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

Nature Communications
Marcela P CataldiQi Long Lu

Abstract

O-mannosylated α-dystroglycan (α-DG) serves as receptors for cell-cell and cell-extracellular matrix adhesion and signaling. Hypoglycosylation of α-DG is involved in cancer progression and underlies dystroglycanopathy with aberrant neuronal development. Here we report that ribitol, a pentose alcohol with previously unknown function in mammalian cells, partially restores functional O-mannosylation of α-DG (F-α-DG) in the dystroglycanopathy model containing a P448L mutation in fukutin-related protein (FKRP) gene, which is clinically associated with severe congenital muscular dystrophy. Oral administration of ribitol increases levels of ribitol-5-phosphate and CDP-ribitol and restores therapeutic levels of F-α-DG in skeletal and cardiac muscles. Furthermore, ribitol, given before and after the onset of disease phenotype, reduces skeletal muscle pathology, significantly decreases cardiac fibrosis and improves skeletal and respiratory functions in the FKRP mutant mice. Ribitol treatment presents a new class, low risk, and easy to administer experimental therapy to restore F-α-DG in FKRP-related muscular dystrophy.

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Citations

Dec 24, 2018·Disease Models & Mechanisms·Alec R Nickolls, Carsten G Bönnemann
Jan 16, 2019·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Tamao Endo
May 20, 2020·Disease Models & Mechanisms·Alec R NickollsCarsten G Bönnemann
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Aug 10, 2019·Biochemistry·Paulina SosickaHudson H Freeze
Jan 29, 2020·Molecular Therapy. Methods & Clinical Development·Marcela P CataldiQi Long Lu

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Datasets Mentioned

BETA
AF6868

Methods Mentioned

BETA
glycosylation
PCR
protein assay
force measurements

Software Mentioned

ImageJ
GraphPad Prism
EMKA iox2
GraphPad
MetaMorph

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