Luo Jinlong, Liang Anlin, Liang Ming, Xia Ruohan, Rizvi Yasmeen, Wang Yun, Cheng Jizhong
Department of Emergency, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China; and Selzman Institute for Kidney Health, Nephrology Division, Baylor College of Medicine, Houston, Texas.
Selzman Institute for Kidney Health, Nephrology Division, Baylor College of Medicine, Houston, Texas.
J Am Soc Nephrol. 2016 Sep;27(9):2797-808. doi: 10.1681/ASN.2015080867. Epub 2016 Feb 15.
Muscle proteolysis in CKD is stimulated when the ubiquitin-proteasome system is activated. Serum glucocorticoid-regulated kinase 1 (SGK-1) is involved in skeletal muscle homeostasis, but the role of this protein in CKD-induced muscle wasting is unknown. We found that, compared with muscles from healthy controls, muscles from patients and mice with CKD express low levels of SGK-1. In mice, SGK-1-knockout (SGK-1-KO) induced muscle loss that correlated with increased expression of ubiquitin E3 ligases known to facilitate protein degradation by the ubiquitin-proteasome, and CKD substantially aggravated this response. SGK-1-KO also altered the phosphorylation levels of transcription factors FoxO3a and Smad2/3. In C2C12 muscle cells, expression of dominant negative FoxO3a or knockdown of Smad2/3 suppressed the upregulation of E3 ligases induced by loss of SGK-1. Additionally, SGK-1 overexpression increased the level of phosphorylated N-myc downstream-regulated gene 1 protein, which directly interacted with and suppressed the phosphorylation of Smad2/3. Overexpression of SGK-1 in wild-type mice with CKD had similar effects on the phosphorylation of FoxO3a and Smad2/3 and prevented CKD-induced muscle atrophy. Finally, mechanical stretch of C2C12 muscle cells or treadmill running of wild-type mice with CKD stimulated SGK-1 production, and treadmill running inhibited proteolysis in muscle. These protective responses were absent in SGK-1-KO mice. Thus, SGK-1 could be a mechanical sensor that mediates exercise-induced improvement in muscle wasting stimulated by CKD.
当泛素-蛋白酶体系统被激活时，慢性肾脏病（CKD）中的肌肉蛋白水解会受到刺激。血清糖皮质激素调节激酶1（SGK-1）参与骨骼肌的稳态，但该蛋白在CKD诱导的肌肉萎缩中的作用尚不清楚。我们发现，与健康对照者的肌肉相比，CKD患者和小鼠的肌肉中SGK-1表达水平较低。在小鼠中，SGK-1基因敲除（SGK-1-KO）诱导肌肉损失，这与已知可促进泛素-蛋白酶体介导的蛋白质降解的泛素E3连接酶表达增加相关，而CKD显著加重了这种反应。SGK-1-KO还改变了转录因子FoxO3a和Smad2/3的磷酸化水平。在C2C12肌肉细胞中，显性负性FoxO3a的表达或Smad2/3的敲低抑制了因SGK-1缺失而诱导的E3连接酶上调。此外，SGK-1过表达增加了磷酸化的N- myc下游调节基因1蛋白的水平，该蛋白直接与Smad2/3相互作用并抑制其磷酸化。在患有CKD的野生型小鼠中过表达SGK-1对FoxO3a和Smad2/3的磷酸化有类似影响，并预防了CKD诱导的肌肉萎缩。最后，对C2C12肌肉细胞进行机械拉伸或让患有CKD的野生型小鼠进行跑步机跑步刺激了SGK-1的产生，并且跑步机跑步抑制了肌肉中的蛋白水解。这些保护性反应在SGK-1-KO小鼠中不存在。因此，SGK-1可能是一种机械传感器，介导运动诱导的对CKD刺激的肌肉萎缩的改善。
