Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals.
Br J Anaesth
; 122(5): 613-621, 2019 May.
Article
em En
| MEDLINE
| ID: mdl-30916033
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Músculo Esquelético
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Hipertermia Maligna
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Mitocôndrias Musculares
Limite:
Adolescent
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Adult
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Aged
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Child
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Br J Anaesth
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido