title: Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage.
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 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.
authors: Department of Veterinary Molecular Biosciences, University of California, Davis, California, USA.
authors: Benjamin
authors: B
authors: Yuen
authors: Simona
authors: S
authors: Boncompagni
authors: Wei
authors: W
authors: Feng
authors: Tianzhong
authors: T
authors: Yang
authors: Jose R
authors: JR
authors: Lopez
authors: Klaus I
authors: KI
authors: Matthaei
authors: Samuel R
authors: SR
authors: Goth
authors: Feliciano
authors: F
authors: Protasi
authors: Clara
authors: C
authors: Franzini-Armstrong
authors: Paul D
authors: PD
authors: Allen
authors: Isaac N
authors: IN
authors: Pessah
mesh_terms: D019943:Amino Acid Substitution; D018685:Anesthetics, Inhalation / Q000008:administration & dosage; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006221:Halothane / Q000008:administration & dosage; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics*; D008564:Membrane Potentials; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism / Q000648:ultrastructure; D012737:Sex Factors
chemical_list: D018685:Anesthetics, Inhalation; D019837:Ryanodine Receptor Calcium Release Channel; D006221:Halothane