CKD Stimulates Muscle Protein Loss Via Rho-associated Protein Kinase 1 Activation

Peng, Hui; Cao, Jin; Yu, Ronghua; Danesh, Farhad R.; Wang, Yanlin; Xu, Jing; Hu, Zhaoyong

doi:10.1681/asn.2014121208

Cited by 26 publications

(36 citation statements)

References 52 publications

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“…For example, we reported that the phosphatase PTEN inhibition protects muscle wasting in CKD mice [3;4]; knockdown of protein phosphatase 2C-alpha (PP2Cα) protects angiotensin II-induced muscle wasting [37]. In the present study, we demonstrated a novel nuclear phosphatase, SCP4, which regulates muscle protein degradation by preventing FoxO1/3a nuclear translocation and activity.…”

Section: Discussionmentioning

confidence: 53%

“…After being fixed with 4% formaldehyde, the frozen tibialis anterior muscles’ sections (5 μm) were subjected to immunostaining or immunohistochemistry as described [3]. For measuring myofiber diameter, C2C12 myotubes were transfected with adenovirus bearing GFP for 24 h to outline cells.…”

Section: Methodsmentioning

confidence: 99%

“…Although the mechanisms leading to muscle wasting are complicated, significant progress has been made towards understanding this catabolic situation. For example, in mice with CKD, we found acidosis or cytokines impaired IGF-1/insulin signaling that triggers a caspase-3/ROCK1/PTEN negative feedback loop to suppress Akt sustainably [1–3]. A decreased Akt activity leads to decreased phosphorylation of downstream effectors, such as forkhead transcription factors (FoxOs) [4;5].…”

Section: Introductionmentioning

confidence: 99%

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The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease

Sun

et al. 2017

Kidney International

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Chronic kidney disease (CKD) and related inflammatory responses stimulate protein-energy wasting, a complication causing loss of muscle mass. Primarily, muscle wasting results from accelerated protein degradation via autophagic/lysosomal and proteasomal pathways, but mechanisms regulating these proteolysis pathways remain unclear. Since dephosphorylation of FoxOs regulates ubiquitin/proteasome protein metabolism, we tested whether a novel nuclear phosphatase, the small C-terminal domain phosphatase (SCP) 4, regulates FoxOs signaling and, in turn, muscle wasting. In cultured mouse myoblast cells, SCP4 overexpression stimulated proteolysis while knockdown of SCP4 prevented the proteolysis stimulated by inflammatory cytokines. SCP4 overexpression led to nuclear accumulation of FoxO1/3a followed by increased expression of catabolic factors including myostatin, Atrogin-1 and MuRF-1, and induction of lysosomal-mediated proteolysis. Treatment of C2C12 myotubes with proinflammatory cytokines stimulated SCP4 expression in an NF-κB-dependent manner. In skeletal muscle of mice with CKD, SCP4 expression was up-regulated. Similarly, in skeletal muscle of patients with CKD, SCP4 expression was significantly increased. Knockdown of SCP4 significantly suppressed FoxO1/3a-mediated expression of Atrogin-1 and MuRF-1 and prevented muscle wasting in mice with CKD. Thus, SCP4 is a novel regulator of FoxO transcription factors and promotes cellular proteolysis. Hence, targeting SCP4 may prevent muscle wasting in CKD and possibly other catabolic conditions.

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Section: Discussionmentioning

confidence: 53%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease

Sun

et al. 2017

Kidney International

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“…) or of PKB activity (Peng et al. ). It was shown that miR‐148b is involved in the PKB pathway by downregulation of ErbB3 receptor (Bischoff et al.…”

Section: Discussionmentioning

confidence: 99%

Transition from physical activity to inactivity increases skeletal muscle miR-148b content and triggers insulin resistance

et al. 2016

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This study investigated miR‐148b as a potential physiological actor of physical inactivity‐induced effects in skeletal muscle. By using animal and human protocols, we demonstrated that the early phase of transition toward inactivity was associated with an increase in muscle miR‐148b content, which triggered the downregulation of NRAS and ROCK1 target genes. Using human myotubes, we demonstrated that overexpression of miR‐148b decreased NRAS and ROCK1 protein levels, and PKB phosphorylation and glucose uptake in response to insulin. Increase in muscle miR‐148b content might thus participate in the decrease in insulin sensitivity at the whole body level during the transition toward physical inactivity.

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“…2 Potential stimuli of muscle wasting in CKD include impaired insulin/IGF-1 signalling, excess glucocorticoids production, up-regulation of myostatin expression and systemic inflammation. 3,4 Unfortunately, the development of therapeutic interventions that block muscle wasting is still at initial stages. 5,6 We examined whether a herbal compound, ursolic acid, will block muscle wasting by inhibiting myostatin expression and inflammatory pathways.…”

Section: Introductionmentioning

confidence: 99%

Suppression of muscle wasting by the plant‐derived compound ursolic acid in a model of chronic kidney disease

Chen

et al. 2016

J cachexia sarcopenia muscle

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BackgroundMuscle wasting in chronic kidney disease (CKD) and other catabolic disorders contributes to morbidity and mortality, and there are no therapeutic interventions that regularly and safely block losses of muscle mass. We have obtained evidence that impaired IGF‐1/insulin signalling and increases in glucocorticoids, myostatin and/or inflammatory cytokines that contribute to the development of muscle wasting in catabolic disorders by activating protein degradation.MethodsUsing in vitro and in vivo models of muscle wasting associated with CKD or dexamethasone administration, we measured protein synthesis and degradation and examined mechanisms by which ursolic acid, derived from plants, could block the loss of muscle mass stimulated by CKD or excessive levels of dexamethasone.ResultsUsing cultured C2C12 myotubes to study muscle wasting, we found that exposure to glucocorticoids cause loss of cell proteins plus an increase in myostatin; both responses are significantly suppressed by ursolic acid. Results from promoter and ChIP assays demonstrated a mechanism involving ursolic acid blockade of myostatin promoter activity that is related to CEBP/δ expression. In mouse models of CKD‐induced or dexamethasone‐induced muscle wasting, we found that ursolic acid blocked the loss of muscle mass by stimulating protein synthesis and decreasing protein degradation. These beneficial responses included decreased expression of myostatin and inflammatory cytokines (e.g. TGF‐β, IL‐6 and TNFα), which are initiators of muscle‐specific ubiquitin‐E3 ligases (e.g. Atrogin‐1, MuRF‐1 and MUSA1).ConclusionsUrsolic acid improves CKD‐induced muscle mass by suppressing the expression of myostatin and inflammatory cytokines via increasing protein synthesis and reducing proteolysis.

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CKD Stimulates Muscle Protein Loss Via Rho-associated Protein Kinase 1 Activation

Cited by 26 publications

References 52 publications

The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease

The nuclear phosphatase SCP4 regulates FoxO transcription factors during muscle wasting in chronic kidney disease

Transition from physical activity to inactivity increases skeletal muscle miR-148b content and triggers insulin resistance

Suppression of muscle wasting by the plant‐derived compound ursolic acid in a model of chronic kidney disease

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