Regulation of Muscle Protein Degradation

Lee, Seoung Woo; Dai, Guoli; Hu, Zhaoyong; Wang, Xiaonan; Du, Jie; Mitch, William E.

doi:10.1097/01.asn.0000127211.86206.e1

Cited by 306 publications

(286 citation statements)

References 41 publications

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“…4 This leads to activation of the FoxO transcription factors and increased expression of atrogin-1/ MAFbx and MuRF-1. 49,50 Given the changes in gene expression and their relationship to PI3-K/Akt signaling, we tested whether Akt signaling was altered in muscle of CKD-control and CKDmXIAP mice and compared them with the normal control mice. We found that both Akt and activated (phospho) Akt were decreased in the CKD mouse, but the levels of Akt protein and phospho-Akt in the CKD-mXIAP mice were comparable to those in control mice.…”

Section: Discussionmentioning

confidence: 99%

XIAP Reduces Muscle Proteolysis Induced by CKD

Hu¹,

Zhang

et al. 2010

Journal of the American Society of Nephrology

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X-chromosome-linked inhibitor of apoptosis protein (XIAP) is an endogenous caspase inhibitor. Caspase-3 contributes to the muscle wasting associated with chronic kidney disease (CKD) and other systemic illnesses, but whether XIAP modulates muscle wasting in CKD is unknown. Here, overexpression of XIAP in cultured skeletal muscle cells decreased protein degradation induced by serum deprivation, suggesting that caspase-mediated proteolysis contributes to muscle atrophy. We generated transgenic mice that overexpress human XIAP specifically in skeletal muscle (mXIAP) and evaluated muscle protein degradation induced by CKD. mXIAP mice with normal kidney function exhibited mild skeletal muscle hypertrophy. Muscle weights of mXIAP mice with CKD (mXIAP-CKD) were indistinguishable from wild-type mice, suggesting that overexpression of XIAP in skeletal muscle protects from CKD-induced muscle atrophy. The rate of total protein degradation, proteasome chymotrypsin-like activity, and caspase-3-mediated actin cleavage all were lower in muscle isolated from mXIAP-CKD mice compared with wild-type CKD mice. Concomitant with the reduction in overall proteolysis, mRNA levels of ubiquitin, muscle-specific ring finger 1, and atrogin-1/muscle atrophy F-box were lower in mXIAP-CKD mice, suggesting that decreased expression of the ubiquitin-proteasome pathway components may contribute to the protein-sparing effects of XIAP. In summary, these results demonstrate that XIAP inhibits multiple aspects of protein degradation in skeletal muscle during CKD.

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Section: Discussionmentioning

confidence: 99%

XIAP Reduces Muscle Proteolysis Induced by CKD

Hu¹,

Zhang

et al. 2010

Journal of the American Society of Nephrology

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“…Previous studies have shown that activation of caspase-3 is an initial step in muscle proteolysis. 16,27 An increase in capase-3-mediated cleavage of actin converts undegradable myofibril complex (i.e., actin/myosin complex) into substrates suitable for proteasome cleavage. In catabolic diseases, 13,14 there is often an upregulation of the ubiquitin-proteasome proteolytic system components that results from increased gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Activated caspase-9 then associates with APAF-1 to form an apoptosome, which activates caspase-3. 24,27 The death receptor pathway is triggered by the inflammatory response that increases circulating cytokines 32 similar to the response seen in type II diabetes. 33 Inflammatory cytokines such as TNFa activate caspase-8 through the death receptor pathway, and caspase-8 then activates caspase-3.…”

Section: X-chromosome Linked Inhibitor Of Apoptosis Protein Xh Wang Ementioning

confidence: 99%

X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice

Wang

et al. 2007

Gene Ther

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Loss of muscle protein is a serious complication of catabolic diseases and contributes substantially to patients' morbidity and mortality. This muscle loss is mediated largely by the activation of the ubiquitin-proteasome system; however, caspase-3 catalyzes an initial step in this process by cleaving actomyosin into small protein fragments that are rapidly degraded by the proteasome-dependent proteolytic pathway. We hypothesized that X-chromosome linked inhibitor of apoptosis protein (XIAP), an endogenous caspase-3 inhibitor, would block this first step in the cleavage of actomyosin that would make XIAP a candidate for treating muscle wasting. To determine if XIAP could attenuate muscle protein degradation, we used a recombinant lentivirus (Len-XIAP) encoding the full-length human XIAP cDNA to express XIAP in vivo. In muscle of streptozotocin-treated insulin-deficient mice, total muscle protein degradation, caspase-3 activity, and myofibril destruction were increased while XIAP was decreased. Overexpression of XIAP in these mice attenuated the excessive muscle protein degradation. Increased proteasome activity, caspase-3 activity and myofibril protein breakdown were all reduced. The ability of XIAP to prevent the loss of muscle protein suggests that XIAP could be a therapeutic reagent for muscle atrophy in catabolic diseases.

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“…8 -10 This is relevant because impaired insulin/ IGF-1 signaling is closely linked to activation of muscle protein degradation. 3,11,12 Indeed, overexpression of IGF-1 in muscle prevents AngII-induced muscle wasting. 3 Additional evidence for impaired insulin/IGF-1 signaling is that glucocorticoids exert a permissive effect in mediating muscle proteolysis in conditions associated with impaired insulin/IGF-1 signaling, such as acidosis, insulin deficiency/resistance, starvation, and sepsis.…”

mentioning

confidence: 99%

IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II–Induced Muscle Wasting

Zhang

et al. 2009

Journal of the American Society of Nephrology

219

244

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Animal studies suggest that increased levels of circulating angiotensin II (AngII) could contribute to the loss of lean body mass in chronic kidney disease, but the mechanism by which this occurs is unclear. Here, AngII infusion increased circulating IL-6 and its hepatic production in wild-type mice, suggesting that AngII-induced inflammation may trigger muscle loss. AngII infusion also stimulated the suppressor of cytokine signaling (SOCS3) in muscle, which led to loss of insulin receptor substrate 1 (IRS-1), thereby impairing insulin/IGF-1 signaling and enhancing protein degradation. All of these responses to AngII were suppressed in IL-6 -deficient mice. Recombinant human IL-6 (rhIL-6) treatment of cultured myotubes only minimally increased SOCS3, however, suggesting the contribution of other mediators. Because AngII increases hepatic serum amyloid A (SAA) expression in an IL-6 -dependent manner, we treated wild-type mice with rhIL-6 and an SAA1-overexpressing adenovirus; the combination led to a significantly greater increase in SOCS3 and decrease in IRS-1 compared with either rhIL-6 or SAA1 alone. We observed similar effects on SOCS3 and IRS-1 when we treated cultured muscle myotubes with rhIL-6 and SAA1. Taken together, these results suggest an interorgan response to high levels of AngII: Hepatic production of IL-6 and SAA increases, and these mediators act synergistically to impair insulin/IGF-1 signaling, which promotes muscle proteolysis. Targeting the high levels of IL-6 and SAA in catabolic disorders might be a therapeutic approach to prevent muscle wasting.

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Regulation of Muscle Protein Degradation

Cited by 306 publications

References 41 publications

XIAP Reduces Muscle Proteolysis Induced by CKD

XIAP Reduces Muscle Proteolysis Induced by CKD

X-chromosome linked inhibitor of apoptosis protein inhibits muscle proteolysis in insulin-deficient mice

IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II–Induced Muscle Wasting

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