Increased amyloid β-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy

Bosch Morató, Mònica, 1986-; Iriondo, Cinta; Guivernau Almazán, Biuse, 1988-; Valls Comamala, Victòria, 1987-; Vidal, Noemí; Olivé, Montse; Querfurth, Henry; Muñoz López, Francisco José, 1964-

doi:http://dx.doi.org/10.18632/oncotarget.7997

Increased amyloid β-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy

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Bosch-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.7997

Abstract

GNE 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.