AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation

Johanna T. Lanner, Dimitra K. Georgiou, Adan Dagnino-Acosta, Alina Ainbinder, Qing Cheng, Aditya D. Joshi, Zanwen Chen, Viktor Yarotskyy, Joshua M. Oakes, Chang Seok Lee, Tanner O. Monroe, Arturo Santillan, Keke Dong, Laurie Goodyear, Iskander I. Ismailov, George G. Rodney, Robert T. Dirksen, Susan L. Hamilton

Research output: Contribution to journalArticle

67 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)244-251
Number of pages8
JournalNature Medicine
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lanner, J. T., Georgiou, D. K., Dagnino-Acosta, A., Ainbinder, A., Cheng, Q., Joshi, A. D., Chen, Z., Yarotskyy, V., Oakes, J. M., Lee, C. S., Monroe, T. O., Santillan, A., Dong, K., Goodyear, L., Ismailov, I. I., Rodney, G. G., Dirksen, R. T., & Hamilton, S. L. (2012). AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nature Medicine, 18(2), 244-251. https://doi.org/10.1038/nm.2598