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Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy.

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Date
2012-01
Authors
Malicdan, May Christine V
Noguchi, Satoru
Tokutomi, Tomoharu
Goto, Yu-ichi
Nonaka, Ikuya
Hayashi, Yukiko K
Nishino, Ichizo
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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
Journal article
Subject
Muscle, Skeletal
Animals
Mice, Transgenic
Humans
Mice
Distal Myopathies
Disease Models, Animal
N-Acetylneuraminic Acid
Hexosamines
Permalink
https://hdl.handle.net/10161/17551
Published Version (Please cite this version)
10.1074/jbc.M111.297051
Publication Info
Malicdan, May Christine V; Noguchi, Satoru; Tokutomi, Tomoharu; Goto, Yu-ichi; Nonaka, Ikuya; Hayashi, Yukiko K; & Nishino, Ichizo (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.
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Scholars@Duke

Tomoharu Tokutomi

Visiting Research Scholar in the Department of Medicine
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