Lopez, JR, Kaura, V orcid.org/0000-0002-8984-9662, Diggle, CP orcid.org/0000-0001-6861-359X et al. (2 more authors) (2018) Malignant hyperthermia, environmental heat stress, and intracellular calcium dysregulation in a mouse model expressing the p.G2435R variant of RYR1. British Journal of Anaesthesia, 121 (4). pp. 953-961. ISSN 0007-0912
Abstract
Background:
The human p.G2434R variant of the RYR1 gene is most frequently associated with malignant hyperthermia (MH) in the UK. We report the phenotype of a knock-in mouse that expresses the RYR1 variant p.G2435R, which is isogenetic with the human variant.
Methods:
We observed the general phenotype; determined the sensitivity of myotubes to caffeine-, KCl, and halothane-induced Ca2+ release; determined the in vivo response to halothane or increased ambient temperature; and determined the in vivo myoplasmic intracellular Ca2+ concentration in skeletal muscle before and during exposure to volatile anaesthetics.
Results:
RYR1 pG2435R/MH normal (MHS-Heterozygous[Het]) or RYR1 pG2435R/pG2435R (MHS-Homozygous[Hom]) mice were fully viable under typical rearing conditions, although some male MHS-Hom mice died spontaneously. The normalised half-maximal effective concentration (95% confidence interval) for intracellular Ca2+ release in myotubes in response to KCl [MH normal, MHN, 21.4 (19.8–23.1) mM; MHS-Het 16.2 (15.2–17.2) mM; MHS-Hom 11.2 (10.2–12.2) mM] and caffeine (MHN, 5.7 (5–6.3) mM; MHS-Het 4.5 (3.9–5.0) mM; MHS-Hom 1.77 (1.5–2.1) mM] exhibited a gene dose-dependent decrease, and there was a gene dose-dependent increase in halothane sensitivity. Intact animals show a gene dose-dependent susceptibility to MH with volatile anaesthetics or to heat stroke. RYR1 p.G2435R mice had elevated skeletal muscle intracellular resting [Ca2+]i, (values are expressed as mean (SD)) (MHN 123 (3) nM; MHS-Het 156 (16) nM; MHS-Hom 265 (32) nM; P<0.001) and [Na+]i (MHN 8 (0.1) mM; MHS-Het 10 (1) mM; MHS-Hom 14 (0.7) mM; P<0.001) that was further increased by exposure to volatile anaesthetics.
Conclusions:
RYR1 pG2435R mice demonstrated gene dose-dependent in vitro and in vivo responses to pharmacological and environmental stressors that parallel those seen in patients with the human RYR1 variant p.G2434R.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. This is an author produced version of a paper published in British Journal of Anaesthesia. Uploaded in accordance with the publisher's self-archiving policyCrown Copyright © 2019 Published by Elsevier B.V. This is an author produced version of a paper published in Journal of Hydrology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | gene knock-in techniques; malignant hyperthermia; mouse; ryanodine receptor 1 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Genetics (LIBACS) (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Trans Anaesthetics & Surgical Sciences (Leeds) |
Funding Information: | Funder Grant number National Institute of Health - DELETED Not Known National Institute of Health - NIH (PHS) 7R01AR068897-02 |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Sep 2018 12:01 |
Last Modified: | 10 Aug 2019 00:42 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.bja.2018.07.008 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:135211 |
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