Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse

FASEB J. 2006 Feb;20(2):329-30. doi: 10.1096/fj.05-4497fje. Epub 2005 Nov 11.


Malignant hyperthermia (MH) is a life-threatening disorder characterized by skeletal muscle rigidity and elevated body temperature in response to halogenated anesthetics such as isoflurane or halothane. Mutation of tyrosine 522 of RyR1 (the predominant skeletal muscle calcium release channel) to serine has been associated with human malignant hyperthermia. In the present study, mice created harboring this mutation were found to represent the first murine model of human malignant hyperthermia. Mice homozygous for the Y522S mutation exhibit skeletal defects and die during embryonic development or soon after birth. Heterozygous mice, which correspond to the human occurrence of this mutation, are MH susceptible, experiencing whole body contractions and elevated core temperatures in response to isoflurane exposure or heat stress. Skeletal muscles from heterozygous mice exhibit increased susceptibility to caffeine- and heat-induced contractures in vitro. In addition, the heterozygous expression of the mutation results in enhanced RyR1 sensitivity to activation by temperature, caffeine, and voltage but not uncompensated sarcoplasmic reticulum calcium leak or store depletion. We conclude that the heterozygous expression of the Y522S mutation confers susceptibility to both heat- and anesthetic-induced MH responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthesia / adverse effects*
  • Anesthetics / adverse effects
  • Anesthetics / toxicity
  • Animals
  • Caffeine / pharmacology
  • Calcium / metabolism
  • Disease Models, Animal
  • Hot Temperature / adverse effects*
  • Isoflurane / adverse effects
  • Isoflurane / toxicity
  • Malignant Hyperthermia / etiology*
  • Malignant Hyperthermia / genetics*
  • Malignant Hyperthermia / metabolism
  • Mice
  • Muscle Contraction / physiology
  • Muscle, Skeletal / metabolism
  • Mutation
  • Ryanodine Receptor Calcium Release Channel / genetics*
  • Ryanodine Receptor Calcium Release Channel / metabolism*


  • Anesthetics
  • Ryanodine Receptor Calcium Release Channel
  • Caffeine
  • Isoflurane
  • Calcium