Clinical and Experimental Nephrology

, Volume 17, Issue 2, pp 174–182 | Cite as

Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin

  • Sandhya S. Thomas
  • William E. Mitch
Review Article


Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle, yielding fragments that are substrates that are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF-1, and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin, which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting, suggesting that therapies that block myostatin could prevent muscle wasting in catabolic conditions.


Ubiquitin-proteasome system (UPS) Muscle wasting Protein degradation Chronic kidney disease (CKD) Caspase-3 


  1. 1.
    Mitch WE. Malnutrition: a frequent misdiagnosis for hemodialysis patients. J Clin Invest. 2002;110:437–9.PubMedGoogle Scholar
  2. 2.
    Stenvinkel P, Heimburger O, Lindholm B. Wasting, but not malnutrition, predicts cardiovascular mortality in end-stage renal disease. Nephrol Dial Transplant. 2004;19:2181–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Hakim RM, Lazarus JM. Initiation of dialysis. J Am Soc Nephrol. 1995;6:1319–20.PubMedGoogle Scholar
  4. 4.
    Fouque D, Kalantar-Zadeh K, Kopple JD, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int. 2008;73:391–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Ikizler TA, Pupim LB, Brouillette JR, et al. Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation. Am J Physiol. 2002;282:E107–16.Google Scholar
  6. 6.
    Pupim LB, Flakoll PJ, Brouillette JR, Levenhagen DK, Hakim RM, Ikizler TA. Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients. J Clin Investig. 2002;110:483–92.PubMedGoogle Scholar
  7. 7.
    Pupim LB, Majchrzak KM, Flakoll PJ, Ikizler TA. Intradialytic oral nutrition improves protein homeostasis in chronic hemodialysis patients with deranged nutritional status. J Am Soc Nephrol. 2006;17:3149–57.PubMedCrossRefGoogle Scholar
  8. 8.
    Cano NJ, Fouque D, Roth H, et al. Intradialytic parenteral nutrition does not improve survival in malnourished hemodialysis patients: a 2-year multicenter, prospective, randomized study. J Am Soc Nephrol. 2007;18:2583–91.PubMedCrossRefGoogle Scholar
  9. 9.
    Mitch WE, Fouque D. Dietary approaches to kidney disease. In: Brenner BM, editor. Brenner and rector’s the kidney. Philadelphia: Elsevier; 2012. p. 2170–204.Google Scholar
  10. 10.
    Kaysen GA, Dubin JA, Muller H-G, Rosales L, Levin NW, Mitch WE. Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients. Kidney Int. 2004;65:1408–15.PubMedCrossRefGoogle Scholar
  11. 11.
    Leal VO, Delgado AG, Leite M, Mitch WE, Mafra D. The influence of renal function and the diet on acid–base status in chronic kidney disease patients. J Ren Nutr. 2009;19:178–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Ballmer PE, McNurlan MA, Hulter HN, Anderson SE, Garlick PJ, Krapf R. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Investig. 1995;95:39–45.PubMedCrossRefGoogle Scholar
  13. 13.
    Movilli E, Viola BF, Camerini C, Mazzola G, Cancarini GC. Correction of metabolic acidosis on serum albumin and protein catabolism in hemodialysis patients. J Ren Nutr. 2009;19:172–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Mitch WE, Goldberg AL. Mechanisms of muscle wasting: the role of the ubiquitin–proteasome system. N Engl J Med. 1996;335:1897–905.PubMedCrossRefGoogle Scholar
  15. 15.
    May RC, Kelly RA, Mitch WE. Mechanisms for defects in muscle protein metabolism in rats with chronic uremia: the influence of metabolic acidosis. J Clin Investig. 1987;79:1099–103.PubMedCrossRefGoogle Scholar
  16. 16.
    Bailey JL, Wang X, England BK, Price SR, Ding X, Mitch WE. The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent, ubiquitin–proteasome pathway. J Clin Investig. 1996;97:1447–53.PubMedCrossRefGoogle Scholar
  17. 17.
    Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin–proteasome pathway in normal and disease states. J Am Soc Nephrol. 2006;17:1807–19.PubMedCrossRefGoogle Scholar
  18. 18.
    Lee SW, Dai G, Hu Z, Wang X, Du J, Mitch WE. Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin–proteasome systems by phosphatidylinositol 3 kinase. J Am Soc Nephrol. 2004;15:1537–45.PubMedCrossRefGoogle Scholar
  19. 19.
    Du J, Wang X, Meireles CL, et al. Activation of caspase 3 is an initial step triggering muscle proteolysis in catabolic conditions. J Clin Investig. 2004;113:115–23.PubMedGoogle Scholar
  20. 20.
    Bailey JL, Price SR, Zheng B, Hu Z, Mitch WE. Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy. J Am Soc Nephrol. 2006;17:1388–94.PubMedCrossRefGoogle Scholar
  21. 21.
    Sandri M, Sandri C, Gilbert A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004;117:399–412.PubMedCrossRefGoogle Scholar
  22. 22.
    Clarke BA, Drujan D, Willis MS, et al. The E3 ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab. 2007;6:376–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Solomon V, Goldberg AL. Importance of the ATP–ubiquitin–proteasome pathway in degradation of soluble and myofibrillar proteins in rabbit muscle extracts. J Biol Chem. 1996;271:26690–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Workeneh B, Rondon-Berrios H, Zhang L, et al. Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions. J Am Soc Nephrol. 2006;17:3233–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Wang XH, Zhang L, Mitch WE, LeDoux JM, Hu J, Du J. Caspase-3 cleaves specific proteasome subunits in skeletal muscle stimulating proteasome activity. J Biol Chem. 2010;285:3527–32.Google Scholar
  26. 26.
    Wei W, Fareed MU, Evenson A, et al. Sepsis stimulates calpain activity in skeletal muscle by decreasing calpastatin activity but does not activate caspase-3. Am J Physiol Regul Integr Comp Physiol. 2005;288:R580–90.PubMedCrossRefGoogle Scholar
  27. 27.
    Pickering WP, Price SR, Bircher G, Marinovic AC, Mitch WE, Walls J. Nutrition in CAPD: serum bicarbonate and the ubiquitin–proteasome system in muscle. Kidney Int. 2002;61:1286–92.PubMedCrossRefGoogle Scholar
  28. 28.
    Mansoor O, Beaufrere Y, Boirie Y, et al. Increased mRNA levels for components of the lysosomal, Ca2+-activated and ATP–ubiquitin-dependent proteolytic pathways in skeletal muscle from head trauma patients. Proc Natl Acad Sci USA. 1996;93:2714–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Tiao G, Hobler S, Wang JJ, et al. Sepsis is associated with increased mRNAs of the ubiquitin–proteasome proteolytic pathway in human skeletal muscle. J Clin Investig. 1997;99:163–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Williams AB, Sun X, Fischer JE, Hasselgren P-O. The expression of genes in the ubiquitin–proteasome proteolytic pathway is increased in skeletal muscle from patients with cancer. Surgery. 1999;126:744–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Stein A, Moorhouse J, Iles-Smith H, et al. Role of an improvement in acid–base status and nutrition in CAPD patients. Kidney Int. 1997;52:1089–95.PubMedCrossRefGoogle Scholar
  32. 32.
    Hu Z, Wang H, Lee IH, Du J, Mitch WE. Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice. J Clin Investig. 2009;119:7650–9.Google Scholar
  33. 33.
    May RC, Kelly RA, Mitch WE. Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism. J Clin Investig. 1986;77:614–21.PubMedCrossRefGoogle Scholar
  34. 34.
    Mitch WE, Bailey JL, Wang X, Jurkovitz C, Newby D, Price SR. Evaluation of signals activating ubiquitin–proteasome proteolysis in a model of muscle wasting. Am J Physiol. 1999;276:C1132–8.PubMedGoogle Scholar
  35. 35.
    Song Y-H, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P. Muscle-specific expression of insulin-like growth factor-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Investig. 2005;115:451–8.PubMedGoogle Scholar
  36. 36.
    Zhang L, Wang XH, Wang H, Hu Z, Du J, Mitch WE. Satellite cell dysfunction and impaired IGF-1 signaling contribute to muscle atrophy in chronic kidney disease. J Am Soc Nephrol. 2010;21:419–27.PubMedCrossRefGoogle Scholar
  37. 37.
    Tedesco FS, Dellavalle A, az-Manera J, Messina G, Cossu G. Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. J Clin Investig. 2010;120:11–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Zimmers TA, Davies MV, Koniaris LG, et al. Induction of cachexia in mice by systemically administered myostatin. Science. 2002;296:1486–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Zhou X, Wang JL, Lu J, et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell. 2010;142:531–43.PubMedCrossRefGoogle Scholar
  40. 40.
    McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA. 1997;94:12457–61.PubMedCrossRefGoogle Scholar
  41. 41.
    Mosher DS, Quignon P, Bustamante CD, et al. A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote dogs. PLoS Genet. 2007;3:e79.PubMedCrossRefGoogle Scholar
  42. 42.
    Binns MM, Boehler DA, Lambert DH. Identification of the myostatin locus (MSTN) as having a major effect on optimum racing distance in the Thoroughbred horse in the USA. Anim Genet. 2010;41(Suppl 2):154–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Reardon KA, Davis J, Kapsa RM, Choong P, Byrne E. Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy. Muscle Nerve. 2001;24:893–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Breitbart A, uger-Messier M, Molkentin JD, Heineke J. Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting. Am J Physiol Heart Circ Physiol. 2011;300:H1973–82.PubMedCrossRefGoogle Scholar
  45. 45.
    Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proc Natl Acad Sci USA. 1998;95:14938–43.PubMedCrossRefGoogle Scholar
  46. 46.
    Verzola D, Procopio V, Sofia A, et al. Apoptosis and myostatin mRNA are upregulated in the skeletal muscle of patients with chronic kidney disease. Kidney Int. 2011;79:773–82.PubMedCrossRefGoogle Scholar
  47. 47.
    Mitch WE. Mechanisms causing muscle wasting in kidney disease and other catabolic conditions. In: Fadem SZ, editor. Dialysis. Nova Science Publishers, Inc., New York; 2012. p. 149–66.Google Scholar

Copyright information

© Japanese Society of Nephrology 2012

Authors and Affiliations

  1. 1.Nephrology Division M/S: BCM 285Baylor College of MedicineHoustonUSA
  2. 2.Nephrology Division M/S: BCM 395HoustonUSA

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