Skeletal muscle sodium channel gating in mice deficient in myotonic dystrophy protein kinase

Myotonic dystrophy, a progressive autosomal dominant disorder, is associate d with an expansion of a CTG repeat tract located in the 3'-untranslated re gion of a serine/threonine protein kinase, DMPK. DMPK modulates skeletal mu scle Na channels in vitro, and thus we hypothesized that mice deficient in DMPK would have altered muscle Na channel gating. We measured macroscopic a nd single channel Na currents from cell-attached patches of skeletal myocyt es from mice heterozygous (DMPK+/-) and homozygous (DMPK-/-) for DMPK loss. In DMPK-/- myocytes, Na current amplitude was reduced because of reduced c hannel number. Single channel recordings revealed Na channel reopenings, si milar to the gating abnormality of human myotonic muscular dystrophy (DM), which resulted in a plateau of Na current. The gating abnormality deteriora ted with increasing age. In DMPK+/- muscle there was reduced Na current amp litude and increased Na channel reopenings identical to those in DMPK-/- mu scle. Thus, these mouse models of complete and partial DMPK deficiency repr oduce the Na channel abnormality of the human disease, providing direct evi dence that DMPK deficiency underlies the Na channel abnormality in DM.