Mammalian γ2 AMPK regulates intrinsic heart rate

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 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 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 Lakatta, Hugh Watkins, Houman Ashrafian

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number1258
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

heart rate
AMP-Activated Protein Kinases
bradycardia
Heart Rate
homeostasis
phenotype
Bradycardia
Homeostasis
Bearings (structural)
mammals
energy
endurance
adenines
nucleotides
physical exercise
Physiological Adaptation
Phenotype
mutations
Pacemakers
cells

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Yavari, A., Bellahcene, M., Bucchi, A., Sirenko, S., Pinter, K., Herring, N., ... Ashrafian, H. (2017). Mammalian γ2 AMPK regulates intrinsic heart rate. Nature Communications, 8(1), [1258]. https://doi.org/10.1038/s41467-017-01342-5

Mammalian γ2 AMPK regulates intrinsic heart rate. / Yavari, Arash; Bellahcene, Mohamed; Bucchi, Annalisa; Sirenko, Syevda; Pinter, Katalin; Herring, Neil; Jung, Julia J.; Tarasov, Kirill V.; Sharpe, Emily J.; Wolfien, Markus; Czibik, Gabor; Steeples, Violetta; Ghaffari, Sahar; Nguyen, Chinh; Stockenhuber, Alexander; Clair, Joshua R.St; Rimmbach, Christian; Okamoto, Yosuke; Yang, Dongmei; Wang, Mingyi; Ziman, Bruce D.; Moen, Jack M.; Riordon, Daniel R.; Ramirez, Christopher; Paina, Manuel; Lee, Joonho; Zhang, Jing; Ahmet, Ismayil; Matt, Michael G.; Tarasova, Yelena S.; Baban, DIlair; Sahgal, Natasha; Lockstone, Helen; Puliyadi, Rathi; De Bono, Joseph; Siggs, Owen M.; Gomes, John; Muskett, Hannah; Maguire, Mahon L.; Beglov, Youlia; Kelly, Matthew; Dos Santos, Pedro P.N.; Bright, Nicola J.; Woods, Angela; Gehmlich, Katja; Isackson, Henrik; Douglas, Gillian; Ferguson, David J.P.; Schneider, Jürgen E.; Tinker, Andrew; Wolkenhauer, Olaf; Channon, Keith M.; Cornall, Richard J.; Sternick, Eduardo B.; Paterson, David J.; Redwood, Charles S.; Carling, David; Proenza, Catherine; David, Robert; Baruscotti, Mirko; DIfrancesco, Dario; Lakatta, Edward; Watkins, Hugh; Ashrafian, Houman.

In: Nature Communications, Vol. 8, No. 1, 1258, 01.12.2017.

Research output: Contribution to journalArticle

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, DI, 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, E, Watkins, H & Ashrafian, H 2017, 'Mammalian γ2 AMPK regulates intrinsic heart rate', Nature Communications, vol. 8, no. 1, 1258. https://doi.org/10.1038/s41467-017-01342-5
Yavari A, Bellahcene M, Bucchi A, Sirenko S, Pinter K, Herring N et al. Mammalian γ2 AMPK regulates intrinsic heart rate. Nature Communications. 2017 Dec 1;8(1). 1258. https://doi.org/10.1038/s41467-017-01342-5
Yavari, Arash ; Bellahcene, Mohamed ; Bucchi, Annalisa ; Sirenko, Syevda ; Pinter, Katalin ; Herring, Neil ; Jung, Julia J. ; Tarasov, Kirill V. ; Sharpe, Emily J. ; Wolfien, Markus ; Czibik, Gabor ; Steeples, Violetta ; Ghaffari, Sahar ; Nguyen, Chinh ; Stockenhuber, Alexander ; Clair, Joshua R.St ; Rimmbach, Christian ; Okamoto, Yosuke ; Yang, Dongmei ; Wang, Mingyi ; Ziman, Bruce D. ; Moen, Jack M. ; Riordon, Daniel R. ; Ramirez, Christopher ; Paina, Manuel ; Lee, Joonho ; Zhang, Jing ; Ahmet, Ismayil ; Matt, Michael G. ; Tarasova, Yelena S. ; Baban, DIlair ; Sahgal, Natasha ; Lockstone, Helen ; Puliyadi, Rathi ; De Bono, Joseph ; Siggs, Owen M. ; Gomes, John ; Muskett, Hannah ; Maguire, Mahon L. ; Beglov, Youlia ; Kelly, Matthew ; Dos Santos, Pedro P.N. ; Bright, Nicola J. ; Woods, Angela ; Gehmlich, Katja ; Isackson, Henrik ; Douglas, Gillian ; Ferguson, David J.P. ; Schneider, Jürgen E. ; Tinker, Andrew ; Wolkenhauer, Olaf ; Channon, Keith M. ; Cornall, Richard J. ; Sternick, Eduardo B. ; Paterson, David J. ; Redwood, Charles S. ; Carling, David ; Proenza, Catherine ; David, Robert ; Baruscotti, Mirko ; DIfrancesco, Dario ; Lakatta, Edward ; Watkins, Hugh ; Ashrafian, Houman. / Mammalian γ2 AMPK regulates intrinsic heart rate. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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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 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.",
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