title: Increased amyloid β-peptide uptake in skeletal muscle is induced by hyposialylation and may account for apoptosis in GNE myopathy.
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.
authors.affiliation: Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Bosch-Morató
authors.affiliation: Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Cinta
authors.initials: C
authors.lastname: Iriondo
authors.affiliation: Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Biuse
authors.initials: B
authors.lastname: Guivernau
authors.affiliation: Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Victòria
authors.initials: V
authors.lastname: Valls-Comamala
authors.affiliation: Institut de Neuropatologia, Servei Anatomia Patològica, Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Noemí
authors.initials: N
authors.lastname: Vidal
authors.affiliation: Institut de Neuropatologia, Servei Anatomia Patològica, Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Olivé
authors.affiliation: Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Querfurth
authors.affiliation: Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Muñoz
mesh_terms: D000328:Adult; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D017209:Apoptosis; D016022:Case-Control Studies; D002478:Cells, Cultured; D049310:Distal Myopathies / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019158:N-Acetylneuraminic Acid
keywords: Akt; Aβ; GNE myopathy; Gerotarget; apoptosis; endocytosis