Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation
Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation
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DOI：
10.1101/gad.1364906
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发表时间：
2006-02-15
影响因子：
10.5
通讯作者：
Kennedy, BK
中科院分区：
文献类型：
--
作者：
Frock, RL;Kudlow, BA;Kennedy, BK
编码A型核纤层蛋白的LMNA内的突变与多种组织特异性疾病相关，包括Emery-Dreifuss（EDMD 2/3）和肢带肌营养不良症（LGMD 1B）。X-连锁EDMD是由核纤层蛋白A相关蛋白emerin突变引起的。这些突变导致肌营养不良的机制尚不清楚。在这里，我们表明，大多数，但不是所有的，培养的肌细胞从核纤层蛋白A/C基因敲除小鼠表现出受损的分化动力学和分化潜力降低。类似地，已经对A型核纤层蛋白或突蛋白进行RNA干扰（RNAi）下调的正常肌细胞具有受损的分化潜能。缺乏A型核纤层蛋白或突蛋白的复制成肌细胞也具有对肌肉分化重要的蛋白质水平降低，包括pRB、MyoD、结蛋白和M-钙粘蛋白;上调Myf 5;但Pax 3、Pax 7、MEF 2C、MEF 2D、c-met和β-连环蛋白没有变化。为了确定受损的肌生成是否与降低的MyoD或结蛋白水平有关，这些蛋白在Lmna（-/-）成肌细胞中单独表达，然后诱导成肌细胞进行肌生成。在Lmna（-/-）成肌细胞中MyoD或更令人惊讶的结蛋白的表达导致分化潜力增加。这些研究表明A型核纤层蛋白和emerin在肌源性分化中的作用，并且还表明这些作用至少部分是由于其他关键成肌细胞蛋白的内源性水平降低。核纤层蛋白A/C缺陷型和emerin缺陷型成肌细胞的延迟分化动力学和降低的分化潜能可能部分地成为EDMD患者中观察到的营养不良表型的基础。
Mutations within LMNA, encoding A-type nuclear lamins, are associated with multiple tissue-specific diseases, including Emery-Dreifuss (EDMD2/3) and Limb-Girdle muscular dystrophy (LGMD1B). X-linked EDMD results from mutations in emerin, a lamin A-associated protein. The mechanisms through which these mutations cause muscular dystrophy are not understood. Here we show that most, but not all, cultured muscle cells from lamin A/C knockout mice exhibit impaired differentiation kinetics and reduced differentiation potential. Similarly, normal muscle cells that have been RNA interference (RNAi) down-regulated for either A-type lamins or emerin have impaired differentiation potentials. Replicative myoblasts lacking A-type lamins or emerin also have decreased levels of proteins important for muscle differentiation including pRB, MyoD, desmin, and M-cadherin; up-regulated Myf5; but no changes in Pax3, Pax7, MEF2C, MEF2D, c-met, and beta-catenin. To determine whether impaired myogenesis is linked to reduced MyoD or desmin levels, these proteins were individually expressed in Lmna(-/-) myoblasts that were then induced to undergo myogenesis. Expression of either MyoD or, more surprisingly, desmin in Lmna(-/-) myoblasts resulted in increased differentiation potential. These studies indicate roles for A-type lamins and emerin in myogenic differentiation and also suggest that these effects are at least in part due to decreased endogenous levels of other critical myoblast proteins. The delayed differentiation kinetics and decreased differentiation potential of lamin A/C-deficient and emerin-deficient myoblasts may in part underlie the dystrophic phenotypes observed in patients with EDMD.