Alternative splicing of SORBS1 affects neuromuscular junction formation and stability in myotonic dystrophy type 1

Abstract

Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disease characterized by a CTG repeat expansion in the 3" untranslated region of the gene coding for the dystrophia myotonica protein kinase (DMPK). Presence of expanded CTG repeats in DMPK-mRNAs leads to the sequestration of RNA binding factors such as the Muscleblind like (MBNL) proteins resulting in widespread splicing defects contributing to progressive muscle weakness and myotonia. Here, we show that abnormal splicing of SORBS1 exon 25 found in skeletal muscle of myotonic dystrophy type 1 patients is a critical contributor to neuromuscular junction (NMJ) formation and maintenance. Forced exclusion of SORBS1 exon 25 in mice results in NMJ degeneration with marked denervation and postsynaptic destabilization. In zebrafish, misregulation of sorbs1 exon 25 results in reduced motor function and abnormal AChR cluster morphology. Finally, we observed that forcing SORBS1 exon 25 exclusion in hiPSC-derived skeletal muscle cells reduces the formation of large AChR clusters upon agrin stimulation. Thus, our study identifies MBNL regulated SORBS1 alternative splicing during skeletal muscle development as a critical event for NMJ formation and maintenance. The aberrant splicing of SORBS1 exon 25 in DM1 expands our understanding of how splicing dysregulation compromises neuromuscular system communication, shedding light on the broader impact of mRNA splicing regulation on NMJ integrity.