Anticachectic effects of formoterol: a drug for potential treatment of muscle wasting.
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.
Busquets
Sílvia
S
Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
Figueras
Maria T
MT
Fuster
Gemma
G
Almendro
Vanessa
V
Moore-Carrasco
Rodrigo
R
Ametller
Elisabet
E
Argilés
Josep M
JM
López-Soriano
Francisco J
FJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012517:Sarcoma, Yoshida / Q000378:metabolism / Q000473:pathology
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D009124:Muscle Proteins; D000068759:Formoterol Fumarate