Dynamic changes in copper homeostasis and post-transcriptional regulation of Atp7a during myogenic differentiation†,Metallomics

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Dynamic changes in copper homeostasis and post-transcriptional regulation of Atp7a during myogenic differentiation†
Metallomics ( IF 2.9 ) Pub Date : 2018-01-04 00:00:00 , DOI: 10.1039/c7mt00324b
Katherine E Vest ₁ , Amanda L Paskavitz , Joseph B Lee , Teresita Padilla-Benavides

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Copper (Cu) is an essential metal required for activity of a number of redox active enzymes that participate in critical cellular pathways such as metabolism and cell signaling. Because it is also a toxic metal, Cu must be tightly controlled by a series of transporters and chaperone proteins that regulate Cu homeostasis. The critical nature of Cu is highlighted by the fact that mutations in Cu homeostasis genes cause pathologic conditions such as Menkes and Wilson diseases. While Cu homeostasis in highly affected tissues like the liver and brain is well understood, no study has probed the role of Cu in development of skeletal muscle, another tissue that often shows pathology in these conditions. Here, we found an increase in whole cell Cu content during differentiation of cultured immortalized or primary myoblasts derived from mouse satellite cells. We demonstrate that Cu is required for both proliferation and differentiation of primary myoblasts. We also show that a key Cu homeostasis gene, Atp7a, undergoes dynamic changes in expression during myogenic differentiation. Alternative polyadenylation and stability of Atp7a mRNA fluctuates with differentiation stage of the myoblasts, indicating post-transcriptional regulation of Atp7a that depends on the differentiation state. This is the first report of a requirement for Cu during myogenic differentiation and provides the basis for understanding the network of Cu transport associated with myogenesis.

中文翻译：

肌原分化过程中铜稳态的动态变化和 Atp7a 的转录后调节†

铜 (Cu) 是参与代谢和细胞信号传导等关键细胞途径的多种氧化还原活性酶的活性所需的必需金属。由于铜也是一种有毒金属，因此必须受到一系列调节铜稳态的转运蛋白和伴侣蛋白的严格控制。铜稳态基因的突变会导致门克斯病和威尔逊病等病理状况，这一事实凸显了铜的关键性质。虽然肝脏和大脑等受影响严重的组织中的铜稳态已被充分了解，但尚无研究探讨铜在骨骼肌发育中的作用，骨骼肌是另一种在这些情况下经常表现出病理的组织。在这里，我们发现在培养的源自小鼠卫星细胞的永生化或原代成肌细胞分化过程中，全细胞铜含量增加。我们证明铜是原代成肌细胞增殖和分化所必需的。我们还表明，关键的铜稳态基因Atp7a在肌原性分化过程中经历表达的动态变化。Atp7a mRNA的选择性多腺苷酸化和稳定性随着成肌细胞的分化阶段而波动，表明Atp7a的转录后调节取决于分化状态。这是关于肌发生分化过程中对铜的需求的第一份报告，并为了解与肌发生相关的铜运输网络提供了基础。

更新日期：2018-01-04

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