Serum Glucocorticoid-Regulated Kinase 1 Blocks CKD-Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3

• Published in: Journal of the American Society of Nephrology Vol. 27; no. 9; pp. 2797 - 2808
• Main Authors: Luo, Jinlong, Liang, Anlin, Liang, Ming, Xia, Ruohan, Rizvi, Yasmeen, Wang, Yun, Cheng, Jizhong
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01-09-2016
• Subjects: Animals; Basic Research; Forkhead Box Protein O3 - physiology; Immediate-Early Proteins - physiology; Mice; Muscular Atrophy - enzymology; Muscular Atrophy - etiology; Protein-Serine-Threonine Kinases - physiology; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - enzymology; Smad2 Protein - physiology; Smad3 Protein - physiology; Cell Signaling; SGK-1; chronic kidney disease; nutrition
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2015080867

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.