LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy

• Published in: Nature (London) Vol. 503; no. 7474; pp. 136 - 140
• Main Authors: Goddeeris, Matthew M., Wu, Biming, Venzke, David, Yoshida-Moriguchi, Takako, Saito, Fumiaki, Matsumura, Kiichiro, Moore, Steven A., Campbell, Kevin P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.11.2013; Nature Publishing Group
• Subjects: 631/80/304; 631/80/458/1524; Animals; Basement Membrane - metabolism; Basement Membrane - pathology; Cell Differentiation; Cell Line; Cell physiology; Cellular control mechanisms; Collagen; Dystroglycans - chemistry; Dystroglycans - metabolism; Dystrophy; Extracellular Matrix - chemistry; Extracellular Matrix - metabolism; Female; Health aspects; Humanities and Social Sciences; Humans; letter; Ligands; Male; Mice; Mice, Inbred C57BL; Microscopy; Molecular biology; Molecular Weight; multidisciplinary; Muscle Development; Muscles - metabolism; Muscles - pathology; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Muscular Dystrophies - prevention & control; Muscular dystrophy; Musculoskeletal system; Mutation; Myoblasts; N-Acetylglucosaminyltransferases - deficiency; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; Neuromuscular Junction - metabolism; Neuromuscular Junction - pathology; Phenotype; Physiological aspects; Polysaccharides; Polysaccharides - chemistry; Polysaccharides - metabolism; Prevention; Proteins; Science; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12605

This study finds a direct correlation between LARGE-glycan extension on dystroglycan and the protein’s capacity for extracellular matrix ligands; in regenerating mouse muscle, short LARGE-glycan polysaccharides cause various defects, including muscle dysfunction and a predisposition to dystrophy, and in muscular dystrophy patients, increased clinical severity of disease corresponds to shorter LARGE-glycans. Dystroglycan's role in muscular dystrophy The extracellular peripheral glycoprotein dystroglycan is post-translationally decorated with sugars, and the addition of glycans by the enzyme called LARGE is necessary for its receptor function. Reduction in LARGE-glycan additions results in various forms of muscular dystrophy, but why is unclear. Here Kevin Campbell and colleagues show that there is a direct correlation between LARGE-glycan extensions on dystroglycan and its avidity for extracellular matrix ligands. Short LARGE-glycan repeats results in various defects, including dysfunctional muscle predisposed to dystrophy. They further show that patients with increased clinical severity of muscle dystrophy have a greater degree of LARGE-glycan shortening. The dense glycan coat that surrounds every cell is essential for cellular development and physiological function 1 , and it is becoming appreciated that its composition is highly dynamic. Post-translational addition of the polysaccharide repeating unit [-3-xylose-α1,3-glucuronic acid-β1-] n by like-acetylglucosaminyltransferase (LARGE) is required for the glycoprotein dystroglycan to function as a receptor for proteins in the extracellular matrix 2 , 3 . Reductions in the amount of [-3-xylose-α1,3-glucuronic acid-β1-] n (hereafter referred to as LARGE-glycan) on dystroglycan result in heterogeneous forms of muscular dystrophy 4 . However, neither patient nor mouse studies has revealed a clear correlation between glycosylation status and phenotype 5 , 6 . This disparity can be attributed to our lack of knowledge of the cellular function of the LARGE-glycan repeat. Here we show that coordinated upregulation of Large and dystroglycan in differentiating mouse muscle facilitates rapid extension of LARGE-glycan repeat chains. Using synthesized LARGE-glycan repeats we show a direct correlation between LARGE-glycan extension and its binding capacity for extracellular matrix ligands. Blocking Large upregulation during muscle regeneration results in the synthesis of dystroglycan with minimal LARGE-glycan repeats in association with a less compact basement membrane, immature neuromuscular junctions and dysfunctional muscle predisposed to dystrophy. This was consistent with the finding that patients with increased clinical severity of disease have fewer LARGE-glycan repeats. Our results reveal that the LARGE-glycan of dystroglycan serves as a tunable extracellular matrix protein scaffold, the extension of which is required for normal skeletal muscle function.