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

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

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 RYR1T4826I/ T4826I (Hom) mice are fully viable under typical rearing conditions but exhibit genotypeand 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.

Original languageEnglish (US)
Pages (from-to)1311-1322
Number of pages12
JournalFASEB Journal
Volume26
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Malignant Hyperthermia
Muscle
Genotype
Halothane
Muscles
Ryanodine Receptor Calcium Release Channel
Mitochondria
Temperature
Body Temperature
Mutation
Hot Temperature
Sexism
Sarcolemma
Muscular Diseases
Anesthesia
Pharmacology

Keywords

  • Anesthesia
  • Ca regulation
  • Heat stress
  • Ryanodine receptor mutation

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

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

In: FASEB Journal, Vol. 26, No. 3, 03.2012, p. 1311-1322.

Research output: Contribution to journalArticle

Yuen, B, Boncompagni, S, Feng, W, Yang, T, Lopez, JR, Matthaei, KI, Goth, SR, Protasi, F, Franzini-Armstrong, C, Allen, PD & Pessah, IN 2012, 'Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage', FASEB Journal, vol. 26, no. 3, pp. 1311-1322. https://doi.org/10.1096/fj.11-197582
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. / Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage. In: FASEB Journal. 2012 ; Vol. 26, No. 3. pp. 1311-1322.
@article{6c54e90ba9ce443ca9539b0cd4ed0c3c,
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 RYR1T4826I/ T4826I (Hom) mice are fully viable under typical rearing conditions but exhibit genotypeand 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.",
keywords = "Anesthesia, Ca regulation, Heat stress, Ryanodine receptor mutation",
author = "Benjamin Yuen and Simona Boncompagni and Wei Feng and Tianzhong Yang and Lopez, {Jose R.} and Matthaei, {Klaus I.} and Goth, {Samuel R.} and Feliciano Protasi and Clara Franzini-Armstrong and Allen, {Paul D.} and Pessah, {Isaac N}",
year = "2012",
month = "3",
doi = "10.1096/fj.11-197582",
language = "English (US)",
volume = "26",
pages = "1311--1322",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "3",

}

TY - JOUR

T1 - Mice expressing T4826I-RYR1 are viable but exhibit sex- and genotype-dependent susceptibility to malignant hyperthermia and muscle damage

AU - Yuen, Benjamin

AU - Boncompagni, Simona

AU - Feng, Wei

AU - Yang, Tianzhong

AU - Lopez, Jose R.

AU - Matthaei, Klaus I.

AU - Goth, Samuel R.

AU - Protasi, Feliciano

AU - Franzini-Armstrong, Clara

AU - Allen, Paul D.

AU - Pessah, Isaac N

PY - 2012/3

Y1 - 2012/3

N2 - 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 RYR1T4826I/ T4826I (Hom) mice are fully viable under typical rearing conditions but exhibit genotypeand 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.

AB - 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 RYR1T4826I/ T4826I (Hom) mice are fully viable under typical rearing conditions but exhibit genotypeand 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.

KW - Anesthesia

KW - Ca regulation

KW - Heat stress

KW - Ryanodine receptor mutation

UR - http://www.scopus.com/inward/record.url?scp=84857771245&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857771245&partnerID=8YFLogxK

U2 - 10.1096/fj.11-197582

DO - 10.1096/fj.11-197582

M3 - Article

C2 - 22131268

AN - SCOPUS:84857771245

VL - 26

SP - 1311

EP - 1322

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 3

ER -