Cell Membrane Integrity in Myotonic Dystrophy Type 1: Implications for Therapy

Myotonic Dystrophy type 1 (DM1) is a multisystemic disease caused by toxic RNA from a DMPK gene carrying an expanded (CTG∗CAG) n repeat. Promising strategies for treatment of DM1 patients are currently being tested. These include antisense oligonucleotides and drugs for elimination of expanded RNA or prevention of aberrant binding of this RNA to RNP proteins. A significant hurdle for preclinical development along these lines is efficient systemic delivery of compounds across endothelial and muscle and brain cell membranes. It has been reported that DM1 patients show elevated levels of muscular markers in their serum and that splicing of dystrophin, an essential protein for muscle membrane structure, is abnormal. Therefore, we studied cell membrane integrity in DM1 mouse models commonly used for preclinical testing. We found that membranes in skeletal muscle, heart and brain were impermeable to Evans Blue Dye. Creatine kinase levels in serum were similar to those in wild type mice and expression of dystrophin protein was unaffected. Also in patient muscle biopsies cell surface distribution of dystrophin was normal. Combined, our findings show that cells in DM1 tissues have a normal functional membrane, which forms a barrier that must be overcome in future work towards effective drug delivery.