The pharmacogenetic disorder malignant hyperthermia (MH) is serious and potentially life-threatening illness caused by mutations in the skeletal muscle Ca2+-release channel (ryanodine receptor, RyR1) located in the membrane of the sarcoplasmic reticulum. An MH episode is triggered by general anesthetics, heat and exercise in warm conditions. Signs of an MH crisis are: elevated core temperature, arrhythmias, hyper-metabolism and rhabdomyolysis. The MH mice created in our laboratory with a Y524S+/- mutation in RyR1 (RyR1Y524S+/-) die upon exposure to elevated environmental temperatures (37°C) (Chelu et al 2006). The muscle relaxant dantrolene is the only known treatment for an MH crisis, but its adverse side-effects preclude prophylactic usage. We find that the treatment of the RyR1Y524S+/- mice with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of AMP-activated protein kinase (AMPK), prevents heat-induced sudden death. Less than 5% of untreated RyR1Y524S+/- mice survive a heat-challenge, but treatment with AICAR leads to 100% survival. Muscle AMPK phosphorylation (AMPKαThr172) levels are not significantly altered after 10 min subcutaneous injection with AICAR compared to saline. This suggests that the rescue may not be due solely to AMPK activation, but may also involve off-target effect(s) of AICAR. Adenine nucleotides are known channel agonists and AICAR is a precursor of the AMP analog, ZMP. We tested the effects of AICAR on 3H -ryanodine binding in the presence of non-hydrolysable ATP (AMP-PCP). We find that AICAR is a partial agonist of RyR1 and prevents full activation of RyR1 in the presence of cellular concentrations of ATP in both RyR1Y524S+/- and wild-type mice. AICAR prevents heat-induced death in mice with MH and, since it is thought to have few side-effects, it is a potential prophylactic treatment for heat induced death associated with some MH mutations.