Clenbuterol suppresses proteasomal and lysosomal proteolysis and atrophy-related genes in denervated rat soleus muscles independently of Akt

Author(s)

Goncalves, Dawit A. P. ^[1] ; Silveira, Wilian A. ^[1] ; Lira, Eduardo C. ^[1] ; Graca, Flavia A. ^[1] ; Paula-Gomes, Silvia ^[2] ; Zanon, Neusa M. ^[1] ; Kettelhut, Isis C. ^{[1, 2]} ; Navegantes, Luiz C. C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Physiol, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biochem Immunol, Sao Paulo - Brazil

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM; v. 302, n. 1, p. E123-E133, JAN 2012.
• Web of Science Citations: 40

Abstract

Goncalves DA, Silveira WA, Lira EC, Gra a FA, Paula-Gomes S, Zanon NM, Kettelhut IC, Navegantes LC. Clenbuterol suppresses proteasomal and lysosomal proteolysis and atrophy-related genes in denervated rat soleus muscles independently of Akt. Am J Physiol Endocrinol Metab 302: E123-E133, 2012. First published September 27, 2011; doi:10.1152/ajpendo.00188.2011.-Although it is well known that administration of the selective beta(2)-adrenergic agonist clenbuterol (CB) protects muscle following denervation (DEN), the underlying molecular mechanism remains unclear. We report that in vivo treatment with CB (3 mg/kg sc) for 3 days induces antiproteolytic effects in normal and denervated rat soleus muscle via distinct mechanisms. In normal soleus muscle, CB treatment stimulates protein synthesis, inhibits Ca(2+)-dependent proteolysis, and increases the levels of calpastatin protein. On the other hand, the administration of CB to DEN rats ameliorates the loss of muscle mass, enhances the rate of protein synthesis, attenuates hyperactivation of proteasomal and lysosomal proteolysis, and suppresses the transcription of the lysosomal protease cathepsin L and of atrogin-1/MAFbx and MuRF1, two ubiquitin (Ub) ligases involved in muscle atrophy. These effects were not associated with alterations in either IGF-I content or Akt phosphorylation levels. In isolated muscles, CB (10(-6) M) treatment significantly attenuated DEN-induced overall proteolysis and upregulation in the mRNA levels of the Ub ligases. Similar responses were observed in denervated muscles exposed to 6-BNZ-cAMP (500 mu M), a PKA activator. The in vitro addition of triciribine (10 mu M), a selective Akt inhibitor, did not block the inhibitory effects of CB on proteolysis and Ub ligase mRNA levels. These data indicate that short-term treatment with CB mitigates DEN-induced atrophy of the soleus muscle through the stimulation of protein synthesis, downregulation of cathepsin L and Ub ligases, and consequent inhibition of lysosomal and proteasomal activities and that these effects are independent of Akt and possibly mediated by the cAMP/PKA signaling pathway. (AU)

• FAPESP's process: 08/06694-6 - Neural control of protein metabolism
• Grantee: Isis Do Carmo Kettelhut
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 09/07584-2 - Role of signaling pathways Akt/Foxo and MEK/ERK on anti-atrophic effect induced by adrenoceptors-B2 in rat skeletal muscle
• Grantee: Dawit Albieiro Pinheiro Gonçalves
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/11015-0 - Intracellular mechanisms involved in anticatabolic effect of the epinephrine in skeletal muscle of fasted rats
• Grantee: Flávia Aparecida Graça
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/11083-6 - ROLE OF EPAC IN CONTROL OF PROTEIN METABOLISM IN SKELETAL MUSCLE
• Grantee: Wilian de Assis Silveira
• Support Opportunities: Scholarships in Brazil - Doctorate