Although it is well known that administration of the selective β(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 μM), a PKA activator. The in vitro addition of
triciribine (10 μM), 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.