Chang, L, Daly, C, Miller, DM et al. (4 more authors) (2019) Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals. British Journal of Anaesthesia, 122 (5). pp. 613-621. ISSN 0007-0912
Abstract
Background: Individuals 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.
Methods: We 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).
Results: Baseline 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.
Conclusions: We present evidence of mitochondrial dysfunction in human MHS skeletal muscle both at baseline and after halothane exposure.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. This is an author produced version of a paper published in British Journal of Anaesthesia. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | electron transport chain; malignant hyperthermia; mitochondria; oxidative phosphorylation; skeletal muscle; volatile anaesthetic |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Trans Anaesthetics & Surgical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 02 Apr 2019 12:34 |
Last Modified: | 20 Mar 2020 01:38 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.bja.2019.02.010 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:144300 |