Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage

Benjamin Yuen, Simona Boncompagni, Wei Feng, Tianzhong Yang, Jose R. Lopez, Klaus I. Matthaei, Samuel R. Goth, Feliciano Protasi, Clara Franzini-Armstrong, Paul D. Allen, Isaac N. Pessah*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    62 Citations (Scopus)

    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 RYR1 T4826I/+ (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.

    Original languageEnglish
    Pages (from-to)1311-1322
    Number of pages12
    JournalFASEB Journal
    Volume26
    Issue number3
    DOIs
    Publication statusPublished - Mar 2012

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