Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage
dc.contributor.author | Yuen, Benjamin | |
dc.contributor.author | Boncompagni, Simona | |
dc.contributor.author | Feng, Wei | |
dc.contributor.author | Yang, Tianzhong | |
dc.contributor.author | Lopez, Jose R | |
dc.contributor.author | Matthaei, Klaus | |
dc.contributor.author | Goth, Samuel | |
dc.contributor.author | Protasi, Feliciano | |
dc.contributor.author | Franzini-Armstrong, Clara | |
dc.contributor.author | Allen, Paul D | |
dc.contributor.author | Pessah, Issac N | |
dc.date.accessioned | 2015-12-10T22:28:23Z | |
dc.date.issued | 2012 | |
dc.date.updated | 2016-02-24T10:27:47Z | |
dc.description.abstract | Mutation T4825I in the type 1 ryanodine receptor (RYR1T4825I/+) confers human malignant hyperthermia susceptibility (MHS). We report a knock-in mouse line that expresses the isogenetic mutation T4826I. Heterozygous RYR1T4826I/+ (Het) or homozygous RYR1T4826I/T4826I (Hom) mice are fully viable under typical rearing conditions but exhibit genotypeand sex-dependent susceptibility to environmental conditions that trigger MH. Hom mice maintain higher core temperatures than WT in the home cage, have chronically elevated myoplasmic[Ca2+]rest, and present muscle damage in soleus with a strong sex bias. Mice subjected to heat stress in an enclosed 37°C chamber fail to trigger MH regardless of genotype, whereas heat stress at 41°C invariably triggers fulminant MH in Hom, but not Het, mice within 20 min. WT and Het female mice fail to maintain euthermic body temperature when placed atop a bed whose surface is 37°C during halothane anesthesia (1.75%) and have no hyperthermic response, whereas 100% Hom mice of either sex and 17% of the Het males develop fulminant MH. WT mice placed on a 41°C bed maintain body temperature while being administered halothane, and 40% of the Het females and 100% of the Het males develop fulminant MH within 40 min. Myopathic alterations in soleus were apparent by 12 mo, including abnormally distributed and enlarged mitochondria, deeply infolded sarcolemma, and frequent Z-line streaming regions, which were more severe in males. These data demonstrate that an MHS mutation within the S4-S5 cytoplasmic linker of RYR1 confers genotype- and sex-dependent susceptibility to pharmacological and environmental stressors that trigger fulminant MH and promote myopathy. | |
dc.identifier.issn | 0892-6638 | |
dc.identifier.uri | http://hdl.handle.net/1885/54452 | |
dc.publisher | Federation of American Societies for Experimental Biology | |
dc.source | FASEB Journal | |
dc.subject | Keywords: calcium ion; halothane; isoleucine; ryanodine receptor 1; tyrosine; amino acid substitution; anesthesia induction; animal cell; animal experiment; animal tissue; article; body temperature; cage; controlled study; core temperature; cytoplasm; disease sever Anesthesia; Ca 2+ regulation; Heat stress; Ryanodine receptor mutation | |
dc.title | Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage | |
dc.type | Journal article | |
local.bibliographicCitation.issue | 3 | |
local.bibliographicCitation.lastpage | 1322 | |
local.bibliographicCitation.startpage | 1311 | |
local.contributor.affiliation | Yuen, Benjamin, University of California | |
local.contributor.affiliation | Boncompagni, Simona, University of California | |
local.contributor.affiliation | Feng, Wei, Univerisity of California | |
local.contributor.affiliation | Yang, Tianzhong, Department of Anesthesia | |
local.contributor.affiliation | Lopez, Jose R, University of California / Brigham Women's Hospital | |
local.contributor.affiliation | Matthaei, Klaus, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Goth, Samuel, University of California | |
local.contributor.affiliation | Protasi, Feliciano, University Gabriele d'Annunzio of Chieti-Pescara | |
local.contributor.affiliation | Franzini-Armstrong, Clara, University of Pennsylvania | |
local.contributor.affiliation | Allen, Paul D, Brigham and Women's Hospital | |
local.contributor.affiliation | Pessah, Issac N, University of California | |
local.contributor.authoremail | u8200697@anu.edu.au | |
local.contributor.authoruid | Matthaei, Klaus, u8200697 | |
local.description.embargo | 2037-12-31 | |
local.description.notes | Imported from ARIES | |
local.identifier.absfor | 060110 - Receptors and Membrane Biology | |
local.identifier.absseo | 970111 - Expanding Knowledge in the Medical and Health Sciences | |
local.identifier.ariespublication | u4020362xPUB301 | |
local.identifier.citationvolume | 26 | |
local.identifier.doi | 10.1096/fj.11-197582 | |
local.identifier.scopusID | 2-s2.0-84857771245 | |
local.identifier.thomsonID | 000300949300033 | |
local.identifier.uidSubmittedBy | u4020362 | |
local.type.status | Published Version |
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