Correction of Clcn1 alternative splicing reverses muscle fiber type transition in mice with myotonic dystrophy

In myotonic dystrophy type 1 (DM1), deregulated alternative splicing of the muscle chloride channel Clcn1 causes myotonia, a delayed relaxation of muscles due to repetitive action potentials. The degree of weakness in adult DM1 is associated with increased frequency of oxidative muscle fibers. However, the mechanism for glycolytic-to-oxidative fiber type transition in DM1 and its relationship to myotonia are uncertain. Here we cross two mouse models of DM1 to create a double homozygous model that features progressive functional impairment, severe myotonia, and near absence of type 2B glycolytic fibers. Intramuscular injection of an antisense oligonucleotide for targeted skipping of Clcn1 exon 7a corrects Clcn1 alternative splicing, increases glycolytic 2B levels to ≥ 40% frequency, reduces muscle injury, and improves fiber hypertrophy relative to treatment with a control oligo. Our results demonstrate that fiber type transitions in DM1 result from myotonia and are reversible, and support the development of Clcn1-targeting therapies for DM1.