Dissection of temporal gene expression signatures of affected and spared muscle groups in dystrophin-deficient (mdx) mice
Dissection of temporal gene expression signatures of affected and spared muscle groups in dystrophin-deficient (mdx) mice
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DOI：
10.1093/hmg/ddg197
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发表时间：
2003-08-01
影响因子：
3.5
通讯作者：
Khanna, S
中科院分区：
文献类型：
--
作者：
Porter, JD;Merriam, AP;Khanna, S
虽然营养不良蛋白突变是Duchenne肌营养不良症(DMD)的直接原因，但不同下游机制之间的相互作用可能是关键的表型决定因素。在出生后7-112d的dystrophin缺陷(MDX)小鼠中，时间基因表达谱被用来识别和关联不同的转录模式彼此之间以及与疾病过程的关系，包括受影响的肌肉组和幸存的肌肉组。虽然在腿部肌肉中有719个转录本在一个或多个年龄差异表达，但在备用眼外肌(EOM)中只有56个基因发生了变化。受影响的肌肉和保留的肌肉的对比分子特征提供了令人信服的证据，表明仅缺少dystrophin是必要的，但不足以导致肌营养不良症的图案化纤维化、炎症和肌肉再生失败。使用综合疾病负荷指数(DLI)进一步量化微阵列图谱中营养不良和适应性的变化，以衡量两个肌肉中阶段相关的转录影响。DLI分析强调了EOM和腿部肌肉组的不同反应。腿部肌肉中的细胞过程特异性DLIS确定了一些基因类别的正相关时间表达谱，以及与主要疾病组成部分相关的其他基因类别的独立性。数据还显示，在坏死前的MDX骨骼肌中，有一种先前未被发现的暂时性和选择性发育延迟，这一点得到了qPCR的证实。综上所述，对负责协调MDX肌肉纤维化、蛋白分解和炎症机制的信号通路进行验证和定位，可能会产生减轻DMD破坏性后果的新的治疗方法。
Although dystrophin mutations are the proximate cause of Duchenne muscular dystrophy (DMD), interactions among heterogeneous downstream mechanisms may be key phenotypic determinants. Temporal gene expression profiling was used to identify and correlate diverse transcriptional patterns to one another and to the disease course, for both affected and spared muscle groups, in postnatal day 7-112 dystrophin-deficient (mdx) mice. While 719 transcripts were differentially expressed at one or more ages in leg muscle, only 56 genes were altered in the spared extraocular muscles (EOM). Contrasting molecular signatures of affected versus spared muscles provide compelling evidence that the absence of dystrophin alone is necessary but not sufficient to cause the patterned fibrosis, inflammation and failure of muscle regeneration characteristic of dystrophinopathy. Dystrophic and adaptive changes in the microarray profiles were further quantified using an aggregate disease load index (DLI) to measure stage-dependent transcriptional impact in both muscles. DLI analysis highlighted the divergent responses of EOM and leg muscle groups. Cellular process-specific DLIs in leg muscle identified positively correlated temporal expression profiles for some gene classes, and the independence of others, that are linked to major disease components. Data also showed a previously unrecognized transient and selective developmental delay in pre-necrotic mdx skeletal muscle that was confirmed by qPCR. Taken together, validation and targeting of signaling pathways responsible for the coordination of the fibrotic, proteolytic and inflammatory mechanisms shown here for mdx muscle may yield new therapeutic means of mitigating the devastating consequences of DMD.