAS, EP300, IL4, CALM3, RELA, EGR2, NPPB, IFNG, NFATC4, KPNA5, CAMK2BNFKB2 , VEGF, IL8RA, IL2,GATA4, MEF2A, PTPRC, ICOS, NFKBIE, CDKN1A, CSNK2B, ACTB, MEF2B and JUNB mRNA´s were repeatedly reduced by CAA exposure. The only gene with upregulation in both experiments was found to be IFN-alpha. Thus CAA exposure for 24 h leads to a downregulation of of the AP-1 members JUNB and FOS, whereas there is small positive effect on CREB mRNA. CAA reproducibly lowers the expression of IL-2, 3, 4, 6 and 8, whereas the levels of TNFalpha and TGFbeta1 and 3 mRNA were not altered. IFN-alpha mRNA levels were reproducibly increased (>2-fold). In conclusion, CAA seems to interact with Ca2+ and cAMP signalling pathways, with a strong impact on AP-1 proteins and inflammatory signalling. Keywords: stress response to toxic agent
2006-06-30 | GSE4956 | GEO
Project description:Cardiomyocyte Ca2+ is buffered by mitochondria via the mitochondrial calcium uniporter (MCU) complex. The MCU complex consists of pore-forming proteins including the mitochondrial calcium uniporter (MCU), and regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca2+ and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 affected the expression of MCU-associated genes. To further explore this, we knocked down Tug1 (Tug1 KD) in H9c2 rat cardiomyocytes using antisense LNA oligo. This led to increased MCU protein expression yet this did not enhance a marker of mitochondrial Ca2+ uptake. RNA-seq revealed that Tug1 KD increased Mcu and led to differential expression of genes and pathways related to Ca2+ regulation in the heart. To understand the effect of this on Ca2+ signalling, we measured phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to promote Mcu gene expression. Tug1 KD attenuated the increase in CAMKII and CREB phosphorylation in response to ionomycin, a Ca2+ ionophore. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD mediated increase in Mcu. Together, these data suggest that Tug1 modulates MCU expression via a mechanism that may involve CAMKII and CREB. The Tug1 mediated regulation of MCU on mitochondrial Ca2+ uptake, may have functional consequences for cellular Ca2+ handling which could have implications for cardiac disease.
2023-07-22 | GSE237787 | GEO