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Sialyllactose ameliorates myopathic phenotypes in symptomatic GNE myopathy model mice.

Brain : a journal of neurology (2014-07-27)
Takahiro Yonekawa, May Christine V Malicdan, Anna Cho, Yukiko K Hayashi, Ikuya Nonaka, Toshiki Mine, Takeshi Yamamoto, Ichizo Nishino, Satoru Noguchi
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Lactose, tested according to Ph. Eur.
Supelco
Lactose, Anhydrous, Pharmaceutical Secondary Standard; Certified Reference Material
Lactose (anhydrous), European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Creatine Phosphokinase from bovine heart, Type III, salt-free, lyophilized powder, ≥30 units/mg protein
Sigma-Aldrich
N-Acetylneuraminic acid, from Escherichia coli, ≥98%
Sigma-Aldrich
N-Acetylneuraminic acid, synthetic, ≥95%
Sigma-Aldrich
Creatine Phosphokinase from rabbit muscle, Type I, salt-free, lyophilized powder, ≥150 units/mg protein
USP
Anhydrous lactose, United States Pharmacopeia (USP) Reference Standard