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Targeting miR-423-5p Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia
Alicia D'Souza1, Charles M Pearman1, Yanwen Wang1
1From the Division of Cardiovascular Sciences, University of Manchester, United Kingdom (A.D., C.M.P., Y.W., S.N., S.J.R.J.L., C.C., H.B., Y.Z., J.E., A.R., A.K., E.J.C., O.M., H.D., D.O., G.M.M., M.R.B.); K.G. Jebsen Center for Exercise in Medicine, Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway (A.B.J., U.W.); Faculty of Health Sciences, NNF Center for Protein Research, University of Copenhagen, Denmark (N.L., P.C.P., A.L.); School of Healthcare Science, Manchester Metropolitan University, United Kingdom (J.C., J.M.); Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, Netherlands (P.A.d.C.M.); and School of Human Movement & Nutrition Sciences, University of Queensland, Australia (U.W.).
Insights
Exercise training lowers heart rate in athletes by reducing the HCN4 channel. MicroRNA-423-5p targets HCN4, causing bradycardia, and may be a therapeutic target for heart rhythm disorders.
Area of Science:
- Cardiology
- Molecular Biology
- Exercise Physiology
Background:
- Downregulation of the HCN4 channel and If current causes exercise-induced sinus bradycardia in rodents.
- This mechanism may explain bradyarrhythmias in veteran athletes, necessitating further investigation.
Purpose of the Study:
- To determine the role of HCN4 in training-induced bradycardia in human athletes.
- To investigate microRNAs (miRs) in the repression of HCN4.
Main Methods:
- Compared intrinsic heart rates and ivabradine response in athletes vs. non-athletes.
- Utilized next-generation sequencing and qPCR to analyze sinus node miRs in swim-trained mice.
- Confirmed miR-423-5p interaction with HCN4 using luciferase reporter assays and anti-miR knockdown.
Main Results:
- Human athletes exhibited lower intrinsic heart rates, correlating with HCN repression.
- miR-423-5p was identified as a key regulator, targeting HCN4's 3'-UTR.
- Knockdown of miR-423-5p reversed training-induced bradycardia by restoring HCN4 and If.
- Nkx2.5 upregulation drove miR-423-5p and NSRP1 expression in trained mice.
Conclusions:
- HCN remodeling is implicated in human athletes, mirroring rodent models.
- miR-423-5p directly targets HCN4, contributing to exercise-induced bradycardia.
- This study reveals microRNA control of HCN4 and heart rate, identifying miR-423-5p as a potential therapeutic target for sinus node dysfunction.
Rationale:
Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), 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 microRNAs (miRs) in the repression of HCN4.
Methods And Results:
As in rodents, the intrinsic heart rate was significantly lower in human athletes than in nonathletes, 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 quantitative real-time reverse transcription polymerase chain reaction showed remodeling 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'-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with anti-miR-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 remodeling likely occurs in human athletes, as well as in 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.
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