Mutations in the skeletal muscle ryanodine receptor gene (RYR1) can cause susceptibility to malignant hyperthermia (MH), a potentially lethal genetic condition triggered by volatile anesthetics. MH is associated with hypermetabolism which has directed research interest into oxidative phosphorylation (OXPHOS) and muscle bioenergetics. The most common cause of MH in the United Kingdom is the c.7300G>A RYR1 variant, which is present in ~16% of MH families. Our study focuses on the MH susceptible G2435R-RYR1 knock-in mouse model, which is the murine equivalent of the human c.7300G>A genotype. Using a combination of transcriptomics, protein expression and functional analysis, we investigated adult muscle fiber bioenergetics in this mouse model. RNA sequencing data showed reduced expression of genes associated with mitochondria and fatty acid oxidation in RYR1 mutants when compared to wild-type (WT) controls. Mitochondrial function was assessed by measuring oxygen consumption rates in permeabilized muscle fibers. Comparisons between WT and homozygous G2435R-RYR1 mitochondria showed a significant increase in complex I-facilitated OXPHOS in mutant muscle. Furthermore, we observed a gene-dose specific increase in reactive oxygen species production in G2435R-RYR1 muscle fibers. Collectively these findings provide evidence of metabolic defects in G2435R-RYR1 knock-in mouse muscle under basal conditions. Differences in metabolic profile could be the result of differential gene expression in metabolic pathways, in conjunction with mitochondrial damage accumulated from chronic exposure to increased oxidative stress.
Maternal temperature increased (0.2±0.1 C;.p¼0.003) only after 4h epidural analgesia, with ERMF subsequently recorded in 7/38 women (18.4%). Bupivacaine did not alter OXPHOS in NRLP3-/-cells, or reverse~75% suppression of OXPHOS/ glycolysis on exposure to labour plasma (n¼5), suggesting bupivacaine is not injurious to mitochondria/pro-inflammatory. Caspase-1 activity was measurable in 14% fewer MNF cells (95%CI:8-20); n¼9) obtained from labouring women after 4h incubation with bupivacaine, which also increased intracellular IL-1ra by 25±9% in MNF (p<0.001; n¼8). Plasma IL-1ra increased by 38±5% over 4h in women without an epidural (n¼6), but not after epidural analgesia (n¼17). Bupivacaine reduces caspase-1 activity in circulating leukocytes and IL-1ra secretion. Reduced circulating levels of anti-pyrogenic IL1-ra, rather than pro-inflammatory inflammation, may promote ERMF
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