Gortan Cappellari Gianluca, Semolic Annamaria, Ruozi Giulia, Vinci Pierandrea, Guarnieri Gianfranco, Bortolotti Francesca, Barbetta Davide, Zanetti Michela, Giacca Mauro, Barazzoni Rocco
Department of Medical, Surgical, and Health Sciences, University of Trieste, Trieste, Italy.
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
FASEB J. 2017 Dec;31(12):5159-5171. doi: 10.1096/fj.201700126R. Epub 2017 Aug 4.
Unacylated ghrelin (UnAG) may lower skeletal muscle oxidative stress, inflammation, and insulin resistance in lean and obese rodents. UnAG-induced autophagy activation may contribute to these effects, likely involving removal of dysfunctional mitochondria (mitophagy) and redox state maintenance. In chronic kidney disease (CKD) oxidative stress, inflammation and insulin resistance may negatively influence patient outcome by worsening nutritional state through muscle mass loss. Here we show in a 5/6 nephrectomy (Nx) CKD rat model that 4 d s.c. UnAG administration (200 µg twice a day) normalizes CKD-induced loss of gastrocnemius muscle mass and a cluster of high tissue mitochondrial reactive oxygen species generation, high proinflammatory cytokines, and low insulin signaling activation. Consistent with these results, human uremic serum enhanced mitochondrial reactive oxygen species generation and lowered insulin signaling activation in C2C12 myotubes while concomitant UnAG incubation completely prevented these effects. Importantly, UnAG enhanced muscle mitophagy and silencing RNA-mediated autophagy protein 5 silencing blocked UnAG activities in myotubes. UnAG therefore normalizes CKD-induced skeletal muscle oxidative stress, inflammation, and low insulin signaling as well as muscle loss. UnAG effects are mediated by autophagy activation at the mitochondrial level. UnAG administration and mitophagy activation are novel potential therapeutic strategies for skeletal muscle metabolic abnormalities and their negative clinical impact in CKD.-Gortan Cappellari, G., Semolic, A., Ruozi, G., Vinci, P., Guarnieri, G., Bortolotti, F., Barbetta, D., Zanetti, M., Giacca, M., Barazzoni, R. Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease.
去酰基胃饥饿素（UnAG）可能会降低瘦型和肥胖型啮齿动物骨骼肌的氧化应激、炎症反应及胰岛素抵抗。UnAG诱导的自噬激活可能有助于产生这些效应，这可能涉及清除功能失调的线粒体（线粒体自噬）并维持氧化还原状态。在慢性肾脏病（CKD）中，氧化应激、炎症反应和胰岛素抵抗可能会通过肌肉量减少导致营养状况恶化，从而对患者预后产生负面影响。在此，我们在5/6肾切除（Nx）的CKD大鼠模型中发现，皮下注射UnAG 4天（每天两次，每次200μg）可使CKD诱导的腓肠肌肌肉量损失恢复正常，并使一组高组织线粒体活性氧生成、高促炎细胞因子及低胰岛素信号激活恢复正常。与这些结果一致的是，人尿毒症血清增强了C2C12肌管中线粒体活性氧的生成并降低了胰岛素信号激活，而同时进行UnAG孵育则完全阻止了这些效应。重要的是，UnAG增强了肌肉线粒体自噬，并且RNA干扰介导的自噬蛋白5沉默阻断了UnAG在肌管中的活性。因此，UnAG可使CKD诱导的骨骼肌氧化应激、炎症反应、低胰岛素信号以及肌肉损失恢复正常。UnAG的作用是通过线粒体水平的自噬激活介导的。给予UnAG和激活线粒体自噬是治疗CKD中骨骼肌代谢异常及其负面临床影响的新型潜在治疗策略。-戈尔坦·卡佩拉里，G.，塞莫利克，A.，罗齐，G.，文奇，P.，瓜尔尼耶里，G.，博托洛蒂，F.，巴尔贝塔，D.，扎内蒂，M.，贾卡，M.，巴拉佐尼，R. 去酰基胃饥饿素通过增强实验性慢性肾脏病中的组织线粒体自噬使骨骼肌氧化应激恢复正常并防止肌肉分解代谢
