In cancer cachexia both cardiac and skeletal muscle suffer an important protein mobilization as a result of increased proteolysis. Administration of the beta2-agonist formoterol to both rats and mice bearing highly cachectic tumors resulted in an important reversal of the muscle-wasting process. The anti-wasting effects of the drug were based on both an activation of the rate of protein synthesis and an inhibition of the rate of muscle proteolysis. Northern blot analysis revealed that formoterol treatment resulted in a decrease in the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscles; this, together with the decreased proteasome activity observed, suggest that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. Interestingly, the beta2-agonist was also able to diminish the increased rate of muscle apoptosis (measured as DNA laddering as well as caspase-3 activity) present in tumor-bearing animals. The present results indicate that formoterol exerted a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation that characterizes cancer cachexia, and it could be revealed as a potential therapeutic tool in pathologic states wherein muscle protein hypercatabolism is a critical feature such as cancer cachexia or other wasting diseases.
PURPOSE: The development of cancer cachexia is the most common manifestation of advanced malignant disease. METHOD: The effects on muscle regeneration of β2-adrenoceptor agonist formoterol (0.3 mg/kg) were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). RESULTS: Administration of formoterol results in a significant increase in the mass and protein content of tibialis muscle in tumour-bearing-rats. This increase is associated with a decreased myogenin mRNA content together with an increased Pax-7 gene expression. Bupivacaine treatment by local injection results in an important reduction in tibialis weight together with significant increases in Pax-7, myogenin and MyoD gene expression. Formoterol treatment in bupivacaine-treated rats results in significant increases in Pax-7 together with significant decreases in myogenin mRNA content, suggesting that this β2-agonist is favouring muscle regeneration by stimulating the proliferation of satellite cells. Altogether, the data reinforce the potential role of formoterol in the treatment of muscle wasting diseases.
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