title: Gene expression profiling in equine polysaccharide storage myopathy revealed inflammation, glycogenesis inhibition, hypoxia and mitochondrial dysfunctions.
abstract: 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, PRKCalpha, VEGFalpha. 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 (GSK3beta) under its active form could be responsible for glycogen synthase (GYS1) inhibition and hypoxia-inducible factor (HIF1alpha) destabilization.
  
  
  CONCLUSIONS
  The main disorders observed in PSSM muscles could be related to mitochondrial dysfunctions, glycogenesis inhibition and the chronic hypoxia of the PSSM muscles.
authors: Unité de Biologie Intégrative des Adaptations à l'Exercice -INSERM 902, Genopole Evry, France. eric.barrey@inserm.fr
authors: Eric
authors: E
authors: Barrey
authors: Elodie
authors: E
authors: Mucher
authors: Nicolas
authors: N
authors: Jeansoule
authors: Thibaut
authors: T
authors: Larcher
authors: Lydie
authors: L
authors: Guigand
authors: Bérénice
authors: B
authors: Herszberg
authors: Stéphane
authors: S
authors: Chaffaux
authors: Gérard
authors: G
authors: Guérin
authors: Xavier
authors: X
authors: Mata
authors: Philippe
authors: P
authors: Benech
authors: Marielle
authors: M
authors: Canale
authors: Olivier
authors: O
authors: Alibert
authors: Péguy
authors: P
authors: Maltere
authors: Xavier
authors: X
authors: Gidrol
mesh_terms: D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006003:Glycogen / Q000378:metabolism*; D006734:Horse Diseases / Q000503:physiopathology*; D006736:Horses; D000860:Hypoxia / Q000209:etiology / Q000662:veterinary*; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000473:pathology*; D018482:Muscle, Skeletal / Q000503:physiopathology; D009135:Muscular Diseases / Q000150:complications / Q000503:physiopathology / Q000662:veterinary*; D010641:Phenotype; D011134:Polysaccharides / Q000378:metabolism*
chemical_list: D011134:Polysaccharides; D006003:Glycogen