Obestatin controls the ubiquitin-proteasome and autophagy-lysosome systems in glucocorticoid-induced muscle cell atrophy.
Obestatin controls the ubiquitin-proteasome and autophagy-lysosome systems in glucocorticoid-induced muscle cell atrophy.
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DOI：
10.1002/jcsm.12222
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Camiña JP
中科院分区：
文献类型：
--
作者：
Cid-Díaz T;Santos-Zas I;González-Sánchez J;Gurriarán-Rodríguez U;Mosteiro CS;Casabiell X;García-Caballero T;Mouly V;Pazos Y;Camiña JP
许多以肌肉萎缩为特征的病理状态与循环中糖皮质激素的增加和患者预后不良有关，使其成为治疗的重要靶点。糖皮质激素诱导和消耗性紊乱相关的骨骼肌萎缩的治疗方法的开发应该基于特定的转录程序是如何协调的，以及肌肉蛋白质合成和降解的平衡是如何被解除调节的。在这里，我们研究了Obestatin/GPR39系统，一个作用于肌肉发生并对骨骼肌具有合成代谢作用的自分泌/旁分泌信号系统，是否可以预防糖皮质激素诱导的肌细胞萎缩。在本研究中，我们利用小鼠C2C12肌管培养，研究了Obestatin/GPR39信号通路是否影响合成的糖皮质激素地塞米松诱导的萎缩。我们已经将这些发现扩展到使用人KM155C25肌管对人类萎缩的体外影响。AKT、PKD/PKCμ、CaMKII和AMPK信号通路及其下游靶点调控蛋白合成、泛素-蛋白酶体系统和自噬-溶酶体系统，通过激活AKT/GPR39系统对糖皮质激素诱导的小鼠细胞萎缩具有保护作用。我们比较了小鼠和人类肌管细胞对糖皮质激素的反应，并确定了在触发萎缩程序和对奥贝他汀刺激的反应方面的差异。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人类肌管中引导FoxO活性以响应他汀类药物起着关键作用。我们的发现强调了Obestatin/GPR39系统在协调参与分解代谢条件下蛋白质降解调节的各种途径中的功能。
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. 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. The activation of the obestatin/GPR39 system protects from glucocorticoid‐induced atrophy by regulation of Akt, PKD/PKCμ, 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. 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.
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影响因子：
29
作者：
Jing, Enxuan;Gesta, Stephane;Kahn, C. Ronald
通讯作者：
Kahn, C. Ronald
影响因子：
15.9
作者：
Backs, Johannes;Song, Kunhua;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
4.8
作者：
Lecker, SH;Jagoe, RT;Goldberg, AL
通讯作者：
Goldberg, AL
DOI：
10.1073/pnas.0406789102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Huang, H;Regan, KM;Tindall, DJ
通讯作者：
Tindall, DJ
影响因子：
4.9
作者：
Mamchaoui, Kamel;Trollet, Capucine;Mouly, Vincent
通讯作者：
Mouly, Vincent