Generation and characterization of a DYNLT1-knockout mouse model reveals electrophysiological alterations and potential mechanistic contributors to atrial fibrillation.

Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke and heart failure and is associated with high morbidity and mortality. However, its molecular pathogenesis remains incompletely understood. In this study, we generated a DYNLT1 knockout (KO) mouse model using CRISPR/Cas9 technology. Through electrocardiography, echocardiography, and histological analysis, we found that DYNLT1 deletion induced spontaneous AF. The KO mice exhibited not only surface electrophysiological remodeling and atrial structural changes but also increased atrial cardiomyocyte apoptosis, downregulation of gap junction proteins, and elevated inflammatory markers at the molecular level. Furthermore, using mass spectrometry, immunofluorescence, and other molecular techniques, we observed that DYNLT1 deletion reduced the distribution of its interacting protein TMCO1 in the endoplasmic reticulum (ER) of atrial cardiomyocytes, leading to ER calcium overload and potentially triggering the onset of AF. This study establishes a novel animal model for AF research, advances our understanding of the molecular mechanisms underlying AF, and provides a theoretical basis for the development of targeted molecular therapies.