Chang 2018 Biophys J

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Mitochondrial dysfunction in malignant hyperthermia susceptible skeletal muscle.

Link: Open Access

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

Event: Biophys J

Malignant Hyperthermia (MH) is a pharmacogenetic condition primarily caused by mutations in RYR1 and CACNA1S which lead to dysregulation in intracellular calcium handling. Individuals with these mutations suffer from potentially fatal, hypermetabolic reactions when exposed to volatile anaesthetics and/or depolarizing muscle relaxants. Several studies have suggested a possible link between MH susceptibility and mitochondrial dysfunction. Here we investigated skeletal muscle mitochondrial function by measuring oxygen consumption rates (OCR) in six respiratory states through high-resolution respirometry using the Oroboros Oxygraph-2k analyser. Human skeletal muscle biopsies from MH susceptible (MHS) and MH normal (MHN) individuals confirmed by IVCT, and skeletal muscle from wild type and MHS RYR1G2435R knock-in mice were permeabilized and subjected to a substrate-inhibitor titration (SUIT) protocol to analyze different stages of oxidative phosphorylation (OXPHOS).

In comparison to MHN controls, human MHS skeletal muscle showed a significantly reduced OCR in two different respiratory states, both involving complex II (succinate dehydrogenase) of the electron transport chain. In contrast, when compared to wild type mice, MHS RYR1G2435R knock-in murine mitochondria showed evidence of defect in complex I (NADH dehydrogenase), in addition to an overall reduction in the maximum capacity of the electron transport system (ETS). We conclude that based on these data there is clear evidence of reduced OXPHOS capacity in MHS human and MHS RYR1G2435R murine mitochondria using permeabilized skeletal muscle. The significantly reduced OCR seen in both datasets, provide additional evidence towards a connection between MH susceptibility and mitochondrial dysfunction, prompting the need for further research in this area.


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


Labels: MiParea: Respiration, Genetic knockout;overexpression 

Stress:Temperature  Organism: Human, Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 


Coupling state: OXPHOS  Pathway: N, S  HRR: Oxygraph-2k 

2018-03