The ubiquitin-proteasome proteolytic system is stimulated in conditions causing muscle atrophy. Signals initiating this response in these conditions are unknown, although glucocorticoids are required but insufficient to stimulate muscle proteolysis in starvation, acidosis, and sepsis. To identify signals that activate this system, we studied acutely diabetic rats that had metabolic acidosis and increased corticosterone production. Protein degradation was increased 52% (P < 0.05), and mRNA levels encoding ubiquitin-proteasome system components, including the ubiquitin-conjugating enzyme E2_14k, were higher (transcription of the ubiquitin and proteasome subunit C3 genes in muscle was increased by nuclear run-off assay). In diabetic rats, prevention of acidemia by oral NaHCO₃ did not eliminate muscle proteolysis. Adrenalectomy blocked accelerated proteolysis and the rise in pathway mRNAs; both responses were restored by administration of a physiological dose of glucocorticoids to adrenalectomized, diabetic rats. Finally, treating diabetic rats with insulin for 24 h reversed muscle proteolysis and returned pathway mRNAs to control levels. Thus acidification is not necessary for these responses, but glucocorticoids and a low insulin level in tandem activate the ubiquitin-proteasome proteolytic system.

protein degradation; transcription; insulin; glucocorticoids

This article has been cited by other articles:

				X. Wang, J. Hu, and S. R. Price Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1874 - C1879. [Abstract] [Full Text] [PDF]

				M. L. Urso, Y.-W. Chen, A. G. Scrimgeour, P. C. Lee, K. F. Lee, and P. M. Clarkson Alterations in mRNA expression and protein products following spinal cord injury in humans J. Physiol., March 15, 2007; 579(3): 877 - 892. [Abstract] [Full Text] [PDF]

				A. C. Marinovic, B. Zheng, W. E. Mitch, and S. R. Price Tissue-specific regulation of ubiquitin (UbC) transcription by glucocorticoids: in vivo and in vitro analyses Am J Physiol Renal Physiol, February 1, 2007; 292(2): F660 - F666. [Abstract] [Full Text] [PDF]

				M. L. Urso, A. G. Scrimgeour, Y.-W. Chen, P. D. Thompson, and P. M. Clarkson Analysis of human skeletal muscle after 48 h immobilization reveals alterations in mRNA and protein for extracellular matrix components J Appl Physiol, October 1, 2006; 101(4): 1136 - 1148. [Abstract] [Full Text] [PDF]

				B. Malik, S. R. Price, W. E. Mitch, Q. Yue, and D. C. Eaton Regulation of epithelial sodium channels by the ubiquitin-proteasome proteolytic pathway Am J Physiol Renal Physiol, June 1, 2006; 290(6): F1285 - F1294. [Abstract] [Full Text] [PDF]

				E. Zhu, C. S. H. Sassoon, R. Nelson, H. T. Pham, L. Zhu, M. J. Baker, and V. J. Caiozzo Early effects of mechanical ventilation on isotonic contractile properties and MAF-box gene expression in the diaphragm J Appl Physiol, August 1, 2005; 99(2): 747 - 756. [Abstract] [Full Text] [PDF]

				S. Dasarathy, M. Dodig, S. M. Muc, S. C. Kalhan, and A. J. McCullough Skeletal muscle atrophy is associated with an increased expression of myostatin and impaired satellite cell function in the portacaval anastamosis rat Am J Physiol Gastrointest Liver Physiol, December 1, 2004; 287(6): G1124 - G1130. [Abstract] [Full Text] [PDF]

				J. M. Sacheck, A. Ohtsuka, S. C. McLary, and A. L. Goldberg IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 Am J Physiol Endocrinol Metab, October 1, 2004; 287(4): E591 - E601. [Abstract] [Full Text] [PDF]

				H. A. Franch, S. Raissi, X. Wang, B. Zheng, J. L. Bailey, and S. R. Price Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis Am J Physiol Renal Physiol, October 1, 2004; 287(4): F700 - F706. [Abstract] [Full Text] [PDF]

				D. Kim, J. M. Sands, and J. D. Klein Role of vasopressin in diabetes mellitus-induced changes in medullary transport proteins involved in urine concentration in Brattleboro rats Am J Physiol Renal Physiol, April 1, 2004; 286(4): F760 - F766. [Abstract] [Full Text] [PDF]

				D. Kim, J. M. Sands, and J. D. Klein Changes in renal medullary transport proteins during uncontrolled diabetes mellitus in rats Am J Physiol Renal Physiol, August 1, 2003; 285(2): F303 - F309. [Abstract] [Full Text] [PDF]

				R. Debigare and S. R. Price Proteolysis, the ubiquitin-proteasome system, and renal diseases Am J Physiol Renal Physiol, July 1, 2003; 285(1): F1 - F8. [Abstract] [Full Text] [PDF]

				Z. Liu and E. J. Barrett Human protein metabolism: its measurement and regulation Am J Physiol Endocrinol Metab, December 1, 2002; 283(6): E1105 - E1112. [Abstract] [Full Text] [PDF]

				R. T. JAGOE, S. H. LECKER, M. GOMES, and A. L. GOLDBERG Patterns of gene expression in atrophying skeletal muscles: response to food deprivation FASEB J, November 1, 2002; 16(13): 1697 - 1712. [Abstract] [Full Text] [PDF]

				J. M. Sands Molecular Approaches to Urea Transporters J. Am. Soc. Nephrol., November 1, 2002; 13(11): 2795 - 2806. [Abstract] [Full Text] [PDF]

				M. F. White IRS proteins and the common path to diabetes Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E413 - E422. [Abstract] [Full Text] [PDF]

				O. A. J. Adegoke, N. Bedard, H. P. Roest, and S. S. Wing Ubiquitin-conjugating enzyme E214k/HR6B is dispensable for increased protein catabolism in muscle of fasted mice Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E482 - E489. [Abstract] [Full Text] [PDF]

				L. Sun, X. Pan, J. Wada, C. S. Haas, R. P. Wuthrich, F. R. Danesh, S. S. Chugh, and Y. S. Kanwar Isolation and Functional Analysis of Mouse UbA52 Gene and Its Relevance to Diabetic Nephropathy J. Biol. Chem., August 9, 2002; 277(33): 29953 - 29962. [Abstract] [Full Text] [PDF]

				J. D. Klein, P. Rouillard, B. R. Roberts, and J. M. Sands Acidosis Mediates the Upregulation of UT-A Protein in Livers from Uremic Rats J. Am. Soc. Nephrol., March 1, 2002; 13(3): 581 - 587. [Abstract] [Full Text] [PDF]

				T. A. Ikizler, L. B. Pupim, J. R. Brouillette, D. K. Levenhagen, K. Farmer, R. M. Hakim, and P. J. Flakoll Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation Am J Physiol Endocrinol Metab, January 1, 2002; 282(1): E107 - E116. [Abstract] [Full Text] [PDF]

				W. E. Mitch Insights into the Abnormalities of Chronic Renal Disease Attributed to Malnutrition J. Am. Soc. Nephrol., January 1, 2002; 13(90001): S22 - 27. [Abstract] [Full Text] [PDF]

				M. I. Masana and M. L. Dubocovich Melatonin Receptor Signaling: Finding the Path Through the Dark Sci. Signal., November 6, 2001; 2001(107): pe39 - pe39. [Abstract] [Full Text] [PDF]

				L. Rui, T. L. Fisher, J. Thomas, and M. F. White Regulation of Insulin/Insulin-like Growth Factor-1 Signaling by Proteasome-mediated Degradation of Insulin Receptor Substrate-2 J. Biol. Chem., October 19, 2001; 276(43): 40362 - 40367. [Abstract] [Full Text] [PDF]

				D. SAHALI, A. PAWLAK, S. L. GOUVELLO, P. LANG, A. VALANCIUTE, P. REMY, C. LOIRAT, P. NIAUDET, A. BENSMAN, and G. GUELLAEN Transcriptional and Post-Transcriptional Alterations of I {kappa}B{alpha} in Active Minimal-Change Nephrotic Syndrome J. Am. Soc. Nephrol., August 1, 2001; 12(8): 1648 - 1658. [Abstract] [Full Text] [PDF]

				W. Long, L. Wei, and E. J. Barrett Dexamethasone inhibits the stimulation of muscle protein synthesis and PHAS-I and p70 S6-kinase phosphorylation Am J Physiol Endocrinol Metab, April 1, 2001; 280(4): E570 - E575. [Abstract] [Full Text] [PDF]

				G. GARIBOTTO, A. SOFIA, A. CANEPA, S. SAFFIOTI, P. SACCO, M. R. SALA, L. DERTENOIS, N. PASTORINO, G. DEFERRARI, and R. RUSSO Acute Effects of Peritoneal Dialysis with Dialysates Containing Dextrose or Dextrose and Amino Acids on Muscle Protein Turnover in Patients with Chronic Renal Failure J. Am. Soc. Nephrol., March 1, 2001; 12(3): 557 - 567. [Abstract] [Full Text]

				J. Du, W. E. Mitch, X. Wang, and S. R. Price Glucocorticoids Induce Proteasome C3 Subunit Expression in L6 Muscle Cells by Opposing the Suppression of Its Transcription by NF-kappa B J. Biol. Chem., June 23, 2000; 275(26): 19661 - 19666. [Abstract] [Full Text] [PDF]

				L. M. Schwartz and R. L. Ruff Changes in contractile properties of skeletal muscle during developmentally programmed atrophy and death Am J Physiol Cell Physiol, June 1, 2002; 282(6): C1270 - C1277. [Abstract] [Full Text] [PDF]