Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy.
Date
2012-01
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Abstract
Distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy (DMRV/hIBM), characterized by progressive muscle atrophy, weakness, and degeneration, is due to mutations in GNE, a gene encoding a bifunctional enzyme critical in sialic acid biosynthesis. In the DMRV/hIBM mouse model, which exhibits hyposialylation in various tissues in addition to muscle atrophy, weakness, and degeneration, we recently have demonstrated that the myopathic phenotype was prevented by oral administration of N-acetylneuraminic acid, N-acetylmannosamine, and sialyllactose, underscoring the crucial role of hyposialylation in the disease pathomechanism. The choice for the preferred molecule, however, was limited probably by the complex pharmacokinetics of sialic acids and the lack of biomarkers that could clearly show dose response. To address these issues, we screened several synthetic sugar compounds that could increase sialylation more remarkably and allow demonstration of measurable effects in the DMRV/hIBM mice. In this study, we found that tetra-O-acetylated N-acetylmannosamine increased cell sialylation most efficiently, and in vivo evaluation in DMRV/hIBM mice revealed a more dramatic, measurable effect and improvement in muscle phenotype, enabling us to establish analysis of protein biomarkers that can be used for assessing response to treatment. Our results provide a proof of concept in sialic acid-related molecular therapy with synthetic monosaccharides.
Type
Department
Description
Provenance
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Malicdan, May Christine V, Satoru Noguchi, Tomoharu Tokutomi, Yu-ichi Goto, Ikuya Nonaka, Yukiko K Hayashi and Ichizo Nishino (2012). Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy. The Journal of biological chemistry, 287(4). pp. 2689–2705. 10.1074/jbc.M111.297051 Retrieved from https://hdl.handle.net/10161/17551.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.