Targeting miR-423-5p Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia
Rationale: Downregulation of the pacemaking ion channel, HCN4, and the corresponding ionic current, If, underlies exercise training-induced sinus bradycardia in rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes and it will be important to understand the underlying processes.
Objective: To test the role of HCN4 in the training-induced bradycardia in human athletes and investigate the role of micro-RNAs (miRs) in the repression of HCN4.
Methods and Results: As in rodents, the intrinsic heart rate was significantly lower in human athletes than non-athletes and in all subjects the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next generation sequencing and qPCR showed remodelling of miRs in the sinus node of swim-trained mice. Computational predictions highlighted a prominent role for miR-423-5p. Interaction between miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in HCN4 3'-UTR luciferase reporter activity on co-transfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with antimiR-423-5p reversed training-induced bradycardia via rescue of HCN4 and If. Further experiments showed that, in the sinus node of swim-trained mice, upregulation of miR-423-5p (intronic miR) and its host gene, NSRP1, is driven by an upregulation of the transcription factor Nkx2.5.
Conclusions:HCN remodelling likely occurs in human athletes as well as rodent models. miR-423-5p contributes to training-induced bradycardia by targeting HCN4. This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p could be a therapeutic target for pathological sinus node dysfunction in veteran athletes.
- Sinus node
- Ion channel remodelling
- ionic remodeling
- exercise training
- sinoatrial node
- Received June 27, 2017.
- Revision received August 15, 2017.
- Accepted August 17, 2017.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.