Authors: 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, and Susan L. Hamilton
Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (RyR1) die when exposed to short periods of temperature elevation (≥ 37 °C). We demonstrate that treatment with 5aminoimidazole-4-carboxamide ribonucleoside (AICAR) prevents heat-induced sudden death in Y524S mice. The AICAR protection is independent of AMPK activation and results from a newly identified action on the mutant RyR1 to reduce Ca2+ leak, preventing Ca2+ dependent increases in both reactive oxygen and reactive nitrogen species that act to further increase resting Ca2+ concentrations. If unchecked, the temperature-driven increases in resting Ca2+ and ROS/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 the heat induced death in vivo. Our findings suggest that AICAR is likely to be effective in prophylactic treatment of humans with enhanced susceptibility to exercise/heat-induced sudden death associated with RyR1 mutations.
