RNA-seq of left ventricular in C57 with or without RBM20 knockin

Dilated cardiomyopathy (DCM) is myocardial disease characterized by ventricular dilation and impaired systolic function, leading to ineffective blood pumping and resulting in heart failure. DCM is the most common cause of heart failure and cardiovascular related death. Recently studies have indicated that mutations in RNA-binding motif protein 20 (RBM20) are linked to hereditary DCM. However, the function of RBM20 in idiopathic DCM is still ambiguous. In this study, we found that RBM20 expression was elevated in patients with idiopathic DCM. Thus, we generated the mouse with cardiomyocyte specific overexpression RBM20, which exhibited dilated ventricle, impaired cardiac function, and increased autophagic activity. Next, dual-luciferase reporter assays and chromatin immunoprecipitation revealed that the transcription factor c-JUN upregulated the RBM20 expression in DCM. Then, we found the exon6-7 skipping isoform of Atp6v0a1 in mice of cardiomyocyte-specific RBM20 overexpression from RNA-sequencing data. And we introduced the lentivirus expressing RFP-GFP-LC3 to demonstrate impaired lysosomal acidification and autophagic flux blockade due to the accumulation of exon6-7 skipping isoform of Atp6v0a1, resulting from aberrant splicing by RBM20. Furthermore, full-length Atp6v0a1 could attenuate cardiac dysfunction and restored lysosomal acidification. Overall, these findings reveal that elevated RBM20 in DCM, driven by increased transcription factor c-JUN, disrupt lysosome acidification and blocked autophagic flux and ultimately leading to heart failure.