Abstract
Distal myopathy with rimmed vacuoles (DMRV)–hereditary inclusion body myopathy (hIBM) is an adult-onset, moderately progressive autosomal recessive myopathy; eventually, affected individuals become wheelchair bound1. It is characterized clinically by skeletal muscle atrophy and weakness, and pathologically by rimmed vacuoles, which are actually accumulations of autophagic vacuoles2,3,4, scattered angular fibers and intracellular accumulation of amyloid and other proteins5. To date, no therapy is available for this debilitating myopathy, primarily because the disease pathomechanism has been enigmatic. It is known that the disease gene underlying DMRV-hIBM is GNE, encoding glucosamine (UDP-N-acetyl)-2-epimerase and N-acetylmannosamine kinase6,7,8—two essential enzymes in sialic acid biosynthesis9. It is still unclear, however, whether decreased sialic acid production causes muscle degeneration, as GNE has been proposed to have roles other than for sialic acid biosynthesis10,11,12. By showing that muscle atrophy and weakness are completely prevented in a mouse model of DMRV-hIBM after treatment with sialic acid metabolites orally, we provide evidence that hyposialylation is indeed one of the key factors in the pathomechanism of DMRV-hIBM. These results support the notion that DMRV-hIBM can potentially be treated simply by giving sialic acids, a strategy that could be applied in clinical trials in the near future.
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Acknowledgements
The authors acknowledge the valuable assistance offered by F. Funato and R. Hoshi in motor performance evaluation of mice, toxicology assays and sialic acid measurement. This study is supported partly by the Research on Psychiatric and Neurological Diseases and Mental Health grant from the Japanese Health Sciences Foundation; the Program for Promotion of Fundamental Studies in Health Sciences of the Japanese National Institute of Biomedical Innovation the Research Grant (19A–7) for Nervous and Mental Disorders from the Ministry of Health Labour and Welfare in Japan, the Kato Memorial Trust for Nambyo Research and the Neuromuscular Disease Foundation.
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M.C.V.M. conducted most of the experiments and wrote the manuscript; S.N. supervised all aspects of this study, including study design, execution and interpretation and manuscript preparation, and participated in the analysis of the in vitro muscle data and sialic acid measurement; I. Nonaka, Y.K.H. and I. Nishino were involved in analyzing and interpreting all the data and also supervised the study design, execution and interpretation and manuscript preparation.
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The National Center of Neurology and Psychiatry (Japan), where the authors are employed, along with the Japan Health Science Foundation have applied to the Japan Patent Office for a patent on the use of sialic acid metabolites and their derivatives in DMRV-hIBM treatment.
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Malicdan, M., Noguchi, S., Hayashi, Y. et al. Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nat Med 15, 690–695 (2009). https://doi.org/10.1038/nm.1956
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DOI: https://doi.org/10.1038/nm.1956
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