The modulation of skeletal muscle glycosylation as a potential therapeutic intervention in muscular dystrophies.

Post-translational modification of proteins following glycosylation is a powerful tool to increase diversity of proteins and ligand interaction. alpha-Dystroglycan, a key muscle fibre receptor for various extracellular matrix ligands, is very heavily glycosylated. In addition heterogeneity of its glycosylation pattern has been described not only in different tissues and organs, but also in different regions of skeletal muscle, such as the sarcolemma and the neuromuscular junction. This review is focused on the potential of hyperglycosylation strategies as a means for therapeutic intervention in several forms of muscular dystrophy. Regarding Duchenne muscular dystrophy (DMD) overexpression of the synaptic CT GalNAc transferase in the sarcolemma of mdx animals was shown to induce the appearance of the CT antigen on the dystroglycan expressed at the sarcolemma. This was followed by the recruitment of utrophin at the sarcolemma and improved muscle pathology in mdx mice. A related strategy has also been used in preclinical models of "dystroglycanopathies". These conditions range in severity from severe and congenital onset to milder forms of limb girdle muscular dystrophy affecting the adult. The mechanism of disease in dystroglycanopathies is presumed to be the uncoupling of the cellular receptor alpha-dystroglycan from its extracellular matrix ligands of which laminin is the most important one. Recent work has demonstrated that the overexpression of 2 related glycosyltransferases, LARGE and LARGE L, results in the hyperglycosylation of alpha-dystroglycan. This hyperglycosylation can also be induced in cells from patients with a dystroglycanopathy, restoring normal dystroglycan ligand binding. LARGE and/or LARGE-L up regulation could therefore represent a therapeutic option for patients affected by dystroglycanopathies, regardless of their primary defect.