Exercise training reduces resting heart rate via downregulation of the funny channel HCN4

Alicia D’Souza, Annalisa Bucchi, Anne Berit Johnsen, Sunil Jit R.J. Logantha, Oliver Monfredi, Joseph Yanni, Sukhpal Prehar, George Hart, Elizabeth Cartwright, Ulrik Wisloff, Halina Dobryznski (), Dario DiFrancesco, Gwilym M. Morris and Mark R. Boyett ()
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Alicia D’Souza: Institute of Cardiovascular Sciences, University of Manchester
Annalisa Bucchi: University of Milano
Anne Berit Johnsen: Norwegian University of Science and Technology
Sunil Jit R.J. Logantha: Institute of Cardiovascular Sciences, University of Manchester
Oliver Monfredi: Institute of Cardiovascular Sciences, University of Manchester
Joseph Yanni: Institute of Cardiovascular Sciences, University of Manchester
Sukhpal Prehar: Institute of Cardiovascular Sciences, University of Manchester
George Hart: Institute of Cardiovascular Sciences, University of Manchester
Elizabeth Cartwright: Institute of Cardiovascular Sciences, University of Manchester
Ulrik Wisloff: Norwegian University of Science and Technology
Halina Dobryznski: Institute of Cardiovascular Sciences, University of Manchester
Dario DiFrancesco: University of Milano
Gwilym M. Morris: Institute of Cardiovascular Sciences, University of Manchester
Mark R. Boyett: Institute of Cardiovascular Sciences, University of Manchester

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: Abstract Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, If. Block of If abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro. We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training.

Date: 2014
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DOI: 10.1038/ncomms4775

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