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. 1996 Mar 15;97(6):1447–1453. doi: 10.1172/JCI118566

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 L Bailey 1, X Wang 1, B K England 1, S R Price 1, X Ding 1, W E Mitch 1
PMCID: PMC507204  PMID: 8617877

Abstract

Chronic renal failure (CRF) is associated with negative nitrogen balance and loss of lean body mass. To identify specific proteolytic pathways activated by CRF, protein degradation was measured in incubated epitrochlearis muscles from CRF and sham-operated, pair-fed rats. CRF stimulated muscle proteolysis, and inhibition of lysosomal and calcium-activated proteases did not eliminate this increase. When ATP production was blocked, proteolysis in CRF muscles fell to the same level as that in control muscles. Increased proteolysis was also prevented by feeding CRF rats sodium bicarbonate, suggesting that activation depends on acidification. Evidence that the ATP-dependent ubiquitin-proteasome pathway is stimulated by the acidemia of CRF includes the following findings: (a) An inhibitor of the proteasome eliminated the increase in muscle proteolysis; and (b) there was an increase in mRNAs encoding ubiquitin (324%) and proteasome subunits C3 (137%) and C9 (251%) in muscle. This response involved gene activation since transcription of mRNAs for ubiquitin and the C3 subunit were selectively increased in muscle of CRF rats. We conclude that CRF stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasome-dependent pathway. The mechanism depends on acidification and increased expression of genes encoding components of the system. These responses could contribute to the loss of muscle mass associated with CRF.

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Selected References

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  1. Ariano M. A., Armstrong R. B., Edgerton V. R. Hindlimb muscle fiber populations of five mammals. J Histochem Cytochem. 1973 Jan;21(1):51–55. doi: 10.1177/21.1.51. [DOI] [PubMed] [Google Scholar]
  2. Bailey J. L., England B. K., Long R. C., Jr, Weissman J., Mitch W. E. Experimental acidemia and muscle cell pH in chronic acidosis and renal failure. Am J Physiol. 1995 Sep;269(3 Pt 1):C706–C712. doi: 10.1152/ajpcell.1995.269.3.C706. [DOI] [PubMed] [Google Scholar]
  3. Baracos V. E., DeVivo C., Hoyle D. H., Goldberg A. L. Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma. Am J Physiol. 1995 May;268(5 Pt 1):E996–1006. doi: 10.1152/ajpendo.1995.268.5.E996. [DOI] [PubMed] [Google Scholar]
  4. Bergström J. Why are dialysis patients malnourished? Am J Kidney Dis. 1995 Jul;26(1):229–241. doi: 10.1016/0272-6386(95)90178-7. [DOI] [PubMed] [Google Scholar]
  5. Blumenkrantz M. J., Kopple J. D., Gutman R. A., Chan Y. K., Barbour G. L., Roberts C., Shen F. H., Gandhi V. C., Tucker C. T., Curtis F. K. Methods for assessing nutritional status of patients with renal failure. Am J Clin Nutr. 1980 Jul;33(7):1567–1585. doi: 10.1093/ajcn/33.7.1567. [DOI] [PubMed] [Google Scholar]
  6. Ciechanover A., Finley D., Varshavsky A. Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85. Cell. 1984 May;37(1):57–66. doi: 10.1016/0092-8674(84)90300-3. [DOI] [PubMed] [Google Scholar]
  7. Clark A. S., Mitch W. E. Comparison of protein synthesis and degradation in incubated and perfused muscle. Biochem J. 1983 Jun 15;212(3):649–653. doi: 10.1042/bj2120649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Clark A. S., Mitch W. E. Muscle protein turnover and glucose uptake in acutely uremic rats. Effects of insulin and the duration of renal insufficiency. J Clin Invest. 1983 Sep;72(3):836–845. doi: 10.1172/JCI111054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coles G. A. Body composition in chronic renal failure. Q J Med. 1972 Jan;41(161):25–47. [PubMed] [Google Scholar]
  10. Costelli P., García-Martínez C., Llovera M., Carbó N., López-Soriano F. J., Agell N., Tessitore L., Baccino F. M., Argilés J. M. Muscle protein waste in tumor-bearing rats is effectively antagonized by a beta 2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway. J Clin Invest. 1995 May;95(5):2367–2372. doi: 10.1172/JCI117929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dice J. F. Molecular determinants of protein half-lives in eukaryotic cells. FASEB J. 1987 Nov;1(5):349–357. doi: 10.1096/fasebj.1.5.2824267. [DOI] [PubMed] [Google Scholar]
  12. Fang C. H., Tiao G., James H., Ogle C., Fischer J. E., Hasselgren P. O. Burn injury stimulates multiple proteolytic pathways in skeletal muscle, including the ubiquitin-energy-dependent pathway. J Am Coll Surg. 1995 Feb;180(2):161–170. [PubMed] [Google Scholar]
  13. Furuno K., Goldberg A. L. The activation of protein degradation in muscle by Ca2+ or muscle injury does not involve a lysosomal mechanism. Biochem J. 1986 Aug 1;237(3):859–864. doi: 10.1042/bj2370859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Garibotto G., Russo R., Sofia A., Sala M. R., Robaudo C., Moscatelli P., Deferrari G., Tizianello A. Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. Kidney Int. 1994 May;45(5):1432–1439. doi: 10.1038/ki.1994.187. [DOI] [PubMed] [Google Scholar]
  15. Goldberg A. L. Functions of the proteasome: the lysis at the end of the tunnel. Science. 1995 Apr 28;268(5210):522–523. doi: 10.1126/science.7725095. [DOI] [PubMed] [Google Scholar]
  16. Goldberg A. L., Rock K. L. Proteolysis, proteasomes and antigen presentation. Nature. 1992 Jun 4;357(6377):375–379. doi: 10.1038/357375a0. [DOI] [PubMed] [Google Scholar]
  17. Greiber S., England B. K., Price S. R., Medford R. M., Ebb R. G., Mitch W. E. Na pump defects in chronic uremia cannot be attributed to changes in Na-K-ATPase mRNA or protein. Am J Physiol. 1994 Apr;266(4 Pt 2):F536–F542. doi: 10.1152/ajprenal.1994.266.4.F536. [DOI] [PubMed] [Google Scholar]
  18. Gronostajski R. M., Pardee A. B., Goldberg A. L. The ATP dependence of the degradation of short- and long-lived proteins in growing fibroblasts. J Biol Chem. 1985 Mar 25;260(6):3344–3349. [PubMed] [Google Scholar]
  19. Hara Y., May R. C., Kelly R. A., Mitch W. E. Acidosis, not azotemia, stimulates branched-chain, amino acid catabolism in uremic rats. Kidney Int. 1987 Dec;32(6):808–814. doi: 10.1038/ki.1987.280. [DOI] [PubMed] [Google Scholar]
  20. Hershko A., Ciechanover A. The ubiquitin system for protein degradation. Annu Rev Biochem. 1992;61:761–807. doi: 10.1146/annurev.bi.61.070192.003553. [DOI] [PubMed] [Google Scholar]
  21. Jensen T. J., Loo M. A., Pind S., Williams D. B., Goldberg A. L., Riordan J. R. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell. 1995 Oct 6;83(1):129–135. doi: 10.1016/0092-8674(95)90241-4. [DOI] [PubMed] [Google Scholar]
  22. Kettelhut I. C., Wing S. S., Goldberg A. L. Endocrine regulation of protein breakdown in skeletal muscle. Diabetes Metab Rev. 1988 Dec;4(8):751–772. doi: 10.1002/dmr.5610040805. [DOI] [PubMed] [Google Scholar]
  23. MacLennan P. A., McArdle A., Edwards R. H. Effects of calcium on protein turnover of incubated muscles from mdx mice. Am J Physiol. 1991 Apr;260(4 Pt 1):E594–E598. doi: 10.1152/ajpendo.1991.260.4.E594. [DOI] [PubMed] [Google Scholar]
  24. Maroni B. J., Haesemeyer R. W., Kutner M. H., Mitch W. E. Kinetics of system A amino acid uptake by muscle: effects of insulin and acute uremia. Am J Physiol. 1990 May;258(5 Pt 2):F1304–F1310. doi: 10.1152/ajprenal.1990.258.5.F1304. [DOI] [PubMed] [Google Scholar]
  25. May R. C., Kelly R. A., Mitch W. E. Mechanisms for defects in muscle protein metabolism in rats with chronic uremia. Influence of metabolic acidosis. J Clin Invest. 1987 Apr;79(4):1099–1103. doi: 10.1172/JCI112924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. May R. C., Kelly R. A., Mitch W. E. Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism. J Clin Invest. 1986 Feb;77(2):614–621. doi: 10.1172/JCI112344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. May R. C., Piepenbrock N., Kelly R. A., Mitch W. E. Leucine-induced amino acid antagonism in rats: muscle valine metabolism and growth impairment. J Nutr. 1991 Mar;121(3):293–301. doi: 10.1093/jn/121.3.293. [DOI] [PubMed] [Google Scholar]
  28. Medina R., Wing S. S., Goldberg A. L. Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. Biochem J. 1995 May 1;307(Pt 3):631–637. doi: 10.1042/bj3070631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Medina R., Wing S. S., Haas A., Goldberg A. L. Activation of the ubiquitin-ATP-dependent proteolytic system in skeletal muscle during fasting and denervation atrophy. Biomed Biochim Acta. 1991;50(4-6):347–356. [PubMed] [Google Scholar]
  30. Mitch W. E., Medina R., Grieber S., May R. C., England B. K., Price S. R., Bailey J. L., Goldberg A. L. Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes. J Clin Invest. 1994 May;93(5):2127–2133. doi: 10.1172/JCI117208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nesher R., Karl I. E., Kaiser K. E., Kipnis D. M. Epitrochlearis muscle. I. Mechanical performance, energetics, and fiber composition. Am J Physiol. 1980 Dec;239(6):E454–E460. doi: 10.1152/ajpendo.1980.239.6.E454. [DOI] [PubMed] [Google Scholar]
  32. Poole B., Ohkuma S. Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages. J Cell Biol. 1981 Sep;90(3):665–669. doi: 10.1083/jcb.90.3.665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Price S. R., England B. K., Bailey J. L., Van Vreede K., Mitch W. E. Acidosis and glucocorticoids concomitantly increase ubiquitin and proteasome subunit mRNAs in rat muscle. Am J Physiol. 1994 Oct;267(4 Pt 1):C955–C960. doi: 10.1152/ajpcell.1994.267.4.C955. [DOI] [PubMed] [Google Scholar]
  34. Price S. R., Mitch W. E. Metabolic acidosis and uremic toxicity: protein and amino acid metabolism. Semin Nephrol. 1994 May;14(3):232–237. [PubMed] [Google Scholar]
  35. Read M. A., Neish A. S., Luscinskas F. W., Palombella V. J., Maniatis T., Collins T. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity. 1995 May;2(5):493–506. doi: 10.1016/1074-7613(95)90030-6. [DOI] [PubMed] [Google Scholar]
  36. Rechsteiner M. Natural substrates of the ubiquitin proteolytic pathway. Cell. 1991 Aug 23;66(4):615–618. doi: 10.1016/0092-8674(91)90104-7. [DOI] [PubMed] [Google Scholar]
  37. Rock K. L., Gramm C., Rothstein L., Clark K., Stein R., Dick L., Hwang D., Goldberg A. L. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994 Sep 9;78(5):761–771. doi: 10.1016/s0092-8674(94)90462-6. [DOI] [PubMed] [Google Scholar]
  38. Tawa N. E., Jr, Kettelhut I. C., Goldberg A. L. Dietary protein deficiency reduces lysosomal and nonlysosomal ATP-dependent proteolysis in muscle. Am J Physiol. 1992 Aug;263(2 Pt 1):E326–E334. doi: 10.1152/ajpendo.1992.263.2.E326. [DOI] [PubMed] [Google Scholar]
  39. Temparis S., Asensi M., Taillandier D., Aurousseau E., Larbaud D., Obled A., Béchet D., Ferrara M., Estrela J. M., Attaix D. Increased ATP-ubiquitin-dependent proteolysis in skeletal muscles of tumor-bearing rats. Cancer Res. 1994 Nov 1;54(21):5568–5573. [PubMed] [Google Scholar]
  40. Tiao G., Fagan J. M., Samuels N., James J. H., Hudson K., Lieberman M., Fischer J. E., Hasselgren P. O. Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle. J Clin Invest. 1994 Dec;94(6):2255–2264. doi: 10.1172/JCI117588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Vinitsky A., Cardozo C., Sepp-Lorenzino L., Michaud C., Orlowski M. Inhibition of the proteolytic activity of the multicatalytic proteinase complex (proteasome) by substrate-related peptidyl aldehydes. J Biol Chem. 1994 Nov 25;269(47):29860–29866. [PubMed] [Google Scholar]
  42. Williams B., Hattersley J., Layward E., Walls J. Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Kidney Int. 1991 Oct;40(4):779–786. doi: 10.1038/ki.1991.275. [DOI] [PubMed] [Google Scholar]
  43. Wing S. S., Goldberg A. L. Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting. Am J Physiol. 1993 Apr;264(4 Pt 1):E668–E676. doi: 10.1152/ajpendo.1993.264.4.E668. [DOI] [PubMed] [Google Scholar]

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