Progressive cardiac phenotypes and reduced reversibility from long-term CUGexp RNA expression in a DM1 mouse model

Area of Science:

• Molecular Biology
• Genetics
• Cardiology

Background:

• Myotonic Dystrophy Type 1 (DM1) involves CTG repeat expansion in the DMPK gene, leading to toxic CUGexp RNA and MBNL protein sequestration.
• DM1 is a multisystemic disorder with progressive manifestations, often attributed to somatic CTG repeat expansion and increased RNA toxicity.

Purpose of the Study:

• To investigate cardiac disease progression in DM1 independent of CTG repeat expansion.
• To assess the reversibility of DM1 cardiac pathology after toxic RNA expression is suppressed.

Main Methods:

• Utilized a transgenic DM1 mouse model with inducible, heart-specific expression of a stable 960-CUG repeat RNA.
• Monitored cardiac function, fibrosis, and survival following sustained CUGexp RNA expression and subsequent transgene suppression.

Main Results:

• Sustained CUGexp RNA expression induced progressive cardiac enlargement, dysfunction, fibrosis, and reduced survival, despite static MBNL-dependent splicing defects.
• Suppression of CUGexp RNA expression partially rescued cardiac abnormalities, with reversibility diminishing after prolonged toxic RNA exposure.

Conclusions:

• Prolonged expression of stable CUGexp RNA drives progressive cardiac pathology in DM1, representing a disease mechanism beyond somatic repeat expansion.
• Cardiac dysfunction in DM1 may progress independently of CTG repeat instability, highlighting the role of persistent toxic RNA expression.