ArticleNature medicine2012
AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation.
Article in Nature medicine, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
74 citing papers in PubMed, 112 citations in OpenAlex.
- Exercise capacity in RYR1-related myopathies.Orphanet journal of rare diseases · 2025Trial
- Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise.Proceedings of the National Academy of Sciences of the United States of America · 2015Trial
- Exercise mimetics: molecular mechanisms, biological and therapeutic effects.Molecular biomedicine · 2026Review
- Dysferlin and the Regulation of CaCells · 2025Review
- Phosphorylation of RYR1 at SerScience signaling · 2025Article
- Article
- NADSkeletal muscle · 2025Article
- Treatments for RYR1-related disorders.The Cochrane database of systematic reviews · 2024Article
- Stable oxidative posttranslational modifications alter the gating properties of RyR1.The Journal of general physiology · 2024Article
- Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review.British journal of anaesthesia · 2024Review
- Cytosolic CaBiophysical reports · 2023Article
- EuBiophysical journal · 2023Article
- Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives.Structure (London, England : 1993) · 2023Article
- AMPK regulates homeostasis of invasion and viability in trophoblasts by redirecting glucose metabolism: Implications for pre-eclampsia.Cell proliferation · 2023Article
- ZBP1 and heatstroke.Frontiers in immunology · 2023Review
- Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies.The Journal of general physiology · 2022Review
- Postdevelopmental knockout of Orai1 improves muscle pathology in a mouse model of Duchenne muscular dystrophy.The Journal of general physiology · 2022Article
- Heat-hypersensitive mutants of ryanodine receptor type 1 revealed by microscopic heating.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Molecular mechanism of the severe MH/CCD mutation Y522S in skeletal ryanodine receptor (RyR1) by cryo-EM.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Endurance exercise attenuates juvenile irradiation-induced skeletal muscle functional decline and mitochondrial stress.Skeletal muscle · 2022Article
14 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors at 3 institutions in 1 country.
Funding
Abstract
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.