Malignant hyperthermia: an investigation of five patients

Britt, Beverley A.; Kalow, W.; Gordon, A.; Humphrey, J. A. C.; Rewcastle, N. B.

doi:10.1007/bf03026208

Cited by 97 publications

(32 citation statements)

References 147 publications

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“…However, other laboratories were not able to show that halothane uncoupling of oxidative phosphorylation could explain the rapid rise in body temperature seen in MH (34). Furthermore, no difference was detected in isolated mitochondria from control and MH patients during halothane exposures (35,36). Most of the metabolic symptoms associated with fulminant MH episodes can be described as the result of an acute mitochondrial dysfunction secondary to abrupt loss of sarcoplasmic reticulum (SR) Ca 2ϩ regulation.…”

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 93%

Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice

Giulivi

Ross-Inta

Omanska-Klusek

et al. 2011

Journal of Biological Chemistry

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Malignant hyperthermia (MH) and central core disease in humans have been associated with mutations in the skeletal ryanodine receptor (RyR1). Heterozygous mice expressing the human MH/central core disease RyR1 R163C mutation exhibit MH when exposed to halothane or heat stress. Considering that many MH symptoms resemble those that could ensue from a mitochondrial dysfunction (e.g. metabolic acidosis and hyperthermia) and that MH-susceptible mice or humans have a higher than normal cytoplasmic Ca 2؉ concentration at rest, we evaluated the role of mitochondria in skeletal muscle from R163C compared with wild type mice under basal (untriggered) conditions. R163C skeletal muscle exhibited a significant increase in matrix Ca 2؉ , increased reactive oxygen species production, lower expression of mitochondrial proteins, and higher mtDNA copy number. These changes, in conjunction with lower myoglobin and glycogen contents, Myh4 and GAPDH transcript levels, GAPDH activity, and lower glucose utilization suggested a switch to a compromised bioenergetic state characterized by both low oxidative phosphorylation and glycolysis. The shift in bioenergetic state was accompanied by a dysregulation of Ca 2؉ -responsive signaling pathways regulated by calcineurin and ERK1/2. Chronically elevated resting Ca 2؉ in R163C skeletal muscle elicited the maintenance of a fast-twitch fiber program and the development of insulin resistance-like phenotype as part of a metabolic adaptation to the R163C RyR1 mutation.

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Section: Malignant Hyperthermia (Mh)mentioning

confidence: 93%

Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice

Giulivi

Ross-Inta

Omanska-Klusek

et al. 2011

Journal of Biological Chemistry

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“…It is indeed remarkable that all proteins for which specific interactions with halothane have been demonstrated [19] process functionally important binding sites for purine nucleotides; examples are microtubules [20], glutamate dehydrogenase [4], calcium-transport ATPases [5,21,22] and phosphoryl transferases [10,23]. This aspect could facilitate the search for the principal halothane receptors in normal anaesthesia.…”

Section: Resultsmentioning

confidence: 99%

“…In the absence of sufficient adenylate kinase activity, the ratio of [ATP] : [ADP] : [AMP] in the cell cannot be regulated any longer [17] which is assumed to precipitate the observed sequence of metabolic derangements in malignant hyperthermia. It should be stressed that this fatal syndrome might not be associated with adenylate kinase deficiency in all cases; other aetiologies have been proposed as well [21][22][23].…”

Section: Resultsmentioning

confidence: 99%

Halothane binds in the adenine‐specific niche of crystalline adenylate kinase

et al. 1977

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“…Muscle of patients suffering from malignant hyperpyrexia has been shown to react abnormally in vitro when exposed to halothane (Ellis et al, 1971;Moulds and Denborough, 1972) and to caffeine (Kalow et al, 1970), and the use of these abnormal reactions as a more accurate predictive test for malignant hyperpyrexia has been suggested (Ellis et al, 1972;Britt et al, 1973). The present investigation was done to try to learn more about the biochemical basis of the myopathy and to try to find a definitive test for identifying those at risk of developing malignant hyperpyrexia.…”

Section: Introductionmentioning

confidence: 99%