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首页> 外文期刊>American Journal of Physiology >Identification of atrogin-1-targeted proteinsθδ during the myostatin-induced skeletal muscle wasting
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Identification of atrogin-1-targeted proteinsθδ during the myostatin-induced skeletal muscle wasting

机译：肌抑素诱导的骨骼肌消瘦过程中atrogin-1靶向蛋白θδ的鉴定

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摘要

Atrogin-1, a musclespecific E3 ligase, targets MyoD for degradation through the ubiquitin- proteasome-mediated system. Myostatin, a member of the transforming growth factor-β superfamily, potently inhibits myogenesis by lowering MyoD levels. While atrogin-1 is upregulated by myostatin, it is currently unknown whether atrogin-1 plays a role in mediating myostatin signaling to regulate myogenesis. In this report, we have confirmed that atrogin-1 increasingly interacts with MyoD upon recombinant human myostatin (hMstn) treatment. The absence of atrogin-1, however, led to elevated MyoD levels and permitted the differentiation of atrogin-1 -/-primary myoblast cultures despite the presence of exogenous myostatin. Furthermore, inactivation of atrogin-1 rescued myoblasts from growth inhibition by hMstn. Therefore, these results highlight the central role of atrogin-1 in regulating myostatin signaling during myogenesis. Currently, there are only two known targets of atrogin-1. Thus, we next characterized the associated proteins of atrogin-1 in control and hMstn-treated C2C12 cell cultures by stably expressing tagged atrogin-1 in myoblasts and myotubes, and sequencing the coimmunoprecipitated proteome. We found that atrogin-1 putatively interacts with sarcomeric proteins, transcriptional factors, metabolic enzymes, components of translation, and spliceosome formation. In addition, we also identified that desmin and vimentin, two components of the intermediate filament in muscle, directly interacted with and were degraded by atrogin-1 in response to hMstn. In summary, the muscle wasting effects of the myostatinatrogin- 1 axis are not only limited to the degradation of MyoD and eukaryotic translation initiation factor 3 subunit f, but also encompass several proteins that are involved in a wide variety of cellular activities in the muscle.
机译：肌特异性E3连接酶Atrogin-1靶向MyoD，可通过遍在蛋白-蛋白酶体介导的系统降解。肌生长抑制素是转化生长因子-β超家族的成员，可通过降低MyoD水平来有效抑制肌发生。尽管atrogin-1被myostatin上调，但目前还不清楚atrogin-1是否在介导myostatin信号调节肌发生中发挥作用。在此报告中，我们已经确认，重组人肌生长抑制素（hMstn）治疗后atrogin-1与MyoD的相互作用越来越大。然而，尽管存在外源性肌生长抑制素，但atrogin-1的缺乏导致MyoD水平升高，并允许atrogin-1-/-原代成肌细胞的分化。此外，atrogin-1的失活使成肌细胞免受hMstn的生长抑制。因此，这些结果突出了atrogin-1在肌发生过程中调节肌生长抑制素信号传导中的核心作用。目前，只有两种已知的atrogin-1靶标。因此，我们接下来通过在成肌细胞和肌管中稳定表达标记的atrogin-1，并对共免疫沉淀的蛋白质组进行测序，来表征对照和hMstn处理的C2C12细胞培养物中atrogin-1的相关蛋白。我们发现atrogin-1可能与肌节蛋白，转录因子，代谢酶，翻译成分和剪接体形成相互作用。此外，我们还发现，响应于hMstn，肌肉中中间丝的两个成分desmin和vimentin与atrogin-1直接相互作用并被其降解。总之，肌抑制素-1轴的肌肉消瘦作用不仅限于MyoD和真核翻译起始因子3亚基f的降解，还包括与肌肉中多种细胞活动有关的几种蛋白质。

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