Dataset Information

Increased amyloid ?-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 ?-peptide (A?) in patient muscles through as yet unknown mechanisms. We found here for the first time that an experimental reduction in sialic acid favors A?1-42 endocytosis in C2C12 myotubes, which is dependent on clathrin and heparan sulfate proteoglycan. Accordingly, A?1-42 internalization in myoblasts from a GNE myopathy patient was enhanced. Next, we investigated signal changes triggered by A?1-42 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 A?1-42 was overexpressed in myotubes. Hence, we propose a novel disease mechanism whereby hyposialylation favors A?1-42 internalization and the subsequent apoptosis in myotubes and in skeletal muscle from GNE myopathy patients.

SUBMITTER: Bosch-Morato M

PROVIDER: S-EPMC4924647 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Bosch-Morató Mònica M Iriondo Cinta C Guivernau Biuse B Valls-Comamala Victòria V Vidal Noemí N Olivé Montse M Querfurth Henry H Muñoz Francisco J FJ

Oncotarget 20160301 12

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 ...[more]

PMID: 26968811

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Project description:BACKGROUND: Retinoid X receptor (RXR) ? is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXR? in skeletal muscle (RXR? mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism. METHODOLOGY/PRINCIPAL FINDINGS: RXR? mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXR? mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXR? mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXR? and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXR? mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXR? and PPAR? resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXR? overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs. CONCLUSIONS/SIGNIFICANCE: Systemic glucose metabolism was increased in transgenic mice overexpressing RXR?. The enhanced glucose tolerance in RXR? mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXR? expression may be a novel therapeutic strategy against type 2 diabetes.

Dataset Information

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

Publications

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

Similar Datasets

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