Journal
CELL
Volume 133, Issue 1, Pages 53-65Publisher
CELL PRESS
DOI: 10.1016/j.cell.2008.02.042
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Funding
- NIAMS NIH HHS [R01 AR050503, R01 AR050503-05, AR44657, R01 AR050503-03, R01 AR053349-03, R01 AR050503-01, 5P01AR052354, R01 AR050503-04, R01 AR053349-01A1S1, AR 050503, P01 AR052354, R01 AR050503-02, R01 AR041802, P01 AR052354-020003, R01 AR053349-01A1, R29 AR044657, AR053349, R01 AR053349, P01 AR052354-01A10003, R01 AR044657, R01 AR053349-02, R01 AR044657-12] Funding Source: Medline
- NIDCR NIH HHS [T32 DE007202, T32-DE07202] Funding Source: Medline
- Telethon [GGP030289] Funding Source: Medline
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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 Ca2+ 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.
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