The inadequate expression of LCRMP-1 leads to sinoatrial dysfunction through disrupting calcium cycling

Introduction and Objectives
The sinoatrial (SA) node acts as the heart's natural pacemaker, regulating muscle contractions for blood flow. Sick sinus syndrome (SSS), caused by SA node dysfunction, can lead to various heart issues. Diagnosis involves electrocardiography and may require an implanted pacemaker. However, there is a need to find new biomarkers for diagnosis and develop alternative therapeutic approaches to address associated limitations and risks. Previously, we found that LCRMP-1 can enhance cancer metastasis and promote tumor angiogenesis. Recently, we observed signs of sinoatrial arrhythmia in both young and older LCRMP-1 knockout (KO) mice, along with bi-atrial enlargement in the older mice. This suggests LCRMP-1 may regulate sinoatrial heart activity, requiring further investigation for a comprehensive understanding.
Methods
To investigate the impact of LCRMP-1 on cardiac function, we created specific LCRMP-1 KO mice using two different methods. We used echocardiography and MRI to evaluate the cardiac structures and functions and monitored the rhythmic activity in LCRMP-1 KO mice using ECGs. Subsequently, we established LCRMP-1 silenced HL-1 stable atrial cardiomyocytes and assessed their electrophysiological properties using a microelectrode array (MEA). To gain insight into the detailed mechanism of LCRMP-1-regulated heart rhythm, we conducted a spatial interactome analysis of LCRMP-1 protein in the tissues. We established a specific LCRMP-1 protein linkage map in the SA node and right atrium regions. Additionally, we investigated the dynamic changes and detailed action mechanisms of LCRMP-1 on calcium cycling in vitro.
Results and Discussion
The presence of occasional absent P waves, particularly noticeable in younger mice, suggests a potential manifestation of SSS due to LCRMP-1 deficiency. This indicates a direct impact on the function of the sinoatrial node, leading to irregular heart rhythms. In our spatial IP-MS analysis, we revealed a network of LCRMP-1 interacting proteins associated with metabolic pathways and ion homeostasis, especially those related to calcium ion channels. This analysis provided a comprehensive view of the proteins that interact with LCRMP-1 and their potential roles in cardiac function. Reciprocal Co-IP assays confirmed the binding of LCRMP-1 to calcium-regulating proteins, emphasizing its role in modulating calcium release channels. Calcium cycling studies in HL-1 cardiomyocytes demonstrated that LCRMP-1 knockdown disrupted calcium dynamics, leading to irregular calcium waves.
Conclusion
LCRMP-1 is critical in maintaining cardiac structure, electrical rhythm, and calcium cycling. LCRMP-1 KO mice showed right atrial dilation and SSS, which were linked to disrupted calcium cycling. These findings emphasize the importance of LCRMP-1 as a key regulator of the sinoatrial area and offer new insights into potential pathways for SSS.

Keywords
Sick sinus syndrome, LCRMP-1, Spatial IP-MS