Signal regulatory protein-α interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease

Thomas, Sandhya S.; Dong, Yanjun; Zhang, Liping; Mitch, William E.

doi:10.1038/ki.2013.97

Cited by 60 publications

(60 citation statements)

References 38 publications

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“…Our previous studies proved that IGF-1 plays a central role in controlling the muscle wasting of CKD. 5,[24][25][26] In this study, we found that LFES upregulates local IGF-1 and thus, provides a means of increasing muscle mass and function. There are four lines of evidence supporting this conclusion.…”

Section: Discussionmentioning

confidence: 81%

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

Klein

Hassounah

et al. 2015

Journal of the American Society of Nephrology

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Effective therapeutic strategies to treat CKD-induced muscle atrophy are urgently needed. Lowfrequency electrical stimulation (LFES) may be effective in preventing muscle atrophy, because LFES is an acupuncture technique that mimics resistance exercise by inducing muscle contraction. To test this hypothesis, we treated 5/6-nephrectomized mice (CKD mice) and control mice with LFES for 15 days. LFES prevented soleus and extensor digitorum longus muscle weight loss and loss of hind-limb muscle grip in CKD mice. LFES countered the CKD-induced decline in the IGF-1 signaling pathway and led to increases in markers of protein synthesis and myogenesis and improvement in muscle protein metabolism. In control mice, we observed an acute response phase immediately after LFES, during which the expression of inflammatory cytokines (IFN-g and IL-6) increased. Expression of the M1 macrophage marker IL-1b also increased acutely, but expression of the M2 marker arginase-1 increased 2 days after initiation of LFES, paralleling the change in IGF-1. In muscle cross-sections of LFES-treated mice, arginase-1 colocalized with IGF-1. Additionally, expression of microRNA-1 and -206, which inhibits IGF-1 translation, decreased in the acute response phase after LFES and increased at a later phase. We conclude that LFES ameliorates CKDinduced skeletal muscle atrophy by upregulation of the IGF-1 signaling pathway, which improves protein metabolism and promotes myogenesis. The upregulation of IGF-1 may be mediated by decreased expression of microRNA-1 and -206 and/or activation of M2 macrophages.

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Section: Discussionmentioning

confidence: 81%

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

Klein

Hassounah

et al. 2015

Journal of the American Society of Nephrology

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“…Reddy et al concluded that a high SUN not only increased reactive oxygen species but also caused insulin resistance (96). However, it is difficult to assign insulin resistance to a single factor considering that there are so many uremia-induced complex metabolic pathways (97,98). It will be interesting to evaluate whether the production of Another potential role of urea in producing uremiainduced toxicity is through the development of protein carbamylation, which could disrupt the structure of a protein interfering with signaling pathways and so forth.…”

Section: Is Urea Toxic?mentioning

confidence: 99%

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

Weiner

Mitch

Sands

2015

Clinical Journal of the American Society of Nephrology

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370

265

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Renal nitrogen metabolism primarily involves urea and ammonia metabolism, and is essential to normal health. Urea is the largest circulating pool of nitrogen, excluding nitrogen in circulating proteins, and its production changes in parallel to the degradation of dietary and endogenous proteins. In addition to serving as a way to excrete nitrogen, urea transport, mediated through specific urea transport proteins, mediates a central role in the urine concentrating mechanism. Renal ammonia excretion, although often considered only in the context of acidbase homeostasis, accounts for approximately 10% of total renal nitrogen excretion under basal conditions, but can increase substantially in a variety of clinical conditions. Because renal ammonia metabolism requires intrarenal ammoniagenesis from glutamine, changes in factors regulating renal ammonia metabolism can have important effects on glutamine in addition to nitrogen balance. This review covers aspects of protein metabolism and the control of the two major molecules involved in renal nitrogen excretion: urea and ammonia. Both urea and ammonia transport can be altered by glucocorticoids and hypokalemia, two conditions that also affect protein metabolism. Clinical conditions associated with altered urine concentrating ability or water homeostasis can result in changes in urea excretion and urea transporters. Clinical conditions associated with altered ammonia excretion can have important effects on nitrogen balance.

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“…42 The cells were treated with a cytokine mixture of IL-6 (2 ng/ml), TNF-a (2 ng/ml), and TGF-b1 (2 ng/ml). 4 Mechanical Stretch C2C12 cells were plated on silicone elastomer-bottomed plates and subjected to mechanical stretch as described. 33 Briefly, at 90% confluence, cells were exposed to a cyclic mechanical stretch with a computercontrolled mechanical Strain Unit (Flexcell 4000) set at cyclic (60 cycles per minute) stretch.…”

Section: Exercise Trainingmentioning

confidence: 99%

“…The degradation of insulin-receptor substrate 1 impairs activities of phosphatidylinositol 3-kinase (PI3K) and the Akt. 4 The reduced phosphorylation of these signaling proteins results in decreased phosphorylation of forkhead transcription factors (FoxOs) with activation of caspase-3 and expression of the ubiquitin E3 ligases, Atrogin1 and MuRF1. The result is stimulation of muscle protein degradation.…”

mentioning

confidence: 99%

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

Luo

Liang

et al. 2016

JASN

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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

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Signal regulatory protein-α interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease

Cited by 60 publications

References 38 publications

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion

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

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