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J Clin Invest. 1996 October 15; 98(8): 1703–1708.
PMCID: PMC507607

Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription.


In normal subjects and diabetic patients, insulin suppresses whole body proteolysis suggesting that the loss of lean body mass and muscle wasting in insulinopenia is related to increased muscle protein degradation. To document how insulinopenia affects organ weights and to identify the pathway for accelerated proteolysis in muscle, streptozotocin-treated and vehicle-injected, pair-fed control rats were studied. The weights of liver, adipose tissue, and muscle were decreased while muscle protein degradation was increased 75% by insulinopenia. This proteolytic response was not eliminated by blocking lysosomal function and calcium-dependent proteases at 7 or 3 d after streptozotocin. When ATP synthesis in muscle was inhibited, the rates of proteolysis were reduced to the same level in insulinopenic and control rats suggesting that the ATP-dependent, ubiquitin-proteasome pathway is activated. Additional evidence for activation of this pathway in muscle includes: (a) an inhibitor of proteasome activity eliminated the increased protein degradation; (b) mRNAs encoding ubiquitin and proteasome subunits were increased two- to threefold; and (c) there was increased transcription of the ubiquitin gene. We conclude that the mechanism for muscle protein wasting in insulinopenia includes activation of the ubiquitin-proteasome pathway with increased expression of the ubiquitin gene.

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Selected References

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  • Nair KS, Ford GC, Halliday D. Effect of intravenous insulin treatment on in vivo whole body leucine kinetics and oxygen consumption in insulin-deprived type I diabetic patients. Metabolism. 1987 May;36(5):491–495. [PubMed]
  • Nair KS, Ford GC, Ekberg K, Fernqvist-Forbes E, Wahren J. Protein dynamics in whole body and in splanchnic and leg tissues in type I diabetic patients. J Clin Invest. 1995 Jun;95(6):2926–2937. [PMC free article] [PubMed]
  • Nakhooda AF, Wei CN, Marliss EB. Muscle protein catabolism in diabetes: 3-methylhistidine excretion in the spontaneously diabetic "BB" rat. Metabolism. 1980 Dec;29(12):1272–1277. [PubMed]
  • Marchesini G, Forlani G, Zoli M, Vannini P, Pisi E. Muscle protein breakdown in uncontrolled diabetes as assessed by urinary 3-methylhistidine excretion. Diabetologia. 1982 Nov;23(5):456–458. [PubMed]
  • Smith OL, Wong CY, Gelfand RA. Skeletal muscle proteolysis in rats with acute streptozocin-induced diabetes. Diabetes. 1989 Sep;38(9):1117–1122. [PubMed]
  • Gulve EA, Dice JF. Regulation of protein synthesis and degradation in L8 myotubes. Effects of serum, insulin and insulin-like growth factors. Biochem J. 1989 Jun 1;260(2):377–387. [PubMed]
  • England BK, Chastain JL, Mitch WE. Abnormalities in protein synthesis and degradation induced by extracellular pH in BC3H1 myocytes. Am J Physiol. 1991 Feb;260(2 Pt 1):C277–C282. [PubMed]
  • Gelfand RA, Barrett EJ. Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest. 1987 Jul;80(1):1–6. [PMC free article] [PubMed]
  • Louard RJ, Fryburg DA, Gelfand RA, Barrett EJ. Insulin sensitivity of protein and glucose metabolism in human forearm skeletal muscle. J Clin Invest. 1992 Dec;90(6):2348–2354. [PMC free article] [PubMed]
  • May RC, Kelly RA, Mitch WE. 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. [PMC free article] [PubMed]
  • May RC, Kelly RA, Mitch WE. Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism. J Clin Invest. 1986 Feb;77(2):614–621. [PMC free article] [PubMed]
  • Furuno K, Goodman MN, Goldberg AL. Role of different proteolytic systems in the degradation of muscle proteins during denervation atrophy. J Biol Chem. 1990 May 25;265(15):8550–8557. [PubMed]
  • Mitch WE, Medina R, Grieber S, May RC, England BK, Price SR, Bailey JL, Goldberg AL. 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. [PMC free article] [PubMed]
  • 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 Invest. 1996 Mar 15;97(6):1447–1453. [PMC free article] [PubMed]
  • Tiao G, Fagan JM, Samuels N, James JH, Hudson K, Lieberman M, Fischer JE, Hasselgren PO. Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle. J Clin Invest. 1994 Dec;94(6):2255–2264. [PMC free article] [PubMed]
  • Wing SS, Goldberg AL. Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting. Am J Physiol. 1993 Apr;264(4 Pt 1):E668–E676. [PubMed]
  • Costelli P, García-Martínez C, Llovera M, Carbó N, López-Soriano FJ, Agell N, Tessitore L, Baccino FM, Argilés JM. 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. [PMC free article] [PubMed]
  • Baracos VE, DeVivo C, Hoyle DH, Goldberg AL. 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. [PubMed]
  • Medina R, Wing SS, Goldberg AL. 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. [PubMed]
  • Goldberg AL. Functions of the proteasome: the lysis at the end of the tunnel. Science. 1995 Apr 28;268(5210):522–523. [PubMed]
  • Hilt W, Wolf DH. Proteasomes: destruction as a programme. Trends Biochem Sci. 1996 Mar;21(3):96–102. [PubMed]
  • Ciechanover A. The ubiquitin-proteasome proteolytic pathway. Cell. 1994 Oct 7;79(1):13–21. [PubMed]
  • Dubiel W, Ferrell K, Pratt G, Rechsteiner M. Subunit 4 of the 26 S protease is a member of a novel eukaryotic ATPase family. J Biol Chem. 1992 Nov 15;267(32):22699–22702. [PubMed]
  • Gronostajski RM, Pardee AB, Goldberg AL. 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]
  • Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell. 1995 Oct 6;83(1):129–135. [PubMed]
  • Read MA, Neish AS, Luscinskas FW, Palombella VJ, Maniatis T, Collins T. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity. 1995 May;2(5):493–506. [PubMed]
  • Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-kappa B1 precursor protein and the activation of NF-kappa B. Cell. 1994 Sep 9;78(5):773–785. [PubMed]
  • Price SR, England BK, Bailey JL, Van Vreede K, Mitch WE. Acidosis and glucocorticoids concomitantly increase ubiquitin and proteasome subunit mRNAs in rat muscle. Am J Physiol. 1994 Oct;267(4 Pt 1):C955–C960. [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Clark AS, Mitch WE. Comparison of protein synthesis and degradation in incubated and perfused muscle. Biochem J. 1983 Jun 15;212(3):649–653. [PubMed]
  • Goodman MN. Myofibrillar protein breakdown in skeletal muscle is diminished in rats with chronic streptozocin-induced diabetes. Diabetes. 1987 Jan;36(1):100–105. [PubMed]
  • Kettelhut IC, Pepato MT, Migliorini RH, Medina R, Goldberg AL. Regulation of different proteolytic pathways in skeletal muscle in fasting and diabetes mellitus. Braz J Med Biol Res. 1994 Apr;27(4):981–993. [PubMed]
  • Temparis S, Asensi M, Taillandier D, Aurousseau E, Larbaud D, Obled A, Béchet D, Ferrara M, Estrela JM, Attaix D. Increased ATP-ubiquitin-dependent proteolysis in skeletal muscles of tumor-bearing rats. Cancer Res. 1994 Nov 1;54(21):5568–5573. [PubMed]
  • Fang CH, Tiao G, James H, Ogle C, Fischer JE, Hasselgren PO. 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]
  • Nesher R, Karl IE, Kaiser KE, Kipnis DM. Epitrochlearis muscle. I. Mechanical performance, energetics, and fiber composition. Am J Physiol. 1980 Dec;239(6):E454–E460. [PubMed]
  • Ariano MA, Armstrong RB, Edgerton VR. Hindlimb muscle fiber populations of five mammals. J Histochem Cytochem. 1973 Jan;21(1):51–55. [PubMed]
  • Medina R, Wing SS, Goldberg AL. 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. [PubMed]

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