AICAR Prevents Heat Induced Sudden Death in RyR1 Mutant Mice Independent of AMPK Activation
| العنوان: | AICAR Prevents Heat Induced Sudden Death in RyR1 Mutant Mice Independent of AMPK Activation |
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| المؤلفون: | Qing Cheng, Johanna T. Lanner, Robert T. Dirksen, George G. Rodney, Susan L. Hamilton, Zanwen Chen, Tanner O. Monroe, Chang Seok Lee, Arturo Santillan, Joshua M. Oakes, Laurie J. Goodyear, Viktor Yarotskyy, Dimitra K. Georgiou, Alina Ainbinder, Adan Dagnino-Acosta, Iskander I. Ismailov, Keke Dong, Aditya D. Joshi |
| المصدر: | Nature medicine |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Male, medicine.medical_specialty, Hot Temperature, chemistry.chemical_element, Mice, Transgenic, Calcium, AMP-Activated Protein Kinases, Heat Stress Disorders, Sudden death, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Death, Sudden, Mice, 0302 clinical medicine, Adenosine Triphosphate, AMP-activated protein kinase, Internal medicine, medicine, Animals, Muscle, Skeletal, 030304 developmental biology, RYR1, 0303 health sciences, biology, Ryanodine receptor, Calcium channel, Malignant hyperthermia, AMPK, Ryanodine Receptor Calcium Release Channel, General Medicine, Ribonucleotides, medicine.disease, Aminoimidazole Carboxamide, Reactive Nitrogen Species, Mice, Mutant Strains, 3. Good health, Enzyme Activation, Sarcoplasmic Reticulum, Endocrinology, chemistry, biology.protein, Reactive Oxygen Species, 030217 neurology & neurosurgery |
| الوصف: | Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation that is associated with malignant hyperthermia in humans, die when exposed to short periods of temperature elevation (≥37 °C). We show here that treatment with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents this heat-induced sudden death in this mouse model. The protection by AICAR is independent of AMP-activated protein kinase (AMPK) activation and results from a newly identified action of the compound on mutant Ryr1 to reduce Ca(2+) leak from the sarcoplasmic reticulum to the sarcoplasm. AICAR thus prevents Ca(2+)-dependent increases in the amount of both reactive oxygen species (ROS) and reactive nitrogen species (RNS) that act to further increase resting Ca(2+) concentrations. If unchecked, the temperature-driven increases in resting Ca(2+) concentrations and the amounts of ROS and RNS create an amplifying cycle that ultimately triggers sustained muscle contractions, rhabdomyolysis and death. Although antioxidants are effective in reducing this cycle in vitro, only AICAR prevents heat-induced death in vivo. Our findings suggest that AICAR is probably effective in prophylactic treatment of humans with enhanced susceptibility to exercise- and/or heat-induced sudden death associated with RYR1 mutations. |
| اللغة: | English |
| تدمد: | 1546-170X 1078-8956 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::24bbf216e1e317b385d7655f89825848Test http://europepmc.org/articles/PMC3274651Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....24bbf216e1e317b385d7655f89825848 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1546170X 10788956 |
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