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CL 316,243, a selective β3-adrenergic agonist, inhibits protein breakdown in rat skeletal muscle

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Abstract

The in vitro effect of CL 316,243 (CL), a selective β3-adrenoceptor agonist in the rate of overall proteolysis, the activity of proteolytic systems (lysosomal, Ca2+-dependent, ATP-dependent, and ATP-independent) and in the process of protein synthesis was investigated in rat skeletal muscles. The rate of overall proteolysis in soleus muscle from rats incubated with CL (10−4 and 10−5 M) or epinephrine (10−5 M) was significantly decreased. In vitro rates of maximal activity of Ca2+-dependent proteolysis in soleus muscles were decreased by about 41% in the presence of 10−5 M CL. No change was observed in the activities of the lysosomal, ATP-dependent or ATP-independent proteolytic systems. The anti-proteolytic effect of CL or epinephrine was partially prevented by 10−5 M SR 59230A, a selective β3-adrenoceptor antagonist. The increase of proteolysis induced by food deprivation in soleus was abolished by in vitro addition of 10−5 M CL. No change in proteolysis was observed in extensor digitorum longus (EDL) muscles incubated with any concentration of the β3-adrenoceptor agonist tested. Rates of protein synthesis were not affected by 10−4 M CL neither in soleus nor EDL. The data suggest that a β3-adrenoceptor-mediated inhibition of Ca2+-dependent proteolysis participates of the antiproteolytic effect of catecholamines in oxidative muscles.

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References

  1. Abe H, Minokoshi Y, Shimazu T(1993) Effect of a β3-adrenergic agonist, BRL35135A, on glucose uptake in rat skeletal muscle in vivo and in vitro. J Endocrinol 139(3):479–486

    PubMed  Google Scholar 

  2. Arch JR (2002) β3-Adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol 440(2–3):99–107

    Article  PubMed  Google Scholar 

  3. Baracos V, Goldberg AL (1986) Maintenance of normal length improves protein balance and energy status in isolated rat skeletal muscle. Am J Physiol Cell Physiol 251:C588–C596

    Google Scholar 

  4. Bardsley RG, Allcock SMJ, Dawson JM, Dumelow NW, Higgins JA, Lasslett YV, Lockley AK, Parr T, Buttery PJ (1992) Effect of β-agonists on expression of calpain and calpastatin activity in skeletal muscle. Biochimie 74:267–273

    Article  PubMed  Google Scholar 

  5. Beitzel F, Gregorevic P, Ryall JG, Plant DR, Sillence MN, Lynch GS (2004) β2-Adrenoceptor agonist fenoterol enhances functional repair of regenerating rat skeletal muscle after injury. J Appl Physiol 96(4):1385–1392

    Article  PubMed  Google Scholar 

  6. Berkowitz DE, Nardone NA, Smiley RM, Price DT, Kreutter DK, Fremeau RT, Schwinn DA (1995) Distribution of beta-3-adrenoceptor mRNA in human tissues. Eur J Pharmacol 289:223–228

    Article  PubMed  Google Scholar 

  7. Board M, Doyle P, Cawthorne MA (2000) BRL37344, but not CGP12177, stimulates fuel oxidation by soleus muscle in vitro. Eur J Pharmacol 406(1):33–40

    Article  PubMed  Google Scholar 

  8. Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dullo A, Seydoux J, Muzzin P, Giacobino J-P (1997) Uncoupling protein 3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett 408:39–42

    Article  PubMed  Google Scholar 

  9. Busquets S, Figueras MT, Fuster G, Almendro V, Moore-Carrasco R, Ametller E, Argiles JM, Lopez-Soriano FJ (2004) Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting. Cancer Res 64(18):6725–6731

    PubMed  Google Scholar 

  10. Chamberlain PD, Jennings KH, Paul F, Cordell J, Berry A, Holmes SD, Park J, Chambers J, Sennitt MV, Stock MJ, Cawthorne MA, Young PW, Murphy GJ (1999) The tissue distribution of the human β3-adrenoceptor studied using a monoclonal antibody: direct evidence of the β3-adrenoceptor in human adipose tissue, atrium, and skeletal muscle. Int J Obes 23:1057–1065

    Article  Google Scholar 

  11. Desautels M, Heal S (1999) Differentiation-dependent inhibition of proteolysis by norepinephrine in brown adipocytes. Am J Physiol Endocrinol Metab 277:E215–E222

    Google Scholar 

  12. Emorine LJ, Marullo S, Briend-Ssutren M-M, Patey G, Tate K, Delavier-Klutchko C, Donny-Strosberg A (1989) Molecular characterization of the human beta 3-adrenergic receptor. Science 245:1118–1121

    PubMed  Google Scholar 

  13. Evans BA, Papaioannou M, Bonazzi VR, Summers RJ (1996) Expression of β3-adrenoceptor mRNA in rat tissues. Br J Pharmacol 117:210–216

    PubMed  Google Scholar 

  14. Fulks RM, Li JB, Goldberg AL (1975) Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J Biol Chem 250:290–298

    Google Scholar 

  15. Kettelhut IC, Wing SS, Goldberg AL (1988) Endocrine regulation of protein breakdown in skeletal muscle. Diab Metab Rev 4:751–772

    Google Scholar 

  16. Killefer J, Koohmaraie M (1994) Bovine skeletal muscle calpastatin: cloning, sequence analysis, and steady-state mRNA expression. J Anim Sci 72:606–614

    PubMed  Google Scholar 

  17. Kim YS, Sainz RD, Molenaar P, Summers RJ (1991) Characterization of β1- and β2-adrenoceptors in rat skeletal muscles. Biochem Pharmacol 42:1783–1789

    Google Scholar 

  18. Li JB, Fulks RM, Goldberg AL (1973) Evidence that the intracellular pool of tyrosine serve as precursor for protein synthesis in muscle. J Biol Chem 248:7272–7275

    Google Scholar 

  19. Largis EE, Burns MG, Muenkel HA, Dolan JA, Claus TH (1994) Antidiabetic and antiobesity effects of a highly selective β3-adrenoceptor agonist (CL 316,243). Drug Develop Res 32:69–76

    Article  Google Scholar 

  20. Liu Y-L, Cawthorne MA, Stock MJ (1996) Biphasic effects of the β-adrenoceptor agonist, BRL 37344, on glucose utilization in rat isolated skeletal muscle. Br J Pharmacol 117:1355–1361

    PubMed  Google Scholar 

  21. Mersmann HJ (1998) Overview of the effects of β-adrenergic receptor agonists on animal growth including mechanisms of action. J Anim Sci 76:160–172

    PubMed  Google Scholar 

  22. Nagase I, Yoshida T, Kumamoto K, Umekawa T, Sakane N, Nikami H, Kawada T, Saito M (1996) Expression of uncoupling protein in skeletal muscle and white fat of obese mice treated with thermogenic β3-adrenergic agonist. J Clin Invest 97(12):2898–2904

    PubMed  Google Scholar 

  23. Nakamura Y, Nagase I, Asano A, Sasaki N, Yoshida T, Umekawa T, Sakane N, Saito M (2001) β3-Adrenergic agonist up-regulates uncoupling proteins 2 and 3 in skeletal muscle of the mouse. J Vet Med Sci 63(3):309–314

    Article  PubMed  Google Scholar 

  24. Navegantes LCC, Migliorini RH, Kettelhut IC (2002) Adrenergic control of protein metabolism in skeletal muscle. Cur Opin Clin Nutr Metab Care 5(3):281–286

    Article  Google Scholar 

  25. Navegantes LCC, Resano NMZ, Baviera AM, Migliorini RH, Kettelhut IC (2004) Effect of sympathetic denervation on the rate of protein synthesis in rat skeletal muscle. Am J Physiol Endocrinol Metab 286:E642–E647

    Article  PubMed  Google Scholar 

  26. Navegantes LCC, Resano NMZ, Migliorini RH, Kettelhut IC (2001) Catecholamines inhibit Ca2+-dependent proteolysis in rat skeletal muscle through β2-adrenoceptors and cAMP. Am J Physiol Endocrinol Metab 281:E449–E454

    PubMed  Google Scholar 

  27. Navegantes LCC, Resano NMZ, Migliorini RH, Kettelhut IC (1999) Effect of guanethidine-induced adrenergic blockade on the different proteolytic systems in rat skeletal muscle. Am J Physiol Endocrinol Metab 277:E883–E889

    Google Scholar 

  28. Navegantes LCC, Resano NMZ, Migliorini RH, Kettelhut IC (2000) Role of adrenoceptors and cAMP on the catecholamine-induced inhibition of proteolysis in rat skeletal muscle. Am J Physiol Endocrinol Metab 279:E663–E668

    PubMed  Google Scholar 

  29. Nisoli E, Tonello C, Landi M, Carruba MO (1996) Functional studies of the first selective β3-adrenergic receptor antagonist SR 59230A in rat brown adipocytes. Mol Pharmacol 49:7–14

    PubMed  Google Scholar 

  30. Nutting DF (1982) Anabolic effects of catecholamines in diaphragm muscle from hypophysectomized rats. Endocrinology 110:307–317

    PubMed  Google Scholar 

  31. Reed PW, Lardy HA (1972) A23187: a divalent cation ionophore. J Biol Chem 247:6970–6977

    PubMed  Google Scholar 

  32. Reeds PJ, Hay SM, Dorwood PM, Palmer RM (1998) The effect of β-agonists and antagonists on muscle growth and body composition of young rats (Rattus Sp). Comp Biochem Physiol 89C:337–341

    Google Scholar 

  33. Scharff R, and Wool IG (1996) Effect of diabetes on the concentration aminoacids in plasma and heart muscle of rats. Biochem J 99:173–178

    Google Scholar 

  34. Statham HE, Duncan CJ, Smith JL (1976) The effect of the ionophore A23187 on the ultrastructure and electrophysiological properties of frog skeletal muscles. Cell Tissue Res 173(2):193–209

    Article  PubMed  Google Scholar 

  35. Strosberg D, Pietri-Rouxel F (1996) Function and regulation of the β3-adrenoceptor. Trends Pharmacol Sci 17:373–381

    Article  PubMed  Google Scholar 

  36. Sugden PH, Fuller SJ (1991) Regulation of protein turnover in skeletal and cardiac muscle. Biochem J 273:21–37

    Google Scholar 

  37. Tischler ME, Desautels M, Goldberg AL (1982) Does leucine, leucyl-tRNA or some metabolic of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle? J Biol Chem 257:1613–1621

    Google Scholar 

  38. Tsuboyama-Kasaoaka N, Tsunoda N, Maruyama K, Takahashi M, Kim H, Ikemoto S, Ezaki O (1998) Upregulation of uncoupling protein 3 (UCP-3) mRNA by exercise training and down-regulation of UCP-3 by denervation in skeletal muscles. Biochem Biophys Res Commun 247:498–503

    Article  PubMed  Google Scholar 

  39. Vidal-Pluig A, Solanes G, Grujic D, Flier JS, Lowel BB (1997) UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun 235:79–82

    Article  PubMed  Google Scholar 

  40. Waalkes TP, Udenfriend S (1957) A fluorometric method for the estimation of tyrosine in plasma and tissues. J Lab Clin Med 50:733–736

    PubMed  Google Scholar 

  41. Yimlamai T, Dodd SL, Borst SE, Park S (2005) Clenbuterol induces muscle specific attenuation of atrophy through effects on the ubiquitin-proteasome pathway. J Appl Physiol 17:1–34

    Google Scholar 

  42. Yoshida T, Umekawa T, Kumamoto K, Sakane N, Kogure A, Kondo M, Wakabayashi Y, Kawada T, Nagase I, Saito M (1998) β3-Adrenergic agonist induces a functionally active uncoupling protein in fat and slow-twitch muscle fibers. Am J Physiol Endocrinol Metab 274:E469–E475

    Google Scholar 

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Acknowledgments

We are grateful to Wyeth-Ayerst Laboratories for providing CL, and Sanofi Midy Research Center for providing SR. This work was supported by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (Fapesp 04/2674-0, 97/3950-5 and 03/13080-0) and from the Conselho Nacional de Pesquisa (CNPq 501252/91-6). During this study L.C.C.N. and A.M.B. received fellowship from FAPESP (98/02591-4) and CNPq (142318/03-6), respectively. We are indebted to Elza Aparecida Filippin, Maria Antonieta R.Garófalo, and Victor Diaz Galbán for technical assistance.

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Authors and Affiliations

  1. Department of Physiology, Biochemistry and Immunology, School of Medicine, University of São Paulo, 14049-900, Ribeirão Preto, São Paulo, Brazil

    Luiz Carlos C. Navegantes, Neusa M. Z. Resano, Amanda Martins Baviera, Renato H. Migliorini & Isis C. Kettelhut

  2. Department of Molecular Biology, School of Medicine of São José do Rio Preto, 15049-900, São Paulo, Brazil

    Luiz Carlos C. Navegantes

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  1. Luiz Carlos C. Navegantes
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  2. Neusa M. Z. Resano
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  4. Renato H. Migliorini
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  5. Isis C. Kettelhut
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Correspondence to Isis C. Kettelhut.

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Navegantes, L.C.C., Resano, N.M.Z., Baviera, A.M. et al. CL 316,243, a selective β3-adrenergic agonist, inhibits protein breakdown in rat skeletal muscle. Pflugers Arch - Eur J Physiol 451, 617–624 (2006). https://doi.org/10.1007/s00424-005-1496-1

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