Mammalian γ2 AMPK regulates intrinsic heart rate

Arash Yavari, Mohamed Bellahcene, Annalisa Bucchi, Syevda Tagirova Sirenko, Katalin Pinter, Neil Herring, Julia Jeannine Jung, Kirill V. Tarasov, Emily J. Sharpe, Markus Wolfien, Gabor Czibik, Violetta Steeples, Sahar Ghaffari, Chinh Duc Nguyen, Alexander Stockenhuber, Joshua R.St Clair, Christian Rimmbach, Yosuke Okamoto, Dongmei Yang, Mingyi WangBruce 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 F. Baban, Natasha Sahgal, Helen E. Lockstone, Rathi Puliyadi, Joseph P. De Bono, Owen Marc Siggs, John Gomes, Hannah Muskett, Mahon L. Maguire, Youlia Beglov, Matthew D. Kelly, Pedro P.N. Dos Santos, Nicola J. Bright, Angela Woods, Katja Gehmlich, Henrik Isackson, Gillian Douglas, David J. Ferguson, Jürgen E. Schneider, Andrew Tinker, Olaf Wolkenhauer, Keith Michael Channon, Richard J. Cornall, Eduardo Back Sternick, David J. Paterson, Charles S. Redwood, D. Carling, Catherine Proenza, Robert G. David, Mirko Baruscotti, Dario DiFrancesco, Edward G. Lakatta, Hugh C. Watkins, Houman Ashrafian

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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 Ca 2+ 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.

Original languageEnglish
Article number1258
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 2 Nov 2017
Externally publishedYes

Keywords

  • AMPK
  • cellular energy
  • heart rate

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    Yavari, A., Bellahcene, M., Bucchi, A., Sirenko, S. T., Pinter, K., Herring, N., Jung, J. J., Tarasov, K. V., Sharpe, E. J., Wolfien, M., Czibik, G., Steeples, V., Ghaffari, S., Nguyen, C. D., Stockenhuber, A., Clair, J. R. S., Rimmbach, C., Okamoto, Y., Yang, D., ... Ashrafian, H. (2017). Mammalian γ2 AMPK regulates intrinsic heart rate. Nature Communications, 8(1), [1258]. https://doi.org/10.1038/s41467-017-01342-5