Abstract
Abstract Background Atrial fibrillation (AF), the most common tachyarrhythmia, is a progressive disease characterized by electrophathology, which is defined as the structural remodeling of atrial cardiomyocytes that underlies electrophysiological remodeling and contractile dysfunction and consequently AF progression. We recently discovered that disruption of microtubule network, by HDAC6 activation, is a key factor underlying structural remodeling and AF promotion in experimental models for AF and patients with AF. However, the molecular mechanism how microtubule disruption induces contractile dysfunction in AF is unclear. Sarcoplasmic reticulum (SR) and mitochondria are the central organelles for normal cardiomyocyte contraction by controlling the Ca2+ and energy (ATP) homeostasis. The crosstalk between SR and mitochondria via contacts, termed SR-mitochondria contacts (SMCs), is essential for normal mitochondrial and cardiac function. Interestingly, functional SMCs are highly dependent on intact microtubule network. This study aims to whether preservation of microtubule protects against AF via SMC pathway. Methods and results Tachypacing of HL-1 cardiomyocytes significantly impaired calcium transient (CaT) amplitude compared to normal paced cardiomyocytes. Pretreatment with microtubule stalilizer taxol and acetyl-CoA inducer β-hydroxybutyrate (βOHB) significantly protected against tachypacing-induced CaT loss. Moreover, by using immunoflurecent staining, mitochondrial associated membrane isolation and seahorse, we showed that tubacin, Taxol and βOHB also significantly inhibited the SMC reduction, attenuated tachypacing-induced mitochondrial dysfunction. Consistently, these microtubule stabilizer drugs also prevented tachypacing-induced contractile dysfunction in the Drosophila model for AF. Conclusions Preservation of microtubule network prevented the reduction of SMCs and the consequent mitochondrial and contractile dysfunction in HL-1 cardiomyocytes and Drosophila models for AF. Therefore, the microtubule-SMC pathway is a novel central therapeutic target for AF. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Heart Foundation
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