title: Serum Glucocorticoid-Regulated Kinase 1 Blocks CKD-Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Luo
authors.affiliation: Selzman Institute for Kidney Health, Nephrology Division, Baylor College of Medicine, Houston, Texas.
authors.forename: Anlin
authors.initials: A
authors.lastname: Liang
authors.affiliation: Selzman Institute for Kidney Health, Nephrology Division, Baylor College of Medicine, Houston, Texas.
authors.forename: Ming
authors.initials: M
authors.lastname: Liang
authors.affiliation: Selzman Institute for Kidney Health, Nephrology Division, Baylor College of Medicine, Houston, Texas.
authors.forename: Ruohan
authors.initials: R
authors.lastname: Xia
authors.affiliation: Selzman Institute for Kidney Health, Nephrology Division, Baylor College of Medicine, Houston, Texas.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Rizvi
authors.affiliation: Selzman Institute for Kidney Health, Nephrology Division, Baylor College of Medicine, Houston, Texas.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Selzman Institute for Kidney Health, Nephrology Division, Baylor College of Medicine, Houston, Texas jizhongc@bcm.edu.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000071316:Forkhead Box Protein O3 / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000502:physiology*; D051379:Mice; D009133:Muscular Atrophy / Q000201:enzymology* / Q000209:etiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000201:enzymology*; D051899:Smad2 Protein / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000071316:Forkhead Box Protein O3; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051899:Smad2 Protein; D051900:Smad3 Protein; D000099184:Serum-Glucocorticoid Regulated Kinases; C474033:FoxO3 protein, mouse; C497783:Smad2 protein, mouse; C497791:Smad3 protein, mouse
keywords: Cell Signaling; SGK-1; chronic kidney disease; nutrition