Mammalian γ2 AMPK regulates intrinsic heart rate

Research output: Contribution to journalArticle

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
  • 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

Colleges, School and Institutes

External organisations

  • Instituto de Pós-Graduação, Faculdade de Ciências Médicas de Minas Gerais, Belo Horizonte, 30.130-110, Brazil.
  • Wellcome Trust Centre for Human Genetics
  • University of Oxford
  • University of Rostock
  • University of Colorado School of Medicine
  • Wellcome Trust Sanger Institute
  • University of Milano-Bicocca
  • NIH
  • University College London
  • Imperial College London
  • Barts and The London Queen Mary's School of Medicine and Dentistry
  • Stellenbosch University

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.

Details

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

Keywords

  • AMP-Activated Protein Kinases/genetics, Adult, Animals, Bradycardia/genetics, 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, Physical Conditioning, Animal, Physical Endurance, Ryanodine Receptor Calcium Release Channel/metabolism, Sarcolemma/metabolism, Sinoatrial Node/metabolism