• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


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