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

Mònica Bosch-Morató,Cinta Iriondo,Victòria Valls-Comamala,Henry Querfurth,Francisco J Muñoz,Biuse Guivernau,Montse Olivé,Noemí Vidal

doi:10.18632/oncotarget.7997

Mònica Bosch-Morató, Cinta Iriondo + Show 6 more

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https://doi.org/10.18632/oncotarget.7997

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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.

Highlights

Amyloid β-peptide (Aβ) has received heightened attention in the last years since biomarker studies point to its early involvement in Alzheimer’s disease (AD) [1, 2]
It is well known that the cause of UDP-Nacetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) myopathy is a mutation in the GNE gene that produces a decrease in the sialic acid content in skeletal muscle cells [15, 16]
To address the first objective, Aβ internalization was examined in C2C12 myotubes and this study reports for the first time that Aβ can be endocytosed by skeletal muscle cells

Summary

Introduction

Amyloid β-peptide (Aβ) has received heightened attention in the last years since biomarker studies point to its early involvement in Alzheimer’s disease (AD) [1, 2]. Aβ plays a major role in GNE myopathy, a degenerative muscle disease, characterized by Aβ and other proteinaceous inclusions in skeletal muscle [3, 4]. GNE myopathy is an autosomal recessive disorder characterized by progressive skeletal muscle weakness and wasting but sparing of the quadriceps [5 ,6]. It starts in young adulthood and induces disability within 15 years after onset. The disease is characterized by the presence of atrophic muscle fibers with rimmed vacuoles, filamentous inclusions and intracellular Aβ accumulation [5, 7]. The cause of GNE myopathy is a mutation in the UDP-N-acetylglucosamine

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