AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation.
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.
Department of Molecular Physiology and Biophysics Baylor College of Medicine, Houston, Texas, USA.
Johanna T
JT
Lanner
Dimitra K
DK
Georgiou
Adan
A
Dagnino-Acosta
Alina
A
Ainbinder
Qing
Q
Cheng
Aditya D
AD
Joshi
Zanwen
Z
Chen
Viktor
V
Yarotskyy
Joshua M
JM
Oakes
Chang Seok
CS
Lee
Tanner O
TO
Monroe
Arturo
A
Santillan
Keke
K
Dong
Laurie
L
Goodyear
Iskander I
II
Ismailov
George G
GG
Rodney
Robert T
RT
Dirksen
Susan L
SL
Hamilton
D055372:AMP-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003645:Death, Sudden / Q000517:prevention & control; D004789:Enzyme Activation; D018882:Heat Stress Disorders / Q000235:genetics / Q000517:prevention & control*; D006358:Hot Temperature / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D012265:Ribonucleotides; D019837:Ryanodine Receptor Calcium Release Channel; D000620:Aminoimidazole Carboxamide; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D002118:Calcium