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 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

doi:10.1038/s41467-017-01342-5

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 G. Lakatta, Hugh Watkins, Houman Ashrafian

School of Medicine

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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 language	English (US)
Article number	1258
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-01342-5
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-017-01342-5

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Yavari, A., Bellahcene, M., Bucchi, A., Sirenko, S., Pinter, K., Herring, N., Jung, J. J., Tarasov, K. V., Sharpe, E. J., Wolfien, M., Czibik, G., Steeples, V., Ghaffari, S., Nguyen, C., 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), Article 1258. https://doi.org/10.1038/s41467-017-01342-5

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, EG, 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

@article{a98b3912200e4addbf9373df89a54f3c,

title = "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.",

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

note = "Funding Information: We thank GenOway (Lyon, France) for generating R299Q γ2 mice; Rachel Hagen and Lee-Anne Stork for technical assistance in the British Heart Foundation (BHF) Experimental MRI Unit (Oxford, UK); Karen McGuire, Kate Thomson, and Jessica Woodley for help with R302Q genotyping (Oxford Medical Genetics Laboratories); Michael Shaw, Ashley Hale, and Craig Lygate (Oxford) for support with phenotyping; James Brown and Phil Townsend (Oxford) for general laboratory support; Shannon Marshall (NIA/NIH) for technical support; Paul Bastian and Elin Lehrmann of the Laboratory of Genetics and Genomics (NIA/NIH) for performing microarray experiments, analysis, and GEO submission. This work was supported by a BHF Intermediate Clinical Fellowship (FS/15/8/ 31155 to N.H.); BHF Senior Basic Science Research Fellowship (FS/11/50/29038 to J.E. S.); MRC/EPSRC Grant (G0600829, H.M. and M.L.M.); the Federal Ministry of Education and Research Germany (FKZ 0312138A and FKZ 316159), the State Mecklenburg-Western Pomerania with EU Structural Funds (ESF/IV-WM-B34-0030/10 and ESF/IV-BM-B35-0010/12), the DFG (DA 1296-1), the German Heart Foundation (F/01/12), the FORUN Program of Rostock University Medical Centre (889001), the EU funded CaSyM project (Grant Agreement #305033), the DAMP Foundation and the BMBF (VIP+ 00240) (to J.J.J., C.Ri., M.W., O.W., and R.D.); Ministero dell{\textquoteright}Istruzione, dell{\textquoteright}Universit{\`a} e della Ricerca (PRIN 2010BWY8E9) and the EU (LSHM-CT-2006-018676 NORMACOR) (D.D.); Fondazione Cariplo (CLARIFY, 2014-0822, M.B., and ACROSS, 2014-0728, D. D.); Intramural Research Program of the National Institutes of Health, National Institute on Aging (E.G.L); the Wellcome Trust (Research Training Fellowship, 086632/Z/08/Z), the Academy of Medical Sciences (Clinical Lecturer Starter Grant), and the National Institute for Health Research in the form of an Academic Clinical Lectureship (A.Y.). A.Y. (RE/08/004), H.W., and H.A. acknowledge support from the BHF Centre of Research Excellence, Oxford. Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-01342-5",

language = "English (US)",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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TY - JOUR

T1 - Mammalian γ2 AMPK regulates intrinsic heart rate

AU - Yavari, Arash

AU - Bellahcene, Mohamed

AU - Bucchi, Annalisa

AU - Sirenko, Syevda

AU - Pinter, Katalin

AU - Herring, Neil

AU - Jung, Julia J.

AU - Tarasov, Kirill V.

AU - Sharpe, Emily J.

AU - Wolfien, Markus

AU - Czibik, Gabor

AU - Steeples, Violetta

AU - Ghaffari, Sahar

AU - Nguyen, Chinh

AU - Stockenhuber, Alexander

AU - Clair, Joshua R.St

AU - Rimmbach, Christian

AU - Okamoto, Yosuke

AU - Yang, Dongmei

AU - Wang, Mingyi

AU - Ziman, Bruce D.

AU - Moen, Jack M.

AU - Riordon, Daniel R.

AU - Ramirez, Christopher

AU - Paina, Manuel

AU - Lee, Joonho

AU - Zhang, Jing

AU - Ahmet, Ismayil

AU - Matt, Michael G.

AU - Tarasova, Yelena S.

AU - Baban, DIlair

AU - Sahgal, Natasha

AU - Lockstone, Helen

AU - Puliyadi, Rathi

AU - De Bono, Joseph

AU - Siggs, Owen M.

AU - Gomes, John

AU - Muskett, Hannah

AU - Maguire, Mahon L.

AU - Beglov, Youlia

AU - Kelly, Matthew

AU - Dos Santos, Pedro P.N.

AU - Bright, Nicola J.

AU - Woods, Angela

AU - Gehmlich, Katja

AU - Isackson, Henrik

AU - Douglas, Gillian

AU - Ferguson, David J.P.

AU - Schneider, Jürgen E.

AU - Tinker, Andrew

AU - Wolkenhauer, Olaf

AU - Channon, Keith M.

AU - Cornall, Richard J.

AU - Sternick, Eduardo B.

AU - Paterson, David J.

AU - Redwood, Charles S.

AU - Carling, David

AU - Proenza, Catherine

AU - David, Robert

AU - Baruscotti, Mirko

AU - DIfrancesco, Dario

AU - Lakatta, Edward G.

AU - Watkins, Hugh

AU - Ashrafian, Houman

N1 - Funding Information: We thank GenOway (Lyon, France) for generating R299Q γ2 mice; Rachel Hagen and Lee-Anne Stork for technical assistance in the British Heart Foundation (BHF) Experimental MRI Unit (Oxford, UK); Karen McGuire, Kate Thomson, and Jessica Woodley for help with R302Q genotyping (Oxford Medical Genetics Laboratories); Michael Shaw, Ashley Hale, and Craig Lygate (Oxford) for support with phenotyping; James Brown and Phil Townsend (Oxford) for general laboratory support; Shannon Marshall (NIA/NIH) for technical support; Paul Bastian and Elin Lehrmann of the Laboratory of Genetics and Genomics (NIA/NIH) for performing microarray experiments, analysis, and GEO submission. This work was supported by a BHF Intermediate Clinical Fellowship (FS/15/8/ 31155 to N.H.); BHF Senior Basic Science Research Fellowship (FS/11/50/29038 to J.E. S.); MRC/EPSRC Grant (G0600829, H.M. and M.L.M.); the Federal Ministry of Education and Research Germany (FKZ 0312138A and FKZ 316159), the State Mecklenburg-Western Pomerania with EU Structural Funds (ESF/IV-WM-B34-0030/10 and ESF/IV-BM-B35-0010/12), the DFG (DA 1296-1), the German Heart Foundation (F/01/12), the FORUN Program of Rostock University Medical Centre (889001), the EU funded CaSyM project (Grant Agreement #305033), the DAMP Foundation and the BMBF (VIP+ 00240) (to J.J.J., C.Ri., M.W., O.W., and R.D.); Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2010BWY8E9) and the EU (LSHM-CT-2006-018676 NORMACOR) (D.D.); Fondazione Cariplo (CLARIFY, 2014-0822, M.B., and ACROSS, 2014-0728, D. D.); Intramural Research Program of the National Institutes of Health, National Institute on Aging (E.G.L); the Wellcome Trust (Research Training Fellowship, 086632/Z/08/Z), the Academy of Medical Sciences (Clinical Lecturer Starter Grant), and the National Institute for Health Research in the form of an Academic Clinical Lectureship (A.Y.). A.Y. (RE/08/004), H.W., and H.A. acknowledge support from the BHF Centre of Research Excellence, Oxford. Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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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U2 - 10.1038/s41467-017-01342-5

DO - 10.1038/s41467-017-01342-5

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AN - SCOPUS:85032975204

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1258

ER -

Mammalian γ2 AMPK regulates intrinsic heart rate

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