Bosch Morató, Mònica, 1986-Iriondo, CintaGuivernau Almazán, Biuse, 1988-Valls Comamala, Victòria, 1987-Vidal, NoemíOlivé, MontseQuerfurth, HenryMuñoz López, Francisco José, 1964-2016-06-102016-06-102016Bosch-Morató M, Iriondo C, Guivernau B, Valls-Comamala V, Vidal N, Olivé M et al. Increased amyloid β-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy. Oncotarget. 2016; 7(12): 13354-13371. DOI 10.18632/oncotarget.79971949-2553http://hdl.handle.net/10230/26905GNE myopathy is an autosomal recessive muscular disorder of young adults characterized by progressive skeletal muscle weakness and wasting. It is caused by a mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, which encodes a key enzyme in sialic acid biosynthesis. The mutated hypofunctional GNE is associated with intracellular accumulation of amyloid β-peptide (Aβ) in patient muscles through as yet unknown mechanisms. We found here for the first time that an experimental reduction in sialic acid favors Aβ1-42 endocytosis in C2C12 myotubes, which is dependent on clathrin and heparan sulfate proteoglycan. Accordingly, Aβ1-42 internalization in myoblasts from a GNE myopathy patient was enhanced. Next, we investigated signal changes triggered by Aβ1-42 that may underlie toxicity. We observed that p-Akt levels are reduced in step with an increase in apoptotic markers in GNE myopathy myoblasts compared to control myoblasts. The same results were experimentally obtained when Aβ1-42 was overexpressed in myotubes. Hence, we propose a novel disease mechanism whereby hyposialylation favors Aβ1-42 internalization and the subsequent apoptosis in myotubes and in skeletal muscle from GNE myopathy patients.application/pdfeng© The Authors. This is the published version of an article http://dx.doi.org/10.18632/oncotarget.7997 that appeared in the journal Oncotarget. It is published under a Creative Commons Attribution 3.0 LicenseMúsculsinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.18632/oncotarget.7997AktAβGNE myopathyGerotargetApoptosisEndocytosisinfo:eu-repo/semantics/openAccess