T.P.9 Sialyllactose reversed myopathic phenotype in symptomatic GNE myopathy model mice

Abstract

GNE myopathy (GM) is caused by mutations in GNE gene, encoding an essential enzyme in sialic acid biosynthesis. We previously provided evidence that sialic acid given to clinically asymptomatic GM mice prevented the development of the myopathic phenotype, indicating that hyposialylation is one of key factors in the pathomechanism underlying GM. In this study, we examined the effect of sialic acid administration on muscle atrophy and weakness in symptomatic, older GM mice to mimic the stage of disease in symptomatic GM patients, using free sialic acid (NeuAc) and the less-metabolized sialic acid conjugate, 6′-sialyllactose (6′SL). Fifty-week-old GM mice and littermates were given either water, NeuAc, or 6’SL for about 30weeks. Voluntary exercise on running wheel was evaluated longitudinally at 10week interval, while the size, force generation, and pathology of gastrocnemius muscle (GC) were evaluated at the end of the study. Voluntary exercise in non-treated model mice markedly decreased with aging, but was maintained in 6′SL group, including one mouse that showed marked recovery to non-affected control level. The NeuAc group, on the other hand, exhibited marked decrease in voluntary wheel running similar to non-treated mice. The response in running performance correlated with findings in analysis of GC, i.e., the GC size and force production in 6′SL group was recovered to levels measured in control littermates, while those in the NeuAc group responded poorly and showed similar findings with non-treated GM mice. We show that 6′SL can ameliorate muscle atrophy and weakness in symptomatic GM mice, providing a proof of principle in the use of this compound in the clinical trial of GM patients with progressive or advanced stage of disease.