Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy
Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy
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DOI：
10.1093/hmg/ddh033
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发表时间：
2004-02-01
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
肌营养不良蛋白的突变是杜氏肌营养不良症（DMD）的近因，但将肌膜中肌营养不良蛋白的缺失与肌纤维坏死联系起来的致病机制尚不完全清楚。肌营养不良症还具有当前疾病模型未考虑的性质，包括疾病发作的时间延迟，严重程度的广泛物种差异和骨骼肌反应的多样性。为了解决肌营养不良症的差异靶向的机制，我们的特点是时间的表达概况肌营养不良蛋白缺陷（mdx）小鼠出生后7天和112天之间使用寡核苷酸微阵列和对比这些数据与发表的后肢肌肉数据。虽然膈肌和后肢肌群对肌营养不良蛋白缺乏反应的严重程度不同，并且在一些转录本类别（包括炎症和肌肉特异性基因）中表现出实质性分歧，但我们的数据表明，肌营养不良症中的一般机制是高度保守的。这两个肌肉群主要不同的差异调节基因的表达水平，而不是非保守的诱导/抑制转录定义根本不同的机制。我们还确定了出生后分歧的两个野生型肌肉群的表达谱，在时间上与营养不良的发病和进展的过程。这些发现支持了保守的疾病机制与肌群特异性转录组的基线差异相互作用的假设，这些机制是肌群特异性转录组对DMD的差异反应的基础。我们进一步表明，肌肉群特异性转录谱有助于肌肉靶向和保留模式观察到的各种代谢和神经肌肉疾病。
Mutations in dystrophin are the proximate cause of Duchenne muscular dystrophy (DMD), but pathogenic mechanisms linking the absence of dystrophin from the sarcolemma to myofiber necrosis are not fully known. The muscular dystrophies also have properties not accounted for by current disease models, including the temporal delay to disease onset, broad species differences in severity, and diversity of skeletal muscle responses. To address the mechanisms underlying the differential targeting of muscular dystrophy, we characterized temporal expression profiles of the diaphragm in dystrophin-deficient (mdx) mice between postnatal days 7 and 112 using oligonucleotide microarrays and contrasted these data with published hindlimb muscle data. Although the diaphragm and hindlimb muscle groups differ in severity of response to dystrophin deficiency, and exhibited substantial divergence in some transcript categories including inflammation and muscle-specific genes, our data show that the general mechanisms operative in muscular dystrophy are highly conserved. The two muscle groups principally differed in expression levels of differentially regulated genes, as opposed to the non-conserved induced/repressed transcripts defining fundamentally distinct mechanisms. We also identified a postnatal divergence of the two wild-type muscle group expression profiles that temporally correlated with the onset and progression of the dystrophic process. These findings support the hypothesis that conserved disease mechanisms interacting with baseline differences in muscle group-specific transcriptomes underlie their differential responses to DMD. We further suggest that muscle group-specific transcriptional profiles contribute toward the muscle targeting and sparing patterns observed for a variety of metabolic and neuromuscular diseases.