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

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.

Pubmed ID: 22131268


  • Yuen B
  • Boncompagni S
  • Feng W
  • Yang T
  • Lopez JR
  • Matthaei KI
  • Goth SR
  • Protasi F
  • Franzini-Armstrong C
  • Allen PD
  • Pessah IN


FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Publication Data

March 1, 2012

Associated Grants

  • Agency: NIAMS NIH HHS, Id: 1P01 AR52354-05
  • Agency: NIEHS NIH HHS, Id: 1R01 ES014901
  • Agency: NIAMS NIH HHS, Id: 3R01 AR043140-15
  • Agency: NIAMS NIH HHS, Id: P01 AR052354

Mesh Terms

  • Amino Acid Substitution
  • Anesthetics, Inhalation
  • Animals
  • Body Temperature
  • Female
  • Gene Expression
  • Genetic Predisposition to Disease
  • Genotype
  • Halothane
  • Hot Temperature
  • Humans
  • Male
  • Malignant Hyperthermia
  • Membrane Potentials
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Electron
  • Muscle Fibers, Skeletal
  • Muscle, Skeletal
  • Mutation
  • Ryanodine Receptor Calcium Release Channel
  • Sarcolemma
  • Sex Factors