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
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.
Cancer cachexia, deacetylase inhibitors, follistatin, myostatin, TNFα.
Department of Clinical and Biological Sciences, Corso Raffaello, 30, 10125 Torino, Italy.