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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM; v. 302, n. 1, p. E123-E133, JAN 2012.
• Citações Web of Science: 40

Resumo

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)

• Processo FAPESP: 08/06694-6 - Controle neural do metabolismo de proteínas
• Beneficiário: Isis Do Carmo Kettelhut
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 09/07584-2 - Papel das vias de sinalização da Akt/Foxo e MEK/ERK no efeito antiatrófico mediado pelos adrenoceptores B2 em músculo esquelético de roedores
• Beneficiário: Dawit Albieiro Pinheiro Gonçalves
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/11015-0 - Mecanismos intracelulares envolvidos na ação anticatabólica da adrenalina em músculos esqueléticos de ratos jejuados
• Beneficiário: Flávia Aparecida Graça
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/11083-6 - Papel da epac no controle do metabolismo protéico em músculos esqueléticos
• Beneficiário: Wilian de Assis Silveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado