Ribitol treatment rescues dystroglycanopathy mice with common L276I mutation.

Matriglycan of alpha dystroglycan (α-DG) serves as a receptor for extracellular matrix proteins. Hypoglycosylation of α-DG underlies specific types of muscular dystrophy, dystroglycanopathy. Fukutin Related Protein (FKRP) gene encodes a glycosyltransferase that adds ribitol-5-phosphate to the core glycan of α-DG and enables the synthesis of matriglycan. Mutations in the FKRP gene are a common cause of dystroglycanopathies. Ribitol is able to restore matriglycan in diseased muscles with FKRP mutations, but this effect relies on partial function of mutant FKRPs. Different mutations affect FKRP function differently, which could affect the efficiency of ribitol treatment. Here we examined the long-term effect of ribitol in mice with FKRP C826A (L276I) mutation, the most common genotype in patient population of LGMD2I/R9. Oral administration of ribitol significantly enhances expression of matriglycan in both cardiac and skeletal muscles up to 40% of normal muscle levels. Importantly, matriglycan is homogeneously expressed in almost all muscle fibers with similar levels especially in cardiac muscle. Consistently, muscle degeneration and regeneration are greatly attenuated with reduced central nucleation and fibrosis especially in the diaphragm. This is associated with improvements in muscle functions, although the diseased mice only show limited deficiency when compared to wild type C57 mice. The higher level of restoration in matriglycan in L276I mice than in P448L mice is consistent with the hypothesis that therapeutic potential of ribitol treatment may depend on the remaining function of mutant FKRPs. These results support clinical trials of ribitol to the majority of patients with FKRP mutations.