Exercise training reduces resting heart rate via downregulation of the funny channel HCN4.
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.
1] Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK [2].
Alicia
A
D'Souza
1] Department of Biosciences, University of Milano, Milano 20133, Italy [2].
Annalisa
A
Bucchi
1] Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim 7491, Norway [2].
Anne Berit
AB
Johnsen
1] Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK [2].
Sunil Jit R J
SJ
Logantha
Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.
Oliver
O
Monfredi
Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.
Joseph
J
Yanni
Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.
Sukhpal
S
Prehar
Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.
George
G
Hart
Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.
Elizabeth
E
Cartwright
Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim 7491, Norway.
Ulrik
U
Wisloff
Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.
Halina
H
Dobryznski
Department of Biosciences, University of Milano, Milano 20133, Italy.
Dario
D
DiFrancesco
Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.
Gwilym M
GM
Morris
Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK.
Mark R
MR
Boyett
D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D001919:Bradycardia / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D006339:Heart Rate / Q000235:genetics*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics* / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012849:Sinoatrial Node / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000099229:RE1-Silencing Transcription Factor
D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000099229:RE1-Silencing Transcription Factor; C542191:MIRN1 microRNA, rat; C517731:Mirn1 microRNA, mouse; C491460:Tbx3 protein, mouse