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 CKDinduced 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 downstreamregulated 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. 27: 279727: -280827: , 201627: . doi: 10.1681 CKD is frequently complicated by muscle atrophy because of stimulation of muscle protein degradation mediated by increased activity of both caspase-3 and the ubiquitin-proteasome system (UPS). 1 In muscles of rodents with CKD, caspase-3 stimulates cleavage of the complex structure of muscle protein to provide substrates for degradation by the UPS; it also stimulates proteolytic activity of the 26S proteasome. 2 The UPS can selectively degrade myofibrillar protein by stimulating the expression of ubiquitin E3 ligases, Atrogin1 and MuRF1. These ligases conjugate ubiquitin to proteins targeted for protein degradation, resulting in their degradation in the 26S proteasome. 3 Conditions associated with CKD that initiate loss of muscle mass include metabolic acidosis, inflammation, excess angiotensin II, myostatin expression, and insulin resistance. 1 J Am Soc Nephrol

Amelioration of muscle wasting by glucagon‐like peptide‐1 receptor agonist in muscle atrophy

“…In the cytosol, the increased GCs form complex with GR and then move to the nucleus for binding to the GC response element on the promoter of GR target genes (MSTN, KLF15, and FoxO3a) . They are well known to activate UPS through E3 ligase that degrades muscle proteins .…”

High expression of FOXO3 is associated with poor prognosis in patients with hepatocellular carcinoma

“…FOXO3 has a relative molecular mass of ~71 kDa and contains five domains: a highly conserved forked-winged helix-turn-helix DnA binding domain (FKH), two nuclear localization sequences (nls), one nuclear export sequence and one c-terminal transactivation domain (tAD) (43). the highly conserved FKH domain primarily regulates the interaction between FOXO3 and DnA, and also mediates its interaction with estrogen receptor α (44) and tumor protein p53 (p53) protein (45). the translocation of FOXO3 from the cytoplasm to the nucleus requires the nls domain, which mediates the release of FOXO3 from the nucleus.…”

“…FOXO3 is phosphorylated by upstream kinases such as AKt, erK, serum/glucocorticoid regulated kinase 1, inhibitor of nuclear factor-κB kinase subunit β and inhibitor of nuclear factor-κB kinase subunit ε. the dysregulation of these kinases often occurs in different types of cancer and facilitates tumor progression by promoting the FOXO nuclear-cytoplasmic shuttle or ubiquitin-dependent protein kinase degradation (46)(47)(48)(49). the carcinogenic effects of FOXO3 dysfunction are mediated by a variety of mechanisms that involve several genes associated with apoptosis, such as Bim, noxa, Puma, Fasl and trAIl, in addition to genes controlling cell proliferation, such as p21, p27, p130, cyclin g2 and gADD45 (45). therefore, the increased expression of the FOXO3 gene is associated with the incidence of cancer.…”

WNK1 regulates skeletal muscle cell hypertrophy by modulating the nuclear localization and transcriptional activity of FOXO4

“…By contrast, CKD had the opposite effect. Previous studies demonstrated that exercise training efficiently attenuated CKD-induced muscle atrophy by suppressing MAFbx and MuRF1 transcription 42 , 43 . Of interest is that a pan-WNK kinase inhibitor WNK463 increased atrogene transcription in mouse skeletal muscle and C2C12 cells (Fig.…”