RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice.
Mice with a malignant hyperthermia mutation (Y522S) in the ryanodine receptor (RyR1) display muscle contractures, rhabdomyolysis, and death in response to elevated environmental temperatures. We demonstrate that this mutation in RyR1 causes Ca(2+) leak, which drives increased generation of reactive nitrogen species (RNS). Subsequent S-nitrosylation of the mutant RyR1 increases its temperature sensitivity for activation, producing muscle contractures upon exposure to elevated temperatures. The Y522S mutation in humans is associated with central core disease. Many mitochondria in the muscle of heterozygous Y522S mice are swollen and misshapen. The mutant muscle displays decreased force production and increased mitochondrial lipid peroxidation with aging. Chronic treatment with N-acetylcysteine protects against mitochondrial oxidative damage and the decline in force generation. We propose a feed-forward cyclic mechanism that increases the temperature sensitivity of RyR1 activation and underlies heat stroke and sudden death. The cycle eventually produces a myopathy with damaged mitochondria.
Durham
William J
WJ
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Aracena-Parks
Paula
P
Long
Cheng
C
Rossi
Ann E
AE
Goonasekera
Sanjeewa A
SA
Boncompagni
Simona
S
Galvan
Daniel L
DL
Gilman
Charles P
CP
Baker
Mariah R
MR
Shirokova
Natalia
N
Protasi
Feliciano
F
Dirksen
Robert
R
Hamilton
Susan L
SL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003645:Death, Sudden / Q000209:etiology*; D018883:Heat Stroke / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D008305:Malignant Hyperthermia / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D015538:Nitrosation; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism*
D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium