Mammalian γ2 AMPK regulates intrinsic heart rate.

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.

• Authors: Arash Yavari, Mohamed Bellahcene, Annalisa Bucchi, Syevda Sirenko, Katalin Pinter, Neil Herring, Julia J Jung, Kirill V Tarasov, Emily J Sharpe, Markus Wolfien, Gabor Czibik, Violetta Steeples, Sahar Ghaffari, Chinh Nguyen, Alexander Stockenhuber, Joshua R St Clair, Christian Rimmbach, Yosuke Okamoto, Dongmei Yang, Mingyi Wang, Bruce D Ziman, Jack M Moen, Daniel R Riordon, Christopher Ramirez, Manuel Paina, Joonho Lee, Jing Zhang, Ismayil Ahmet, Michael G Matt, Yelena S Tarasova, Dilair Baban, Natasha Sahgal, Helen Lockstone, Rathi Puliyadi, Joseph de Bono, Owen M Siggs, John Gomes, Hannah Muskett, Mahon L Maguire, Youlia Beglov, Matthew Kelly, Pedro P N Dos Santos, Nicola J Bright, Angela Woods, Katja Gehmlich, Henrik Isackson, Gillian Douglas, David J P Ferguson, Jürgen E Schneider, Andrew Tinker, Olaf Wolkenhauer, Keith M Channon, Richard J Cornall, Eduardo B Sternick, David J Paterson, Charles S Redwood, David Carling, Catherine Proenza, Robert David, Mirko Baruscotti, Dario DiFrancesco, Edward G Lakatta, Hugh Watkins, Houman Ashrafian
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 1258 (11 02 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29097735 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ryanodine Receptor Calcium Release Channel
• PRKAG2 protein, human
• AMP-Activated Protein Kinases
• Calcium

Topics

• AMP-Activated Protein Kinases (genetics)
• Adult
• Animals
• Bradycardia (genetics, metabolism)
• Calcium (metabolism)
• Electrocardiography, Ambulatory
• Exercise
• Heart (diagnostic imaging)
• Heart Rate (genetics)
• Humans
• Magnetic Resonance Imaging, Cine
• Magnetic Resonance Spectroscopy
• Mice
• Microscopy, Electron, Transmission
• Mutation
• Myocardium (metabolism, pathology, ultrastructure)
• Physical Conditioning, Animal
• Physical Endurance
• Ryanodine Receptor Calcium Release Channel (metabolism)
• Sarcolemma (metabolism)
• Sinoatrial Node (metabolism, pathology)