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

• Published in: Oncotarget 2016-03, Vol.7 (12), p.13354-13371
• Main Authors: Bosch-Morató, Mònica, Iriondo, Cinta, Guivernau, Biuse, Valls-Comamala, Victòria, Vidal, Noemí, Olivé, Montse, Querfurth, Henry, Muñoz, Francisco J
• Format: Article
• Language: English
• Subjects: Adult; Akt; Amyloid beta-Peptides - metabolism; Apoptosis; Case-Control Studies; Cells, Cultured; Distal Myopathies - metabolism; Distal Myopathies - pathology; Endocytosis; Female; Gerotarget; GNE myopathy; Humans; Male; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Myoblasts - metabolism; Myoblasts - pathology; Músculs; N-Acetylneuraminic Acid - metabolism; Research Paper: Gerotarget (Focus on Aging)
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.7997

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.