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Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions

BACKGROUND: Several cases of myopathies have been observed in the horse Norman Cob breed. Muscle histology examinations revealed that some families suffer from a polysaccharide storage myopathy (PSSM). It is assumed that a gene expression signature related to PSSM should be observed at the transcrip...

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Autores principales: Barrey, Eric, Mucher, Elodie, Jeansoule, Nicolas, Larcher, Thibaut, Guigand, Lydie, Herszberg, Bérénice, Chaffaux, Stéphane, Guérin, Gérard, Mata, Xavier, Benech, Philippe, Canale, Marielle, Alibert, Olivier, Maltere, Péguy, Gidrol, Xavier
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741442/
https://www.ncbi.nlm.nih.gov/pubmed/19664222
http://dx.doi.org/10.1186/1746-6148-5-29
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author Barrey, Eric
Mucher, Elodie
Jeansoule, Nicolas
Larcher, Thibaut
Guigand, Lydie
Herszberg, Bérénice
Chaffaux, Stéphane
Guérin, Gérard
Mata, Xavier
Benech, Philippe
Canale, Marielle
Alibert, Olivier
Maltere, Péguy
Gidrol, Xavier
author_facet Barrey, Eric
Mucher, Elodie
Jeansoule, Nicolas
Larcher, Thibaut
Guigand, Lydie
Herszberg, Bérénice
Chaffaux, Stéphane
Guérin, Gérard
Mata, Xavier
Benech, Philippe
Canale, Marielle
Alibert, Olivier
Maltere, Péguy
Gidrol, Xavier
author_sort Barrey, Eric
collection PubMed
description BACKGROUND: Several cases of myopathies have been observed in the horse Norman Cob breed. Muscle histology examinations revealed that some families suffer from a polysaccharide storage myopathy (PSSM). It is assumed that a gene expression signature related to PSSM should be observed at the transcriptional level because the glycogen storage disease could also be linked to other dysfunctions in gene regulation. Thus, the functional genomic approach could be conducted in order to provide new knowledge about the metabolic disorders related to PSSM. We propose exploring the PSSM muscle fiber metabolic disorders by measuring gene expression in relationship with the histological phenotype. RESULTS: Genotypying analysis of GYS1 mutation revealed 2 homozygous (AA) and 5 heterozygous (GA) PSSM horses. In the PSSM muscles, histological data revealed PAS positive amylase resistant abnormal polysaccharides, inflammation, necrosis, and lipomatosis and active regeneration of fibers. Ultrastructural evaluation revealed a decrease of mitochondrial number and structural disorders. Extensive accumulation of an abnormal polysaccharide displaced and partially replaced mitochondria and myofibrils. The severity of the disease was higher in the two homozygous PSSM horses. Gene expression analysis revealed 129 genes significantly modulated (p < 0.05). The following genes were up-regulated over 2 fold: IL18, CTSS, LUM, CD44, FN1, GST01. The most down-regulated genes were the following: mitochondrial tRNA, SLC2A2, PRKCα, VEGFα. Data mining analysis showed that protein synthesis, apoptosis, cellular movement, growth and proliferation were the main cellular functions significantly associated with the modulated genes (p < 0.05). Several up-regulated genes, especially IL18, revealed a severe muscular inflammation in PSSM muscles. The up-regulation of glycogen synthase kinase-3 (GSK3β) under its active form could be responsible for glycogen synthase (GYS1) inhibition and hypoxia-inducible factor (HIF1α) destabilization. CONCLUSION: The main disorders observed in PSSM muscles could be related to mitochondrial dysfunctions, glycogenesis inhibition and the chronic hypoxia of the PSSM muscles.
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spelling pubmed-27414422009-09-11 Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions Barrey, Eric Mucher, Elodie Jeansoule, Nicolas Larcher, Thibaut Guigand, Lydie Herszberg, Bérénice Chaffaux, Stéphane Guérin, Gérard Mata, Xavier Benech, Philippe Canale, Marielle Alibert, Olivier Maltere, Péguy Gidrol, Xavier BMC Vet Res Research Article BACKGROUND: Several cases of myopathies have been observed in the horse Norman Cob breed. Muscle histology examinations revealed that some families suffer from a polysaccharide storage myopathy (PSSM). It is assumed that a gene expression signature related to PSSM should be observed at the transcriptional level because the glycogen storage disease could also be linked to other dysfunctions in gene regulation. Thus, the functional genomic approach could be conducted in order to provide new knowledge about the metabolic disorders related to PSSM. We propose exploring the PSSM muscle fiber metabolic disorders by measuring gene expression in relationship with the histological phenotype. RESULTS: Genotypying analysis of GYS1 mutation revealed 2 homozygous (AA) and 5 heterozygous (GA) PSSM horses. In the PSSM muscles, histological data revealed PAS positive amylase resistant abnormal polysaccharides, inflammation, necrosis, and lipomatosis and active regeneration of fibers. Ultrastructural evaluation revealed a decrease of mitochondrial number and structural disorders. Extensive accumulation of an abnormal polysaccharide displaced and partially replaced mitochondria and myofibrils. The severity of the disease was higher in the two homozygous PSSM horses. Gene expression analysis revealed 129 genes significantly modulated (p < 0.05). The following genes were up-regulated over 2 fold: IL18, CTSS, LUM, CD44, FN1, GST01. The most down-regulated genes were the following: mitochondrial tRNA, SLC2A2, PRKCα, VEGFα. Data mining analysis showed that protein synthesis, apoptosis, cellular movement, growth and proliferation were the main cellular functions significantly associated with the modulated genes (p < 0.05). Several up-regulated genes, especially IL18, revealed a severe muscular inflammation in PSSM muscles. The up-regulation of glycogen synthase kinase-3 (GSK3β) under its active form could be responsible for glycogen synthase (GYS1) inhibition and hypoxia-inducible factor (HIF1α) destabilization. CONCLUSION: The main disorders observed in PSSM muscles could be related to mitochondrial dysfunctions, glycogenesis inhibition and the chronic hypoxia of the PSSM muscles. BioMed Central 2009-08-07 /pmc/articles/PMC2741442/ /pubmed/19664222 http://dx.doi.org/10.1186/1746-6148-5-29 Text en Copyright © 2009 Barrey et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Barrey, Eric
Mucher, Elodie
Jeansoule, Nicolas
Larcher, Thibaut
Guigand, Lydie
Herszberg, Bérénice
Chaffaux, Stéphane
Guérin, Gérard
Mata, Xavier
Benech, Philippe
Canale, Marielle
Alibert, Olivier
Maltere, Péguy
Gidrol, Xavier
Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions
title Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions
title_full Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions
title_fullStr Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions
title_full_unstemmed Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions
title_short Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions
title_sort gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741442/
https://www.ncbi.nlm.nih.gov/pubmed/19664222
http://dx.doi.org/10.1186/1746-6148-5-29
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