Sialic acids are
monosaccharides found in terminal
sugar chains of cell surfaces and
proteins; they have various biological functions and have been implicated in health and disease. Genetic defects of the GNE gene which encodes a critical bifunctional
enzyme for
sialic acid biosynthesis, lead to GNE
myopathy, a disease manifesting with progressive
muscle atrophy and weakness. The likely mechanism of disease is a lack of
sialic acids. There remains, however, an unexplained link between hyposialylation and the
muscle atrophy and weakness. In this study, we found that
muscle proteins were highly modified by S-nitrosylation, and that oxidative stress-responsive genes were significantly upregulated, in hyposialylated muscles from human GNE
myopathy patients and model mice. In both in vitro and in vivo models, the production of
reactive oxygen species (ROS) was elevated with cellular hyposialylation, and increasing overall sialylation by extrinsic
sialic acid intake reduced ROS and
protein S-nitrosylation. More importantly, the
antioxidant, oral
N-acetylcysteine led to amelioration of the
muscle atrophy and weakness in Gne mutant mice. Our data provide evidence of additional important function of
sialic acids as a ROS scavenger in skeletal muscles, expanding our understanding on how
sialic acid deficiency contributes to disease pathology, and identify oxidative stress as a therapeutic target in GNE
myopathy.