Chang 2018 Br J Anaesth

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Oxygen metabolism in malignant hyperthermia susceptible skeletal muscle and the effects of static halothane exposure.

Link: [1]

Chang L, Baines KN, Allen PD, Hopkins PM, Shaw MA, Boyle JP (2018)

Event: Br J Anaesth

Individuals susceptible to Malignant Hyperthermia (MH) may undergo potentially fatal hypermetabolic responses following exposure to volatile anaesthetics and/or depolarizing muscle relaxants. A link between MH susceptibility and potential impairment in oxygen metabolism suggests the possibility of chronic mitochondrial dysfunction. Here we evaluated mitochondrial function in skeletal muscle biopsies after in vitro contracture test (IVCT) from MH susceptible (MHS) and nonsusceptible (MHN) individuals, by measuring oxygen consumption rate as flux control ratios (FCR) using the Oroboros Oxygraph-2k analyzer. Biopsy samples were permeabilized with saponin and subjected to a protocol adapted for high-resolution respirometry[1,2]. Samples taken before and after static halothane IVCT were assessed for differences in FCR for each mitochondrial complex state. Compared with MHN samples, human MHS samples showed significant activity reduction in complex II, likely the result of mitochondrial damage caused by chronically elevated resting calcium previously reported in MHS muscle[3]. Halothane exposure during IVCT significantly increased FCR in complex II and the max electron transport system (ETS) state of MHS muscle only (Fig. 6). Based on these data we conclude that there is clear evidence of altered oxygen metabolism in MHS skeletal muscle mitochondria, which we hypothesize to be a result of chronic mutant RYR1 induced increases in cytoplasmic Ca2+, supporting a connection between MH susceptibility and mitochondrial dysfunction.


Bioblast editor: Kandolf G O2k-Network Lab: UK Leeds Peers C


Labels: MiParea: Respiration, Pharmacology;toxicology 

Stress:Temperature 

Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 



HRR: Oxygraph-2k 


References

  1. Kuznetsov AV, Veksler V, Gellerich FN et al. (2008) Nat Protoc 3:965e976.
  2. Pesta D, Gnaiger E (2012) Methods Mol Biol 810:25e58.
  3. Giulivi C, Ross-Inta C, Omanska-Klusek A et al. (2011) J Biol Chem 286:99e113.