Título:
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Increased amyloid β-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy
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Autor/a:
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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-
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Abstract:
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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. |
Abstract:
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This work was supported by Fundació la Marató de TV3 (100310); Supported by the Plan Estatal de I+D+I 2013-2016 and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Grants PI13/00408, PI08/00574 and Red HERACLES RD12/0042/0014) and FEDER; Generalitat de Catalunya (SGR09-1369). |
Materia(s):
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-Músculs -Akt -Aβ -GNE myopathy -Gerotarget -Apoptosis -Endocytosis |
Derechos:
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https://creativecommons.org/licenses/by/3.0/
© 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 License |
Tipo de documento:
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Artículo Artículo - Versión publicada |
Editor:
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Impact Journals
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