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

Abstract

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 5-aminoimidazole-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.

Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca 2+ leak after one session of high-intensity interval exercise

“…Moreover, the ROS dependency of RyR1 modifications offers a tentative explanation as to why an effective antioxidant treatment hampers beneficial adaptations induced by endurance training (17)(18)(19). Finally, destabilized RyR1 has predominantly been linked to muscle weakness in several pathological conditions as well as in normal aging (8)(9)(10)(11)(12)(13), but here we show that RyR1 modifications can also have an integral role in physiological muscle adaptations.…”

“…Defective RyR1 function is also implied in several pathological states, including generalized inflammatory disorders (10), heart failure (11), and inherited conditions such as malignant hyperthermia (12) and Duchenne muscular dystrophy (13). In many of the above conditions, there is a link between the impaired RyR1 function and modifications induced by reactive oxygen/nitrogen species (ROS) (6,8,10,12,13).…”

“…Defective RyR1 function is also implied in several pathological states, including generalized inflammatory disorders (10), heart failure (11), and inherited conditions such as malignant hyperthermia (12) and Duchenne muscular dystrophy (13). In many of the above conditions, there is a link between the impaired RyR1 function and modifications induced by reactive oxygen/nitrogen species (ROS) (6,8,10,12,13). Conversely, altered RyR1 function may also be beneficial by increasing the cytosolic free [Ca 2+ ] ([Ca 2+ ] i ) at rest, which can stimulate mitochondrial biogenesis and thereby increase fatigue resistance (14)(15)(16).…”

The AMPK-PPARGC1A pathway is required for antimicrobial host defense through activation of autophagy

“…7G and H). In vivo administration of AICAR (500 mg kg-1 body weight) in BCG-infected Atg7 fl/fl LysM-Cre + mice 34 significantly inhibited in vivo bacterial growth in spleens, whereas this was markedly reduced in their Atg7 + littermates (Fig. 7I).…”

Bile acids activate ryanodine receptors in pancreatic acinar cells via a direct allosteric mechanism

“…The desired ionized Ca 2+ concentrations were adjusted with EGTA [17][18][19]. Aliquots (32 l) containing 16 g protein were incubated at 37 • C for 120 min, with various concentrations of radioligand, as indicated in the figure legends.…”