Metabolic changes in sialic acid synthesis pathway in GNE‐myopathy model mice with long‐term sialic acid treatment

Abstract

GNE‐myopathy is an autosomal recessive disorder characterized by muscle atrophy, distal muscle weakness, and accumulation of proteins and rimmed vacuoles in myofibers and is due to mutations in the GNE gene that encodes an essential enzyme in sialic acid (SA) biosynthesis. We recently showed that muscle atrophy and weakness were completely prevented in the GNE‐myopathy model mouse with SA (NeuAc and sialyllactose) and ManNAc. In this study, we aimed to clarify if long‐term SA treatment can influence SA pathway in the GNE‐myopathy model. Gene expression analysis of SA pathway enzymes/transporter in various organs of non‐treated wild mouse showed high expression of synthesis‐related genes in the liver and degradation‐related genes in the kidney, suggesting that liver is an anabolic organ and kidney is a catabolic organ for SA synthesis. Expression analysis of genes in tissues of GNE‐myopathy model mouse after long‐term treatment for more than 300 days showed further upregulation of genes for catabolic enzymes in kidney, and downregulation of genes for anabolic enzymes in skeletal muscle. The change in gene expression was, however, smaller in disease model compared to control. These results suggest that long‐term SA administration may somehow diminish the effects of treatment, and that the effect on the expression of SA‐metabolic genes are variable with compounds administered.