Resveratrol enhances splicing of insulin receptor exon 11 in myotonic dystrophy type 1 fibroblasts.

Abstract

Myotonic dystrophy type 1 (DM1) is characterized by splicing abnormalities caused by CUG expansion of the DMPK gene transcript. Splicing of exon 11 of the insulin receptor (IR) gene is deregulated to suppress exon 11 inclusion into mRNA in DM1. Consequently, the exon 11-deleted IR isoform that is less sensitive to insulin is predominantly produced, leading to glucose intolerance in DM1. Upregulation of exon 11 retaining full-length IR mRNA is a potential way to recover insulin sensitivity in DM1. We examined candidate chemicals for their ability to enhance inclusion of exon 11 of the IR gene in cultured cells by reverse transcription-PCR amplification of a fragment extending from exons 10 to 12 of IR mRNA. We revealed that resveratrol (RES) enhanced the percentage of exon 11-containing IR mRNA among the total IR mRNA in HeLa cells. The RES-mediated enhancement of exon 11 inclusion was cell-specific and highest in fibroblasts. We tested RES on four fibroblast samples from three generations of one DM1 family. In each sample, RES treatment significantly upregulated the percentage of exon 11-containing IR mRNA to levels higher than that of the control, irrespective of the length of the sample's CTG repeat expansion. A natural compound, RES, was shown for the first time to upregulate the full-length IR mRNA in fibroblasts from DM1 cases. Our results provide the justification of RES as a leading compound to improve glucose tolerance in DM1.