LRRc17-RANKL pathway regulates mitophagy and contributes to atrial remodeling in diabetes

Abstract

Background

Impaired autophagy and mitochondrial dysfunction are significant causes of atrial remodeling, increasing the risk of atrial fibrillation (AF) in type 2 diabetes mellitus (T2DM). Both LRRc17 and RANKL proteins are involved in the autophagic mechanism. Nevertheless, there is limited understanding of the mechanisms how LRRc17 and RANKL regulate mitophagy to facilitate atrial remodeling under diabetic conditions.

Methods

Echocardiography, intracardiac programmed electrical stimulation, and epicardial electrical activation mapping were used to identify atrial remodeling. Mitophagy was identified by western blot analysis and immunofluorescence techniques. The regulatory relationship between LRRc17 and RANKL was validated using lentiviral transfection and siRNA knockdown. This work employed AAV9-cTNT-RANKL vectors to overexpress RANKL in the myocardium of diabetic mice for determining its specific involvement.

Results

Significant atrial remodeling caused by diabetes was characterized by enlarged atrium, increased fibrotic interstitial deposits, and abnormal electrical conduction. In diabetic atrial tissue, the level of LRRc17 protein was downregulated and RANKL protein expression was elevated. The negative regulatory function of LRRc17 on RANKL in atrial myocytes was elucidated using HL-1 cells. Overexpression of RANKL highlighted its critical role in causing mitochondrial malfunction. And the administration of the RANKL antagonist, denosumab, markedly improved the compromised mitophagy.

Conclusion

In atrial myocytes, mitophagy is mediated by the LRRc17-RANKL pathway. Diabetes induced atrial remodeling may worsen due to the overexpression of RANKL brought on by the decrease in LRRc17. The LRRc17-RANKL pathway may be a therapy option for diabetic atrial remodeling by improving mitochondrial function.