Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0024591 (
malignant hyperthermia
)
2,353
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. 1839 87
Central core disease (CCD) is a congenital myopathy linked to mutations in the ryanodine receptor type 1 (RYR1), the sarcoplasmic reticulum Ca
2+
release channel of skeletal muscle. CCD is characterized by formation of amorphous
cores
within muscle fibers, lacking mitochondrial activity. In skeletal muscle of RYR1
Y522S/WT
knock-in mice, carrying a human mutation in RYR1 linked to
malignant hyperthermia
(MH) with
cores
, oxidative stress is elevated and fibers present severe mitochondrial damage and
cores
. We treated RYR1
Y522S/WT
mice with
N-acetylcysteine
(
NAC
), an antioxidant provided
ad libitum
in drinking water for either 2 or 6 months. Our results show that 2 months of
NAC
treatment starting at 2 months of age, when mitochondrial and fiber damage was still minimal, (i) reduce formation of
unstructured
and
contracture cores
, (ii) improve muscle function, and (iii) decrease mitochondrial damage. The beneficial effect of
NAC
treatment is also evident following 6 months of treatment starting at 4 months of age, when structural damage was at an advanced stage.
NAC
exerts its protective effect likely by lowering oxidative stress, as supported by the reduction of 3-NT and SOD2 levels. This work suggests that
NAC
administration is beneficial to prevent mitochondrial damage and formation of
cores
and improve muscle function in RYR1
Y522S/WT
mice.
...
PMID:Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1
Y522S/WT
Mice. 2906 63
