Área de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS), Servicio Gallego de Salud (SERGAS), Choupana s/n, 15706, Santiago de Compostela, Spain.
Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada.
J Cachexia Sarcopenia Muscle. 2017 Dec;8(6):974-990. doi: 10.1002/jcsm.12222. Epub 2017 Jul 3.
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.
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，因此成为治疗的重要靶点。糖皮质激素诱导的和消耗性疾病相关的骨骼肌萎缩的治疗方法的开发应该基于特定转录程序的协调方式以及肌肉蛋白合成和降解平衡如何失调。在这里，我们研究了肥胖素/GPR39 系统（一种作用于肌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）是否可以防止糖皮质激素诱导的肌肉细胞萎缩。
在本研究中，我们利用小鼠 C2C12 肌管培养物来研究肥胖素/GPR39 信号通路是否可以影响合成糖皮质激素地塞米松诱导的萎缩。我们将这些发现扩展到体外对人萎缩的影响，使用人 KM155C25 肌管。
肥胖素/GPR39 系统的激活通过调节 Akt、PKD/PKCμ、CAMKII 和 AMPK 信号及其下游靶标来防止糖皮质激素诱导的萎缩，从而控制蛋白质合成、泛素-蛋白酶体系统和自噬-溶酶体系统在小鼠细胞中的作用。我们比较了小鼠和人肌管细胞对糖皮质激素的反应，发现萎缩程序的触发和肥胖素刺激的反应存在差异。值得注意的是，我们证明了 FoxO4 和 FoxO1 的特定翻译后修饰模式在指导肥胖素刺激下人类肌管中 FoxO 活性方面起着关键作用。
我们的研究结果强调了肥胖素/GPR39 系统在协调参与调节分解代谢条件下蛋白质降解的多种途径中的作用。
