title: 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.
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: May Christine V
authors.initials: MC
authors.lastname: Malicdan
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Tokutomi
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D049310:Distal Myopathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006595:Hexosamines / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*
chemical_list: D006595:Hexosamines; D019158:N-Acetylneuraminic Acid; C002022:N-acetylmannosamine