A sugar-transferring enzyme known as LARGE could help to restore muscle function in patients with muscular dystrophy, according to research from Kevin Campbell and colleagues published in Nature Medicine online on 6 June. And in a related Cell paper, published online on 3 June, Campbell and co-workers showed that LARGE might exert its effects by mediating the attachment of sugar molecules to α-dystroglycan, a key component of the dystrophin–glycoprotein complex that forms a link between the inside and outside of muscle cells.

Muscular dystrophies are a group of genetic disorders that are characterized by progressive weakening and wasting of muscles. In a subset of congenital muscular dystrophies (CMD), mutations in genes that encode glycosyltransferase enzymes, which add sugars to proteins, lead to muscle degeneration and defects in brain development. In these disorders, α-dystroglycan, which is normally heavily glycosylated, lacks its sugars and is unable to bind its ligands in the extracellular matrix. The disruption of this crucial link between the inside and outside of muscle cells is thought to make the cells more vulnerable to stress-induced damage.

In the Cell paper, experiments showed that an interaction between LARGE and α-dystroglycan is crucial for the production of functional, glycosylated α-dystroglycan and therefore the maintenance of healthy muscle. In their Nature Medicine paper, Campbell and colleagues used LARGE to investigate whether restoring glycosyltransferase activity in CMD could prevent the defects associated with this subset of muscular dystrophies.

They began their analysis using a mouse model of CMD, which has a mutation in the gene encoding LARGE. An adenovirus that was engineered to express the LARGE gene was injected into the muscle of mutated mice that were just a few days old. These muscle cells produced functional LARGE protein and α-dystroglycan that was enriched with sugar molecules. The ability of α-dystroglycan to bind to proteins in the extracellular matrix was restored, and when viewed under a microscope, the muscle looked like normal, healthy tissue. Furthermore, mice expressing the transferred gene were shown to suffer significantly less from exercise-induced muscle damage than untreated littermates. LARGE overexpression also increased the binding of α-dystroglycan to the extracellular matrix in the muscles of normal, healthy mice, without introducing any abnormalities.

The researchers then decided to test the effects of LARGE in the cells of patients with CMD. They treated the cells of patients with three different types of CMD — Fukuyama CMD, muscle–eye–brain disease and Walker–Warburg syndrome — with the adenovirus that carried the LARGE gene. And although these diseases are caused by mutations in different glycosyltransferase enzymes, expression of LARGE generated functional, glycosylated α-dystroglycan in all three cases.

These results, say the authors, suggest that stimulating the addition of sugar to α-dystroglycan by LARGE could provide a potential therapy for certain muscular dystrophies, regardless of the type of glycosyltransferase enzyme that has been mutated.