In Vivo Evaluation of CTG Repeat-Affected Muscle Pathology in a Myotonic Dystrophy Model Mouse Using Electromyography and Fluorescence In Situ Hybridization.

Abstract

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, caused by an expanded CTG repeat in the DMPK gene. Patients with DM1 develop multisystemic symptoms including myotonia, which manifests as delayed relaxation of muscles following voluntary contraction. This myotonic phenomenon can be assessed by electromyography (EMG), where it presents as a prolonged action potential duration, referred to as myotonic discharge. In both patients and mouse models, the expanded CUG repeat RNA transcribed from the mutated gene aberrantly accumulates in nuclei. This accumulation can be visualized using fluorescence in situ hybridization (FISH). The abnormal RNA accumulation leads to the dysregulation of alternative splicing in specific genes, resulting in disease symptoms that include myotonia and progressive muscle wasting. Given the pathogenesis, RNA-targeted therapeutics, such as antisense oligonucleotides, represent one of the promising approaches for DM1 treatment. This chapter describes a method for conducting needle EMG with a portable device, as well as a FISH method for a representative mouse model of DM1, the HSAmouse harboring an expanded CTG repeat. These methods can be applied to evaluate the therapeutic efficiency of emerging therapies in DM1 model mice.