Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia‐susceptible individuals

  title={Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia‐susceptible individuals},
  author={Leon Chang and Catherine Daly and Dorota M Miller and Paul D. Allen and John P Boyle and Philip M Hopkins and Marie A. Shaw},
  journal={BJA: British Journal of Anaesthesia},

Figures and Tables from this paper

Untargeted metabolomics profiling of skeletal muscle samples from malignant hyperthermia susceptible patients
This metabolomics study indicates a shift from utilization of carbohydrates towards lipids for energy production in MH-susceptible individuals, which may result in inefficiency of beta-oxidation, and increased muscle protein turnover, oxidative stress, and/or lysophosphatidylcholine levels.
Bioenergetic defects in muscle fibers of RYR1 mutant knock-in mice associated with malignant hyperthermia
Findings provide evidence of metabolic defects in G2435R-RYR1 knock-in mouse muscle under basal conditions, which could be the result of differential gene expression in metabolic pathways, in conjunction with mitochondrial damage accumulated from chronic exposure to increased oxidative stress.
Unravelling the unseen metabolic changes in patients with malignant hyperthermia
This present study contains the most comprehensive evidence of defective fatty acid metabolism in MH, and supports a connection between mitochondrial function and MH development.
Defining molecular mechanisms of calcium dysregulation in malignant hyperthermia susceptibility
Next generation sequencing of fifty genes associated with Ca2+ handling, performed by the Leeds MH Unit, identified two calsequestrin-1 (CASQ1) variants, p.I138T and p.F186Y, in an MH individual and an exertional heat illness (EHI) individual, respectively, which suggest that the highly conserved CASQ1 p.
Sex‐specific alterations in whole body energetics and voluntary activity in heterozygous R163C malignant hyperthermia‐susceptible mice
It is shown that the R163C mutations alters energetics even at temperatures that do not typically induce MH, and voluntary wheel running in mice is decreased.
Molecular Modification of Transient Receptor Potential Canonical 6 Channels Modulates Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia.
Findings that genetically suppressing the function of TRPC6 can partially ameliorate muscle cation dyshomeostasis and the response to halothane in a mouse model relevant to malignant hyperthermia support previous findings that TRPC channels play an important role in causing intracellular calcium and sodium dys homeostasis associated with RYR1 variants.


Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice*
R163C skeletal muscle exhibited a significant increase in matrix Ca2+, increased reactive oxygen species production, lower expression of mitochondrial proteins, and higher mtDNA copy number, which suggested a switch to a compromised bioenergetic state characterized by both low oxidative phosphorylation and glycolysis.
Skeletal Muscle Metabolic Dysfunction in Patients With Malignant Hyperthermia Susceptibility
Results of this exploratory study suggest that MH-positive patients have impaired aerobic metabolism compared to healthy individuals, which could explain the exercise intolerance exhibited in MH-susceptible patient population.
High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle.
Intrinsic uncoupling and dyscoupling are evaluated as the flux control ratio between nonphosphorylating LEAK respiration and ETS capacity and if OXPHOS capacity is less than ETScapacity, the phosphorylation system contributes to flux control.
Porcine Malignant Hyperthermia:: Effects of Halothane on Mitochondrial Respiration and Calcium Accumulation
The results suggest a mitochondrial membrane component for the defect of porcine malignant hyperthermia, since calcium is normally associated with the formation of the phospholiptd lattice of this membrane.
Skeletal Muscle Mitochondria in Porcine Malignant Hyperthermia: Respiratory Activity, Calcium Functions, and Depression by Halothane
The authors conclude that the reduced respiratory and calcium binding activities in mitochondria from susceptible swine support the diagnosis of a myopathy, but that these do not account for the functional and biochemical derangement observed in clinical malignant hyperthermia.
Mitochondrial Complex I Function Affects Halothane Sensitivity in Caenorhabditis elegans
Rates of oxidative phosphorylation and changes in adenosine triphosphate concentrations by themselves do not control anesthetic-induced immobility of wild-type C. elegans, but they may contribute to the increased sensitivity to volatile anesthetics of the gas-1 mutant.
Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers
This mechanism of mitochondrial respiratory control in the hypothermic mammalian heart is comparable to the pattern in ectotherm species, pointing towards NADH-linked mt-matrix dehydrogenases and the phosphorylation system rather than electron transfer complexes as the primary drivers of thermal sensitivity at low temperature.
Skeletal Muscle Microalterations in Patients Carrying Malignant Hyperthermia-Related Mutations of the e-c Coupling Machinery
Although a specific ultrastructural signature for MH mutants cannot be demonstrated, an MH related pattern of minor alterations does exist, including the tendency for micro damage to the contractile apparatus and a higher than normal level of mitochondrial abnormalities.