Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Myotonic dystrophy type I (DM1) is a genetic disorder affecting skeletal muscle.
• It stems from expanded CTG repeats in the DMPK gene, causing RNA toxicity and splicing defects.

Purpose of the Study:

• Investigate the link between DM1 muscle pathology and central metabolic pathways.
• Identify potential therapeutic targets for DM1.

Main Methods:

• Utilized a well-characterized DM1 mouse model (HSALR mice) and cultured human DM1 myotubes.
• Assessed AMPK and mTORC1 signaling pathways and autophagic flux.
• Administered pharmacological agents AICAR (AMPK activator) and Rapamycin (mTORC1 inhibitor).

Main Results:

• HSALR mice exhibited impaired AMPK activation and persistent mTORC1 activity under starvation.
• Autophagic flux was disrupted in DM1 muscle and myotubes.
• AICAR treatment reduced myotonia and partially corrected splicing errors; Rapamycin improved muscle relaxation and force.

Conclusions:

• Deregulation of AMPK/mTORC1 signaling contributes to DM1 muscle pathophysiology.
• Targeting these metabolic pathways offers potential therapeutic strategies for DM1.