Advances in Cancer Drug Targets

Volume: 2

Indexed in: EBSCO, Scopus

Advances in Cancer Drug Targets is an e-book series that brings together recent expert reviews published on the subject with a focus on strategies for synthesizing and isolating organic compounds and ...
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Modulation of the Myostatin/Follistatin Axis by Deacetylase Inhibitors: Improvement of TNFα-Induced Myotube Atrophy But Not of Experimental Cancer Cachexia

Pp. 274-295 (22)

Andrea Bonetto, Fabio Penna, Gabriella Bonelli, Francesco M. Baccino and Paola Costelli

Abstract

Myostatin, a negative regulator of skeletal muscle mass, is increased in several conditions characterized by muscle wasting, among which cancer cachexia. Physiological inhibitors, such as follistatin, negatively regulate myostatin bioactivity.

Histone deacetylase inhibitors have been shown to improve muscle wasting and function in dystrophic mdx mice, mainly by modulating the myostatin/follistatin axis. The present study was aimed at investigating the efficacy of two histone deacetylase inhibitors, namely valproic acid and trichostatin A, in preventing muscle atrophy in C26 tumor-bearing mice and in C2C12 myotubes exposed to TNFα

The progressive muscle depletion that occurs in the C26 hosts was associated with increased expression of myostatin and muscle-specific ubiquitin ligases. Administration of valproic acid, but not trichostatin A, resulted in decreased muscle myostatin expression and increased follistatin levels. Neither agent, however, was able to effectively counteract muscle atrophy or ubiquitin ligase hyperexpression. By contrast, morphological analysis suggested that both valproic acid and trichostatin A are protective against TNFα-induced myotube atrophy.

Altogether, these results suggest that modulation of the myostatin/follistatin axis can prevent TNFα-associated myofiber atrophy, although it is not sufficient to correct muscle atrophy in cancer cachexia.

Keywords:

Cancer cachexia, deacetylase inhibitors, follistatin, myostatin, TNFα.

Affiliation:

Department of Clinical and Biological Sciences, Corso Raffaello, 30, 10125 Torino, Italy.