RNA-Binding Protein RBM20 Upregulation Enhances Dilated Cardiomyopathy by Alternative Splicing of Atp6v0a1

Dilated cardiomyopathy (DCM) is a common cause of heart failure and mutations in RNA-binding motif protein 20 (RBM20) are linked to hereditary DCM. However, the role of unmutated RBM20 in idiopathic DCM is still ambiguous. In this study, we found that RBM20 expression was upregulated by the transcription factor c-JUN in idiopathic DCM. Mice with cardiomyocyte-specific RBM20 overexpression (RBM20cKI) resulted in heart failure with ventricle dilation and lysosome accumulation. Using LysoTracker and a tandem fluorescence RFP-GFP-LC3 reporter system, we elucidated RBM20 blocks autophagic flux in DCM by alkalinizing lysosomal pH. RNA sequencing revealed RBM20 overexpression leads to vacuolar H+-ATPase proton translocation domain subunit a1 (Atp6v0a1) exon6 and exon7 exclusion, which was validated by sanger sequencing and serial amplification product electrophoresis. Transgenic expression of full-length Atp6v0a1 isotype attenuated cardiac dysfunction and restored lysosomal acidification in RBM20cKI mice. Our data suggest that RBM20 activity precisely regulates various cellular process in cardiomyocytes and any therapy targeting RBM20 requires extra cautious.