• Br J Anaesth · May 2019

    Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals.

    • Leon Chang, Catherine Daly, Dorota M Miller, Paul D Allen, John P Boyle, Philip M Hopkins, and Marie-Anne Shaw.
    • Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK.
    • Br J Anaesth. 2019 May 1; 122 (5): 613-621.

    BackgroundIndividuals genetically susceptible to malignant hyperthermia (MH) exhibit hypermetabolic reactions when exposed to volatile anaesthetics. Mitochondrial dysfunction has previously been associated with the MH-susceptible (MHS) phenotype in animal models, but evidence of this in human MH is limited.MethodsWe used high resolution respirometry to compare oxygen consumption rates (oxygen flux) between permeabilised human MHS and MH-negative (MHN) skeletal muscle fibres with or without prior exposure to halothane. A substrate-uncoupler-inhibitor titration protocol was used to measure the following components of the electron transport chain under conditions of oxidative phosphorylation (OXPHOS) or after uncoupling the electron transport system (ETS): complex I (CI), complex II (CII), CI+CII and, as a measure of mitochondrial mass, complex IV (CIV).ResultsBaseline comparisons without halothane exposure showed significantly increased mitochondrial mass (CIV, P=0.021) but lower flux control ratios in CI+CII(OXPHOS) and CII(ETS) of MHS mitochondria compared with MHN (P=0.033 and 0.005, respectively) showing that human MHS mitochondria have a functional deficiency. Exposure to halothane triggered a hypermetabolic response in MHS mitochondria, significantly increasing mass-specific oxygen flux in CI(OXPHOS), CI+CII(OXPHOS), CI+CII(ETS), and CII(ETS) (P=0.001-0.012), while the rates in MHN samples were unaltered by halothane exposure.ConclusionsWe present evidence of mitochondrial dysfunction in human MHS skeletal muscle both at baseline and after halothane exposure.Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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