Sialidase Neu2 is an exoglycosidase that removes terminal sialic acids from glycolipids and glycoproteins. In this study, we investigated Neu2 expression during muscle hypertrophy and atrophy. Neu2 mRNA and enzymatic activity were significantly increased in hypertrophic myofibers. A rise in Neu2 activity was observed after constitutive activation of AKT or Igf-1 treatment as well as in myoblasts treated with vasopressin or trichostatin, an inhibitor of histone deacetylases. In contrast, myofiber atrophy obtained by dexamethasone treatment or starvation triggered a significant loss of Neu2 activity and was paralleled by downregulation of Neu2 transcript levels. Overall, we may conclude that Neu2 enzymatic activity is causally linked to proper muscle differentiation and growth.