Muscle myostatin signalling is enhanced in experimental cancer cachexia

Authors: Costelli, P.¹; Muscaritoli, M.²; Bonetto, A.¹; Penna, F.¹; Reffo, P.¹; Bossola, M.³; Bonelli, G.¹; Doglietto, G. B.³; Baccino, F. M.¹; Fanelli, F. Rossi²

Source: European Journal of Clinical Investigation, Volume 38, Number 7, July 2008 , pp. 531-538(8)

Publisher: Wiley-Blackwell

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Abstract:

Background/Aims

Myostatin belongs to the transforming growth factor-β 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-α may be relevant in this regard. Materials and 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-α contributed to induce such changes, rats were administered pentoxifylline, an inhibitor of tumour necrosis factor-α 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.

Eur J Clin Invest 2008; 38 (7): 531-538

Keywords: Cancer cachexia; myostatin; muscle wasting; tumour necrosis factor-α

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2362.2008.01970.x

Affiliations: 1: Università di Torino, Italy, 2: Università La Sapienza, Roma, 3: Università Cattolica, Roma, Italy

Publication date: 2008-07-01