Abstract
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 to RNP proteins. A significant hurdle for preclinical development along these lines is efficient systemic delivery of compounds across endothelial and target cell membranes. It has been reported that DM1 patients show elevated levels of markers of muscle damage or loss of sarcolemmal integrity 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 expression of dystrophin was normal and calcium-positive fibers, indicating elevated intracellular calcium levels, were only rarely seen. Combined, our findings indicate that cells in DM1 tissues do not display compromised membrane integrity. Hence, the cell membrane is a barrier that must be overcome in future work towards effective drug delivery in DM1 therapy.
Highlights
Myotonic Dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults
We report on membrane integrity and related membrane characteristics in these models, in comparison to findings in wild type (WT) mice and mdx mice, a Duchenne muscular dystrophy (DMD) mouse model with leaky muscle membranes [32,33]
For our study of cell membrane integrity we compared WT mice with DM500, DMSXL and HSALR mice, three transgenic models frequently used in preclinical DM1 studies [39] (Table 1)
Summary
Myotonic Dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. Patients with this disease carry an unstable (CTG)n repeat in the 3’ UTR of the DMPK gene, the length of which correlates with disease severity [1,2]. Mutant DMPK RNAs with a long (CUG)n repeat are retained in the cell nucleus, where they abnormally bind transcription and splicing factors, resulting in aberrant protein production and different downstream cellular effects [3]. PLOS ONE | DOI:10.1371/journal.pone.0121556 March 23, 2015
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