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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >Obestatin controls the ubiquitin?￠????proteasome and autophagy?￠????lysosome systems in glucocorticoid-induced muscle cell atrophy
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Obestatin controls the ubiquitin?￠????proteasome and autophagy?￠????lysosome systems in glucocorticoid-induced muscle cell atrophy

机译：肥胖抑制素控制糖皮质激素诱导的肌肉细胞萎缩中的泛素蛋白酶体和自噬酶体系统

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Abstract Background Many pathological states characterized by muscle atrophy are associated with an increase in circulating glucocorticoids and poor patient prognosis, making it an important target for treatment. The development of treatments for glucocorticoid-induced and wasting disorder-related skeletal muscle atrophy should be designed based on how the particular transcriptional program is orchestrated and how the balance of muscle protein synthesis and degradation is deregulated. Here, we investigated whether the obestatin/GPR39 system, an autocrine/paracrine signaling system acting on myogenesis and with anabolic effects on the skeletal muscle, could protect against glucocorticoid-induced muscle cell atrophy. Methods In the present study, we have utilized mouse C2C12 myotube cultures to examine whether the obestatin/GPR39 signaling pathways can affect the atrophy induced by the synthetic glucocorticoid dexamethasone. We have extended these findings to in vitro effects on human atrophy using human KM155C25 myotubes. Results The activation of the obestatin/GPR39 system protects from glucocorticoid-induced atrophy by regulation of Akt, PKD/PKC????, CAMKII and AMPK signaling and its downstream targets in the control of protein synthesis, ubiquitin?￠????proteasome system and autophagy?￠????lysosome system in mouse cells. We compared mouse and human myotube cells in their response to glucocorticoid and identified differences in both the triggering of the atrophic program and the response to obestatin stimulation. Notably, we demonstrate that specific patterns of post-translational modifications of FoxO4 and FoxO1 play a key role in directing FoxO activity in response to obestatin in human myotubes. Conclusions Our findings emphasize the function of the obestatin/GPR39 system in coordinating a variety of pathways involved in the regulation of protein degradation during catabolic conditions.
机译：摘要背景许多以肌肉萎缩为特征的病理状态与循环糖皮质激素的增加和患者预后不良有关，使其成为重要的治疗目标。应根据如何协调特定的转录程序以及如何放松调节肌肉蛋白质合成和降解的平衡来设计糖皮质激素诱导的和与消耗性疾病有关的骨骼肌萎缩的治疗方法。在这里，我们调查了Obestatin / GPR39系统（一种作用于肌生成并对骨骼肌具有合成代谢作用的自分泌/旁分泌信号传导系统）是否可以预防糖皮质激素诱导的肌肉细胞萎缩。方法在本研究中，我们利用小鼠C2C12肌管培养物来检查obestatin / GPR39信号通路是否可以影响合成糖皮质激素地塞米松所致的萎缩。我们已将这些发现扩展到使用人KM155C25肌管对人萎缩的体外作用。结果肥胖抑制素/ GPR39系统的激活可通过调节Akt，PKD /PKCβ，CAMKII和AMPK信号及其下游靶标来调节糖皮质激素诱导的萎缩，从而控制蛋白质合成，泛素或β-泛素。蛋白酶体系统和小鼠细胞中的自噬溶酶体系统。我们比较了小鼠和人类的肌管细胞对糖皮质激素的反应，并确定了萎缩程序的触发和对雌激素刺激的反应的差异。值得注意的是，我们证明了FoxO4和FoxO1的翻译后修饰的特定模式在指导FoxO响应人类肌管中的obestatin方面起着关键作用。结论我们的发现强调了obestatin / GPR39系统在协调分解代谢条件下蛋白质降解调控的各种途径中的功能。

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