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
Unité de Biologie Intégrative des Adaptations à l'Exercice -INSERM 902, Genopole Evry, France.
BMC Vet Res. 2009 Aug 7;5:29. doi: 10.1186/1746-6148-5-29.
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.
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.
The main disorders observed in PSSM muscles could be related to mitochondrial dysfunctions, glycogenesis inhibition and the chronic hypoxia of the PSSM muscles.
在诺曼马品种中观察到了几例肌病病例。肌肉组织学检查显示，一些家族患有多糖贮积性肌病（PSSM）。由于糖原贮积病也可能与基因调控中的其他功能障碍有关，因此推测在转录水平应观察到与PSSM相关的基因表达特征。因此，可以采用功能基因组学方法来提供有关与PSSM相关的代谢紊乱的新知识。我们建议通过测量与组织学表型相关的基因表达来探索PSSM肌纤维代谢紊乱。
GYS1突变的基因分型分析显示有2匹纯合（AA）和5匹杂合（GA）PSSM马。在PSSM肌肉中，组织学数据显示PAS阳性淀粉酶抗性异常多糖、炎症、坏死、脂肪化生以及纤维的活跃再生。超微结构评估显示线粒体数量减少和结构紊乱。异常多糖的大量积累取代并部分替代了线粒体和肌原纤维。两匹纯合PSSM马的疾病严重程度更高。基因表达分析显示129个基因有显著调节（p < 0.05）。以下基因上调超过2倍：IL18、CTSS、LUM、CD44、FN1、GST01。下调最明显的基因如下：线粒体tRNA、SLC2A2、PRKCalpha、VEGFalpha。数据挖掘分析表明，蛋白质合成、细胞凋亡、细胞运动、生长和增殖是与调节基因显著相关的主要细胞功能（p < 0.05）。几个上调基因，尤其是IL18，显示PSSM肌肉中有严重的肌肉炎症。活性形式的糖原合酶激酶-3（GSK3beta）上调可能导致糖原合酶（GYS1）抑制和缺氧诱导因子（HIF1alpha）不稳定。
PSSM肌肉中观察到的主要紊乱可能与线粒体功能障碍、糖原生成抑制和PSSM肌肉的慢性缺氧有关。
