Affiliation:
1. Department of Physiology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands
2. Amsterdam Cardiovascular Sciences Heart Failure and Arrhythmias Amsterdam The Netherlands
3. Division of Metabolism, Endocrinology and Diabetes and Department of Internal Medicine University of Michigan Medical School Ann Arbor MI
4. Human and Animal Physiology Wageningen University Wageningen The Netherlands
5. Department of Cardiology Erasmus Medical Center Rotterdam The Netherlands
Abstract
Background
Atrial fibrillation (AF) is the most common and progressive tachyarrhythmia. Diabetes is a common risk factor for AF. Recent research findings revealed that microtubule network disruption underlies AF. The microtubule network mediates the contact between sarcoplasmic reticulum and mitochondria, 2 essential organelles for normal cardiomyocyte function. Therefore, disruption of the microtubule network may impair sarcoplasmic reticulum and mitochondrial contacts (SRMCs) and subsequently cardiomyocyte function. The current study aims to determine whether microtubule‐mediated SRMCs disruption underlies diabetes‐associated AF.
Methods and Results
Tachypacing (mimicking AF) and high glucose (mimicking diabetes) significantly impaired contractile function in HL‐1 cardiomyocytes (loss of calcium transient) and
Drosophila
(reduced heart rate and increased arrhythmia), both of which were prevented by microtubule stabilizers. Furthermore, both tachypacing and high glucose significantly reduced SRMCs and the key SRMC tether protein mitofusin 2 (MFN2) and resulted in consequent mitochondrial dysfunction, all of which were prevented by microtubule stabilizers. In line with pharmacological interventions with microtubule stabilizers, cardiac‐specific knockdown of MFN2 induced arrhythmia in
Drosophila
and overexpression of MFN2 prevented tachypacing‐ and high glucose–induced contractile dysfunction in HL‐1 cardiomyocytes and/or
Drosophila
. Consistently, SRMCs/MFN2 levels were significantly reduced in right atrial appendages of patients with persistent AF compared with control patients, which was aggravated in patients with diabetes.
Conclusions
SRMCs may play a critical role in clinical AF, especially diabetes‐related AF. Furthermore, SRMCs can be regulated by microtubules and MFN2, which represent novel potential therapeutic targets for AF.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
4 articles.
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