circARHGAP10 as a candidate biomarker and therapeutic target in myotonic dystrophy type 1.

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the 3'-UTR of the DMPK gene that lead to nuclear foci accumulation and splicing defects. Circular RNAs (circRNAs) are emerging regulators of muscular disorders, but their role in DM1 remains largely unknown. By analyzing available RNA-sequencing datasets from DM1 patients, followed by validation in patients and matching control muscle biopsies, we identified seven circRNAs that were significantly increased in DM1 muscles and displayed high circular-to-linear isoform ratios. Among them, circARHGAP10 correlated positively with CTG repeat length and inversely with muscle strength, indicating its potential as a biomarker. Silencing of circARHGAP10 in DM1 myogenic cells reduced DMPK expression, decreased nuclear foci, and partially rescued normal splicing. Bioinformatics prediction and pull-down of circARHGAP10 indicated that circARHGAP10 binds miR-409-3p. circARHGAP10 and miR-409-3p were both found to be upregulated in DM1 muscle biopsies and silencing of circARHGAP10 led to the downregulation of miR-409-3p, indicating their co-regulation. Interestingly, miR-409-3p overexpression blocked the beneficial effects of circARHGAP10 silencing on DMPK levels, foci, and splicing. Thus, circARHGAP10-dependent regulation of DM1-associated mechanisms is mediated, at least in part, via interaction with miR-409-3p. In conclusion, circARHGAP10 exhibits promising potential as a biomarker and therapeutic target for DM1.