1. Mammalian γ2 AMPK regulates intrinsic heart rate.
- Author
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Yavari A, Bellahcene M, Bucchi A, Sirenko S, Pinter K, Herring N, Jung JJ, Tarasov KV, Sharpe EJ, Wolfien M, Czibik G, Steeples V, Ghaffari S, Nguyen C, Stockenhuber A, Clair JRS, Rimmbach C, Okamoto Y, Yang D, Wang M, Ziman BD, Moen JM, Riordon DR, Ramirez C, Paina M, Lee J, Zhang J, Ahmet I, Matt MG, Tarasova YS, Baban D, Sahgal N, Lockstone H, Puliyadi R, de Bono J, Siggs OM, Gomes J, Muskett H, Maguire ML, Beglov Y, Kelly M, Dos Santos PPN, Bright NJ, Woods A, Gehmlich K, Isackson H, Douglas G, Ferguson DJP, Schneider JE, Tinker A, Wolkenhauer O, Channon KM, Cornall RJ, Sternick EB, Paterson DJ, Redwood CS, Carling D, Proenza C, David R, Baruscotti M, DiFrancesco D, Lakatta EG, Watkins H, and Ashrafian H
- Subjects
- Adult, Animals, Bradycardia metabolism, Electrocardiography, Ambulatory, Exercise, Heart diagnostic imaging, Humans, Magnetic Resonance Imaging, Cine, Magnetic Resonance Spectroscopy, Mice, Microscopy, Electron, Transmission, Mutation, Myocardium metabolism, Myocardium pathology, Myocardium ultrastructure, Physical Conditioning, Animal, Physical Endurance, Ryanodine Receptor Calcium Release Channel metabolism, Sinoatrial Node pathology, AMP-Activated Protein Kinases genetics, Bradycardia genetics, Calcium metabolism, Heart Rate genetics, Sarcolemma metabolism, Sinoatrial Node metabolism
- Abstract
AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current (I
f ) and ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.- Published
- 2017
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