ArticleBritish journal of anaesthesia2026
Mitochondrial bioenergetics and intracellular calcium concentration in primary myotubes from mouse models of malignant hyperthermia.
Article in British journal of anaesthesia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMalignant hyperthermia (MH) is a potentially fatal hypermetabolic reaction to general anaesthesia arising from skeletal muscle calcium dysregulation. Previous studies of resting cells support an association between MH susceptibility, mitochondrial dysfunction, and defects in fatty acid metabolism, which are understood to be downstream consequences of calcium dysregulation. We hypothesised that in mouse models of MH susceptibility, genotypes associated with higher cytoplasmic calcium concentrations would have a proportionally higher mitochondrial oxygen consumption rate (OCR). We aimed to test this and validate a cell-based assay system.
methodsA high-throughput mitochondrial assay was used to compare OCR between myotubes derived from control and three different genotypes of mice containing ryanodine receptor 1 variants (p.G2435R heterozygous and homozygous, p.T4826I heterozygous) that confer susceptibility to MH.
resultsBaseline comparisons showed effects of genotype on OCR (P<0.0001), with Ryr1 p.G2435R homozygous myotubes having the highest basal normalised OCR (P<0.01). Ryr1 p.G2435R homozygous required a greater proportion of basal respiration to produce adenosine triphosphate (ATP), and had a higher proton leak and greater non-mitochondrial OCR (P<0.01). All genotypes except Ryr1 p.G2435R homozygous were primarily dependent on the glucose/pyruvate pathway for achieving their maximal OCR upon uncoupling.
conclusionsThe high-throughput method used produced data consistent with findings in skeletal muscle fibres, but with a greater sensitivity to genotypic effects. This validates the use of cultured myotubes in lieu of muscle fibres in studying mitochondrial bioenergetics in models of MH, and indicates that mitochondrial bioenergetics are not directly affected by myoplasmic calcium concentrations in young MH mice.
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