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Brain. 2014 Oct;137(Pt 10):2670-9. doi: 10.1093/brain/awu210. Epub 2014 Jul 24.

Sialyllactose ameliorates myopathic phenotypes in symptomatic GNE myopathy model mice.

Author information

1
1 Department of Neuromuscular Research, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan 2 Department of Education, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
2
3 Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
3
1 Department of Neuromuscular Research, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan.
4
1 Department of Neuromuscular Research, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan 4 Department of Clinical Development, Translational Medical Centre, NCNP, Tokyo, Japan 5 Department of Neurophysiology, Tokyo Medical University, Tokyo, Japan.
5
6 Glycotechnology Business Unit, Japan Tabacco Inc, Shizuoka, Japan.
6
1 Department of Neuromuscular Research, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan 2 Department of Education, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan 4 Department of Clinical Development, Translational Medical Centre, NCNP, Tokyo, Japan.
7
1 Department of Neuromuscular Research, National Institute of Neuroscience, National Centre of Neurology and Psychiatry (NCNP), Tokyo, Japan 4 Department of Clinical Development, Translational Medical Centre, NCNP, Tokyo, Japan noguchi@ncnp.go.jp.

Abstract

Patients with GNE myopathy, a progressive and debilitating disease caused by a genetic defect in sialic acid biosynthesis, rely on supportive care and eventually become wheelchair-bound. To elucidate whether GNE myopathy is treatable at a progressive stage of the disease, we examined the efficacy of sialic acid supplementation on symptomatic old GNE myopathy mice that have ongoing, active muscle degeneration. We examined the therapeutic effect of a less metabolized sialic acid compound (6'-sialyllactose) or free sialic acid (N-acetylneuraminic acid) by oral, continuous administration to 50-week-old GNE myopathy mice for 30 weeks. To evaluate effects on their motor performance in living mice, spontaneous locomotion activity on a running wheel was measured chronologically at 50, 65, 72 and 80 weeks of age. The size, force production, and pathology of isolated gastrocnemius muscle were analysed at the end point. Sialic acid level in skeletal muscle was also measured. Spontaneous locomotion activity was recovered in 6'-sialyllactose-treated mice, while NeuAc-treated mice slowed the disease progression. Treatment with 6'-sialyllactose led to marked restoration of hyposialylation in muscle and consequently to robust improvement in the muscle size, contractile parameters, and pathology as compared to NeuAc. This is due to the fact that 6'-sialyllactose is longer working as it is further metabolized to free sialic acid after initial absorption. 6'-sialyllactose ameliorated muscle atrophy and degeneration in symptomatic GNE myopathy mice. Our results provide evidence that GNE myopathy can be treated even at a progressive stage and 6'-sialyllactose has more remarkable advantage than free sialic acid, providing a conceptual proof for clinical use in patients.

KEYWORDS:

GNE myopathy; amyloid inclusion; distal myopathy with rimmed vacuoles (DMRV)/hereditary inclusion body myopathy (hIBM); hyposialylation; sialyllactose

PMID:
25062695
PMCID:
PMC4172045
DOI:
10.1093/brain/awu210
[Indexed for MEDLINE]
Free PMC Article

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