Research Papers: Gerotarget (Focus on Aging):
Increased amyloid β-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy
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Mònica Bosch-Morató1, Cinta Iriondo1, Biuse Guivernau1, Victòria Valls-Comamala1, Noemí Vidal2, Montse Olivé2, Henry Querfurth3 and Francisco J. Muñoz1
1 Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
2 Institut de Neuropatologia, Servei Anatomia Patològica, Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain
3 Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA
Francisco J. Muñoz, email:
Keywords: Aβ, Akt, apoptosis, endocytosis, GNE myopathy, Gerotarget
Received: January 18, 2016 Accepted: February 23, 2016 Published: March 08, 2016
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.
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