Sialyllactose ameliorates myopathic phenotypes in symptomatic GNE myopathy model mice.

Abstract

Patients with GNE myopathy, a progressive and debilitating disease caused by a genetic defect in sialic acid biosynthesis, rely on supportive care and eventually become wheelchair-bound. To elucidate whether GNE myopathy is treatable at a progressive stage of the disease, we examined the efficacy of sialic acid supplementation on symptomatic old GNE myopathy mice that have ongoing, active muscle degeneration. We examined the therapeutic effect of a less metabolized sialic acid compound (6'-sialyllactose) or free sialic acid (N-acetylneuraminic acid) by oral, continuous administration to 50-week-old GNE myopathy mice for 30 weeks. To evaluate effects on their motor performance in living mice, spontaneous locomotion activity on a running wheel was measured chronologically at 50, 65, 72 and 80 weeks of age. The size, force production, and pathology of isolated gastrocnemius muscle were analysed at the end point. Sialic acid level in skeletal muscle was also measured. Spontaneous locomotion activity was recovered in 6'-sialyllactose-treated mice, while NeuAc-treated mice slowed the disease progression. Treatment with 6'-sialyllactose led to marked restoration of hyposialylation in muscle and consequently to robust improvement in the muscle size, contractile parameters, and pathology as compared to NeuAc. This is due to the fact that 6'-sialyllactose is longer working as it is further metabolized to free sialic acid after initial absorption. 6'-sialyllactose ameliorated muscle atrophy and degeneration in symptomatic GNE myopathy mice. Our results provide evidence that GNE myopathy can be treated even at a progressive stage and 6'-sialyllactose has more remarkable advantage than free sialic acid, providing a conceptual proof for clinical use in patients.

• Authors: Takahiro Yonekawa, May Christine V Malicdan, Anna Cho, Yukiko K Hayashi, Ikuya Nonaka, Toshiki Mine, Takeshi Yamamoto, Ichizo Nishino, Satoru Noguchi
• Journal: Brain : a journal of neurology (Brain) Vol. 137 Issue Pt 10 Pg. 2670-9 (Oct 2014) ISSN: 1460-2156 [Electronic] England
• PMID: 25062695 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• 6'-sialyllactose
• Amyloid beta-Peptides
• Hexosamines
• Peptide Fragments
• amyloid beta-protein (1-40)
• amyloid beta-protein (1-42)
• Creatine Kinase
• N-Acetylneuraminic Acid
• Lactose
• N-acetylmannosamine

Topics

• Aging (pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Body Weight (drug effects)
• Cells, Cultured
• Creatine Kinase (metabolism)
• Disease Models, Animal
• Distal Myopathies (drug therapy, pathology)
• Enzyme-Linked Immunosorbent Assay
• Hexosamines (therapeutic use)
• Lactose (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Mice
• Muscle Contraction (physiology)
• Muscle, Skeletal (pathology)
• Mutation (genetics)
• Myoblasts (drug effects, metabolism)
• N-Acetylneuraminic Acid (metabolism, therapeutic use)
• Peptide Fragments (metabolism)
• Phenotype