Peracetylated N-acetylmannosamine, a synthetic sugar molecule, efficiently rescues muscle phenotype and biochemical defects in mouse model of sialic acid-deficient myopathy.
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 articleSubject
Muscle, SkeletalAnimals
Mice, Transgenic
Humans
Mice
Distal Myopathies
Disease Models, Animal
N-Acetylneuraminic Acid
Hexosamines
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https://hdl.handle.net/10161/17551Published Version (Please cite this version)
10.1074/jbc.M111.297051Publication 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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Show full item recordScholars@Duke
Tomoharu Tokutomi
Visiting Research Scholar in the Department of Medicine

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