title: Muscle myostatin signalling is enhanced in experimental cancer cachexia.
abstract: OBJECTIVE
  Myostatin belongs to the transforming growth factor-beta superfamily and negatively regulates skeletal muscle mass. Its deletion induces muscle overgrowth, while, on the contrary, its overexpression or systemic administration cause muscle atrophy. The present study was aimed at investigating whether muscle depletion as occurring in an experimental model of cancer cachexia, the rat bearing the Yoshida AH-130 hepatoma, is associated with modulations of myostatin signalling and whether the cytokine tumour necrosis factor-alpha may be relevant in this regard.
  
  
  METHODS
  Protein levels of myostatin, follistatin (myostatin endogenous inhibitor) and the activin receptor type IIB have been evaluated in the gastrocnemius of tumour-bearing rats by Western blotting. Circulating myostatin and follistatin in tumour hosts were evaluated by immunoprecipitation, while the DNA-binding activity of the SMAD transcription factors was determined by electrophoretic-mobility shift assay.
  
  
  RESULTS
  In day 4 tumour hosts muscle myostatin levels were comparable to controls, yet follistatin was reduced, and SMAD DNA-binding activity was enhanced. At day 7, both myostatin and follistatin increased in tumour bearers, while SMAD DNA-binding activity was unchanged. To investigate whether tumour necrosis factor-alpha contributed to induce such changes, rats were administered pentoxifylline, an inhibitor of tumour necrosis factor-alpha synthesis that partially corrects muscle depletion in tumour-bearing rats. The drug reduced both myostatin expression and SMAD DNA-binding activity in day 4 tumour hosts and up-regulated follistatin at day 7.
  
  
  CONCLUSIONS
  These observations suggest that myostatin pathway should be regarded as a potential therapeutic target in cancer cachexia.
authors.affiliation: Department of Experimental Medicine and Oncology Università di Torino, Italy. paola.costelli@unito.it
authors.forename: P
authors.initials: P
authors.lastname: Costelli
authors.forename: M
authors.initials: M
authors.lastname: Muscaritoli
authors.forename: A
authors.initials: A
authors.lastname: Bonetto
authors.forename: F
authors.initials: F
authors.lastname: Penna
authors.forename: P
authors.initials: P
authors.lastname: Reffo
authors.forename: M
authors.initials: M
authors.lastname: Bossola
authors.forename: G
authors.initials: G
authors.lastname: Bonelli
authors.forename: G B
authors.initials: GB
authors.lastname: Doglietto
authors.forename: F M
authors.initials: FM
authors.lastname: Baccino
authors.forename: F
authors.initials: F
authors.lastname: Rossi Fanelli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism*; D055435:Myostatin; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C525913:Mstn protein, rat; D055435:Myostatin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha