Ribitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• O-mannosylated α-dystroglycan (α-DG) is crucial for cell adhesion and signaling.
• Defects in α-DG glycosylation are linked to cancer progression and muscular dystrophies.

Purpose of the Study:

• To investigate the therapeutic potential of ribitol in restoring functional α-DG (F-α-DG) glycosylation.
• To evaluate ribitol's efficacy in a mouse model of FKRP-related congenital muscular dystrophy.

Main Methods:

• Utilized a mouse model with a P448L mutation in the FKRP gene.
• Administered ribitol orally to assess its impact on ribitol-5-phosphate and CDP-ribitol levels.
• Evaluated F-α-DG levels in skeletal and cardiac muscles.
• Assessed muscle pathology, cardiac fibrosis, and functional improvements.

Main Results:

• Ribitol administration restored therapeutic levels of F-α-DG in skeletal and cardiac muscles.
• Treatment reduced skeletal muscle pathology and cardiac fibrosis.
• Ribitol improved skeletal and respiratory functions in FKRP mutant mice.

Conclusions:

• Ribitol shows promise as a novel therapeutic agent for FKRP-related muscular dystrophy.
• Oral ribitol administration is a low-risk, easily administered therapy.
• Restoring F-α-DG levels via ribitol offers a new treatment strategy for dystroglycanopathies.