Molecular characterization of impaired sialylation in skeletal muscle cells

Abstract

GNE Myopathy (GNEM) is a rare genetic disease affecting the skeletal muscles of patients, leading to atrophy. Until today, there is no cure or effective therapy to treat GNEM patients, mainly due to a lack of understanding of the exact pathomechanism. GNE is a bifunctional enzyme that catalyzes the rate-limiting step in the endogenous sialic acid biosynthesis pathway. Sialic acids decorate the terminal ends of glycan structures of membrane and secreted proteins and are hence important for proper protein function. This work generated a new cell model to mimic loss of sialic acids using the C2C12 murine myoblast cell line. Gne knock-out resulted in impaired differentiation of myoblasts into mature myofibers, highlighting the important role of sialylation during cellular differentiation. Furthermore, a complex regulatory circuit between muscle-specific genes and the loss of Gne was explored, giving new insights into the tissue-specificity of the disease.