Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia

Aleman, Monica R; Riehl, Joyce; Aldridge, Brian; Lecouteur, Richard A; Stott, Jeffrey L; Pessah, Isaac N.

doi:10.1002/mus.20084

Cited by 71 publications

(58 citation statements)

References 34 publications

(27 reference statements)

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“…Because MH syndromes are linked to mutations in the RyR1 channel in various vertebrates, as well as in humans (2,4,34,35), and because dantrolene binds to a specific site on RyR1 (36), previous studies have focused on the role of dantrolene in modulating RyR1 channel activity. Functional studies demonstrate only partial inhibition of Ca 2ϩ release from isolated SR membrane vesicles (11,12,15) and partial suppression of the elemental Ca 2ϩ spark signals in adult muscle fibers (16).…”

Section: Discussionmentioning

confidence: 99%

Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

Zhao

Weisleder

Han

et al. 2006

Journal of Biological Chemistry

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Dantrolene reduces the elevated myoplasmic Ca2؉ generated during malignant hyperthermia, a pharmacogenetic crisis triggered by volatile anesthetics. Although specific binding of dantrolene to the type 1 ryanodine receptor (RyR1), the Ca 2؉ release channel of skeletal muscle sarcoplasmic reticulum, has been demonstrated, there is little evidence for direct dantrolene inhibition of RyR1 channel function. Recent studies suggest storeoperated Ca 2؉ entry (SOCE) contributes to skeletal muscle function, but the effect of dantrolene on this pathway has not been examined. Here we show that azumolene, an equipotent dantrolene analog, inhibits a component of SOCE coupled to activation of RyR1 by caffeine and ryanodine, whereas the SOCE component induced by thapsigargin is not affected. Our data suggest that azumolene distinguishes between two mechanisms of cellular signaling to SOCE in skeletal muscle, one that is coupled to and one independent from RyR1. Malignant hyperthermia (MH)2 is a potentially fatal pharmacogenetic syndrome in which exposure to volatile anesthetics triggers uncontrolled elevation of myoplasmic Ca 2ϩ concentrations ([Ca 2ϩ ] i ), skeletal muscle hypercontracture, and hypermetabolism, resulting in a dramatic rise in body temperature (1, 2). Mutations in the type 1 ryanodine receptor (RyR1), the major Ca 2ϩ release channel in skeletal muscle, are linked to MH susceptibility in pigs in an autosomal recessive manner (3-5). In humans, MH is transmitted as an autosomal dominant trait with incomplete penetrance, and the more than 80 mutations in RyR1 that have been identified appear in only about 50% of affected families (6, 7). Muscle bundles from MH-susceptible patients are hypersensitive to RyR1 agonists, including caffeine, Ca 2ϩ , and halothane (8, 9), the latter a member of the class of volatile anesthetics that triggers MH. Thus, the loss of control of RyR1-mediated Ca 2ϩ release likely contributes to the elevation of [Ca 2ϩ ] i observed in MH patients. To date, the only effective treatment for MH is dantrolene sodium, a skeletal muscle relaxant, which suppresses the uncontrolled rise in myoplasmic Ca 2ϩ , presumably by targeting RyR1 and suppressing its Ca 2ϩ channel activity (10 -12). Azumolene sodium is a structurally similar, equipotent analog of dantrolene, with an ϳ30-fold greater water solubility (13,14).Whereas hyperactivity or leakiness of the RyR1 channel has been described as the primary physiological defect in MH-susceptible muscle, the molecular mechanism underlying the suppression of [ -sensitive fluorescence measurements of RyR1-dependent intracellular Ca 2ϩ transients and extracellular Ca 2ϩ entry via SOCE, we show that azumolene inhibits SOCE both in skeletal muscle fibers and in cultured cells expressing RyR1. Our results reveal two modes of SOCE activation. One mode is RyR1-dependent and can be inhibited by the action of azumolene; the other is RyR1-independent and is insensitive to azumolene. EXPERIMENTAL PROCEDURESCell Culture-C1148 cells, a Chinese hamster ovary (CHO) ce...

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Section: Discussionmentioning

confidence: 99%

Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

Zhao

Weisleder

Han

et al. 2006

Journal of Biological Chemistry

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“…CCD has a typical onset in infancy and presents with hypotonia and motor developmental delay. MH can manifest in the absence of any clinical diagnosis of CCD (1,(5)(6)(7)(8) and is one of the main causes of death due to anesthesia affecting humans, dogs, pigs, and horses (9,10). The fulminant MH episode is characterized by muscular rigidity, rhabdomyolysis, rapid increase in body temperature, and signs of generalized metabolic decompensation, which can rapidly lead to death of the patient if unabated (11).…”

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 99%

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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“…28 Severe degenerative myopathy in equids can be fatal. 17,19,25,31,32,35 Causes of muscular disorders in adult horses include nutritional myopathy, 5,17,31 infectious disease, 10,17,32,35,38 immune-mediated disorders, 17,25,26 toxic myopathy, 19,36 inherited myopathies, 5,29 endocrinopathy, 2 pasture-associated rhabdomyolysis, 15,44,45 malignant hyperthermia, 1 and exertional rhabdomyolysis. 4,6,23,39 Disorders affecting the peripheral nerves resulting in denervation atrophy of muscle also occur.…”

Section: Introductionmentioning

confidence: 99%

Pathologic Findings in Equine Muscle (Excluding Polysaccharide Storage): A Necropsy Study

Valentine

2008

J VET Diagn Invest

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Abstract. Gross and histopathologic evaluation of skeletal muscle was performed in 229 equids (217 horses, 8 ponies, 3 donkeys, and 1 mule) 1 year of age or older undergoing postmortem examination at Oregon State University in a 2.5-year period. Animals were evaluated for grossly evident muscle lesions, and muscle samples were fixed in formalin, processed routinely, and stained with hematoxylin and eosin (HE) and periodic acid-Schiff (PAS) for glycogen. Muscle lesions were detected in 149 animals (65%). Chronic myopathic change (excessive fiber size variation and internal nuclei) was evaluated in horses without polysaccharide storage myopathy and was the most common finding (36 animals; 15.7%). Chronic myopathic change was more common in older animals. Generalized muscle atrophy was present in 30 animals (13.1%). Myonecrosis was attributed to endotoxic injury (11 animals; 4.8%), bone fracture (8 animals; 3.5%), bacterial infection (5 animals; 2.2%), muscle rupture (3 animals; 1.3%), selenium deficiency (2 animals; 0.9%), and exertional rhabdomyolysis (1 horse; 0.4%); cause was not determined in 9 animals (3.9%). Intramyofiber protozoa were detected in 19 horses and ponies (8.3%). Denervation atrophy was detected in 14 animals (6.1%). Neoplasia involving muscle occurred in 3 animals (1.3%), injection site reactions were detected in 4 animals (1.7%), and focal lymphocytic infiltrates were found in 6 animals (2.6%). Other findings were ring fibers (2 horses; 0.9%), fiber splitting (2 horses; 0.9%), and fat infiltration (1 horse; 0.4%). Skeletal muscle lesions are common in equids examined at postmortem. Transverse sections stained with HE and PAS are invaluable when evaluating equine muscle.

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Association of a mutation in the ryanodine receptor 1 gene with equine malignant hyperthermia

Cited by 71 publications

References 34 publications

Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

Azumolene Inhibits a Component of Store-operated Calcium Entry Coupled to the Skeletal Muscle Ryanodine Receptor

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

Pathologic Findings in Equine Muscle (Excluding Polysaccharide Storage): A Necropsy Study

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