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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

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

Published In FASEB J, (2012 Mar)

Abstract: Mutation T4825I in the type 1 ryanodine receptor (RYR1(T4825I/+)) 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 RYR1(T4826I/T4826I) (Hom) mice are fully viable under typical rearing conditions but exhibit genotype- and 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[Ca(2+)](rest), and present muscle damage in soleus with a strong sex bias. Mice subjected to heat stress in an enclosed 37ýýC chamber fail to trigger MH regardless of genotype, whereas heat stress at 41ýýC 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 37ýýC 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 41ýýC 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.

PubMed ID: 22131268 Exiting the NIEHS site

MeSH Terms: Amino Acid Substitution; Anesthetics, Inhalation/administration & dosage; Animals; Body Temperature/drug effects; Body Temperature/genetics; Body Temperature/physiology; Female; Gene Expression; Genetic Predisposition to Disease/genetics*; Genotype; Halothane/administration & dosage; Hot Temperature; Humans; Male; Malignant Hyperthermia/genetics*; Membrane Potentials; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Muscle Fibers, Skeletal/metabolism; Muscle Fibers, Skeletal/physiology; Muscle, Skeletal/metabolism*; Muscle, Skeletal/pathology; Mutation*; Ryanodine Receptor Calcium Release Channel/genetics*; Ryanodine Receptor Calcium Release Channel/physiology; Sarcolemma/metabolism; Sarcolemma/ultrastructure; Sex Factors

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