Skeletal myopathy in mice over-expressing the human myotonic dystrophy protein kinase (DMPK) gene

Abstract

Myotonic dystrophy (DM) is caused by the expansion of a trinucleotide repeat located in the 3’-untranslated region of a serine-threonine kinase (DMPK), such that repeat size corresponds with severity of disease and age of onset. The mechanism by which this mutation causes DM remains unclear. Recent reports indicate that over-expression of DMPK in murine C2C12 myoblasts inhibits myogenesis, reminiscent of the marked immaturity observed in DM patient muscle. Accordingly, we generated transgenic mice over-expressing the human DMPK gene with expression enhancing matrix attachment region (MAR) sequences. These mice show substantial over-expression of human DMPK transcript and protein in brain, skeletal muscle, tongue, and eye - tissues typically affected in DM. Cryostat sections of skeletal muscle from these transgenic animals revealed diagnostic hallmarks of DM including increased centronucleation, type 1 fiber atrophy and ringed fibers. Additionally, primary myoblasts established from these mice showed reduced fusion potential indicating a delay or defect in myoblast differentiation. These results suggest that over-expression of the human DMPK gene in these mice confers a skeletal muscle pathology similar to that seen in DM patients.