Dataset Information

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.

SUBMITTER: Luo J

PROVIDER: S-EPMC5004658 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Luo Jinlong J Liang Anlin A Liang Ming M Xia Ruohan R Rizvi Yasmeen Y Wang Yun Y Cheng Jizhong J

Journal of the American Society of Nephrology : JASN 20160215 9

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 liga ...[more]

PMID: 26880799

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Project description:BackgroundInstrumental gait analysis in nephrology is widely neglected, although patients with chronic kidney disease (CKD) show brain changes due to cerebrovascular disease and metabolic disorders that can potentially influence gait quality. Our study assesses the association between CKD stages and gait parameters, to understand the prevalent status of brain related gait parameters (i.e. variability) and of performance related parameters (i.e. gait speed, stride length). We hypothesize that gait changes are detectable already in early stages of CKD.MethodsForty-five participants distributed in 5 CKD severity groups underwent an instrumental gait analysis via a triaxial accelerometer affixed to the lower trunk under single- and dual-task conditions. In addition to spatio-temporal parameters, variability and dual-task cost of gait were extracted. A battery of clinical assessments was conducted with the aim of helping to better explain the findings of the gait analysis. A correlation analysis was made to investigate a linear relation between gait parameters and CKD severity.ResultsStatistically significant correlations (Pearson correlation coefficient) with CKD severity were found for gait speed (p < 0.01, r = -0.55, 95% CI [-0.73;-0.30]), stride length ( p < 0.01, r = -0.40, 95% CI [-0.62;-0.12]), step length (p < 0.01, r = -0.41, 95% CI [-0.63;-0.13], coefficient of variance (CV) of step length (p = 0.01, r = 0.36, 95% CI [0.08;0.59]), gait regularity (p < 0.01, r = -0.38, 95% CI [-0.61;-0.10]), dual-task cost of gait speed (p < 0.01, r = 0.40, 95% CI [0.13;0.62]) and dual-task cost of stride time (p = 0.03, r = 0.32, 95% CI [0.03;0.57]). Adjustment for age and gender confirmed all results except for gait regularity. With increasing severity of renal failure, Handgrip strength, Time for the Expanded Timed Get Up and Go test, executive functions, haemoglobin, and haematocrit, worsen.ConclusionsThe correlation of CKD severity with spatio-temporal parameters (performance indices mainly relatable to peripheral functionality) and with variability of gait (related to central factors) supported by the results of the clinical assessments, suggests that gait disturbance in CKD patients is not only due to metabolic factors that lead to muscle wasting, but also to brain changes that affect motor control. This suggests that the treatment of renal disease should include cognitive aspects in addition to metabolic and functional factors.

Dataset Information

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

Publications

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

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