Microarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy
Microarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy
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DOI：
10.1371/journal.pone.0012922
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发表时间：
2010-09-23
期刊：
影响因子：
3.7
通讯作者：
Monks, D. Ashley
中科院分区：
文献类型：
--
作者：
Mo, Kaiguo;Razak, Zak;Monks, D. Ashley
背景：新出现的证据表明骨骼肌内基因表达的改变与肯尼迪病/脊髓延髓肌萎缩症（KD/SBMA）的发病机制有关。因此，我们广泛地表征了三种独立生成的这种疾病小鼠模型的骨骼肌中的基因表达。小鼠模型包括聚谷氨酰胺扩展（polyQ）AR敲入模型（AR113Q）、polyQ AR转基因模型（AR97Q）和仅在骨骼肌中过表达野生型AR的转基因小鼠（HSA-AR）。 HSA-AR 小鼠被包括在内，因为尽管不存在 PolyQ AR，它们仍基本上再现了 KD/SBMA 表型。 方法/主要发现：我们使用高密度寡核苷酸阵列，对取自这三个模型的下后肢肌肉（相对于野生型对照）进行了微阵列分析。所有微阵列比较均在每种条件下对至少3只动物进行，并且只有那些具有至少2倍差异且方差系数小于100%的基因被认为是差异表达的。从整体上考虑，这 3 个模型之间的基因变化有类似的重叠：HSA-AR 和 AR97Q 之间有 19%，AR97Q 和 AR113Q 之间有 21%，HSA-AR 和 AR113Q 之间有 17%，所有模型共有 8%。观察到与疾病过程相关的几种基因表达模式。值得注意的是，在所有三个模型中都观察到了典型的 AR 功能丧失的基因表达模式，以及涉及细胞粘附、能量平衡、肌肉萎缩和肌生成的基因的改变。我们还测量了与亨廷顿病小鼠模型骨骼肌中观察到的变化类似的变化，以及与不同原因引起的肌肉萎缩常见的变化类似的变化。结论/意义：通过比较三个独立的 KD/SBMA 模型中的基因表达模式，我们已经能够识别可能介导 KD/SBMA 核心肌源性特征的候选基因。
Background: Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disease. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q), a polyQ AR transgenic model (AR97Q), and a transgenic mouse that overexpresses wild type AR solely in skeletal muscle (HSA-AR). HSA-AR mice were included because they substantially reproduce the KD/SBMA phenotype despite the absence of polyQ AR.Methodology/Principal Findings: We performed microarray analysis of lower hindlimb muscles taken from these three models relative to wild type controls using high density oligonucleotide arrays. All microarray comparisons were made with at least 3 animals in each condition, and only those genes having at least 2-fold difference and whose coefficient of variance was less than 100% were considered to be differentially expressed. When considered globally, there was a similar overlap in gene changes between the 3 models: 19% between HSA-AR and AR97Q, 21% between AR97Q and AR113Q, and 17% between HSA-AR and AR113Q, with 8% shared by all models. Several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, muscle atrophy and myogenesis. We additionally measured changes similar to those observed in skeletal muscle of a mouse model of Huntington's Disease, and to those common to muscle atrophy from diverse causes.Conclusions/Significance: By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA.