N-Acetylglucosamine, which increases the biosynthesis of ligands for galectin-3, promotes myogenesis and mitigate the burden of Duchenne muscular dyst


Non-Gene Targeting Therapies

Poster Number: 129


Sachiko Sato, PhD, Ann Rancourt, BSc, Guillaume St-Pierre, B. Sc, M. Sc, Sebastien S. Dufresne, B. Sc. Ph. D, Masahiko Sato, PhD, Jérôme Frenette, B.Sc, Ph. D


1. Faculty of Medicine, Laval University, and CHUL-CHU de Québec, 2. Faculty of Medicine, Laval University, and CHUL-CHU de Québec, 3. Research Centre of CHU de Quebec Laval University, 4. Research Centre of CHU de Quebec Laval University, 5. Faculty of Medicine, Laval University, and CHUL-CHU de Québec, 6. Faculty of Medicine, Laval University

Repeated eccentric contractions cause muscle injury. To protect against this damage, muscle fibres are attached to the basal lamina, such as laminin. The failure of proper attachment results in muscle injury, which is the underlying cause of DMD, where mutations in the dystrophin gene disrupts the adhesion. In DMD patients, moderate contraction causes damage, leading to muscle degeneration. The damaged muscles are repaired through myogenesis. Consequently, myogenesis is active in DMD patients, and the repeated activation of myogenesis leads to myogenic stem cell exhaustion. An approach to reducing the risk of the exhaustion is to develop a treatment that strengthens the interaction between the sarcolemma and laminin and increases the efficiency of myogenesis. Galectin-3 is an oligosaccharide-binding protein, which was originally found as a laminin-binding protein. It can act as a cell adhesion molecule and modifier of membrane protein dynamics. Interestingly, galectin-3 is one of the most highly expressed proteins in myoblasts and DMD skeletal muscles while its function(s) in the muscular system have never been investigated. We found evidence that both galectin-3 and the monosaccharide N-acetylglucosamine (GlcNAc), which increases the synthesis of galectin ligands, promotes myogenesis, while non-acetylated form of GlcNAc, glucosamine showed some toxicity in myoblasts. A long term live cell imaging showed that myogenesis of primary myoblasts that lack either galectin-3 or dystrophin was partially impaired and the treatment with either of both galectin-3 and GlcNAc increased the myogenesis. Treatment (intraperitoneal) with GlcNAc for 10 days improved maximum force strength of dystrophic muscle in a mdx mouse model of DMD. Furthermore, our preliminary results suggest that oral GlcNAc treatment also mitigate some progression of DMD. Since GlcNAc is uniquely found in human milk (0–4 months after birth) at levels as high as 1.5 g/l and was shown to be safe in a 52-week rat toxicology study (2.5 g/kg body weight/day) and in a 4-week clinical trial (6 g/day) in patients with inflammatory bowel disease. Together, the results suggest an interesting potential of GlcNAc as a therapy to mitigate the progression of DMD.