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Updated: Jun 22, 2026
The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia
Published on: November 30, 2016
Deacetylase inhibitors modulate the myostatin/follistatin axis without improving cachexia in tumor-bearing mice
A Bonetto1, F Penna, V G Minero
1Department of Experimental Medicine and Oncology, University of Torino, 10125 Torino, Italy.
Abstract:
Muscle wasting, as occurring in cancer cachexia, is primarily characterized by protein hypercatabolism and increased expression of ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1. Myostatin, a member of the TGFbeta superfamily, negatively regulates skeletal muscle mass and we showed that increased myostatin signaling occurs in experimental cancer cachexia. On the other hand, enhanced expression of follistatin, an antagonist of myostatin, by inhibitors of histone deacetylases, such as valproic acid or trichostatin-A, has been shown to increase myogenesis and myofiber size in mdx mice. For this reason, in the present study we evaluated whether valproic acid or trichostatin-A can restore muscle mass in C26 tumor-bearing mice. Tumor growth induces a marked and progressive loss of body and muscle weight, associated with increased expression of myostatin and ubiquitin ligases. Treatment with valproic acid decreases muscle myostatin levels and enhances both follistatin expression and the inactivating phosphorylation of GSK-3beta, while these parameters are not affected by trichostatin-A. Neither agent, however, counteracts muscle atrophy or ubiquitin ligase hyperexpression. Therefore, modulation of the myostatin/follistatin axis in itself does not appear sufficient to correct muscle atrophy in cancer cachexia.
Insights
Histone deacetylase inhibitors like valproic acid did not restore muscle mass in cancer cachexia. While valproic acid affected myostatin signaling, neither it nor trichostatin-A counteracted muscle atrophy or ubiquitin ligase overexpression.
Area of Science:
- Biochemistry
- Molecular Biology
- Physiology
Background:
- Cancer cachexia involves muscle wasting due to protein hypercatabolism and increased ubiquitin ligase expression (e.g., atrogin-1/MAFbx, MuRF-1).
- Myostatin, a negative regulator of skeletal muscle mass, shows increased signaling in experimental cancer cachexia.
- Follistatin, a myostatin antagonist, can promote myogenesis and myofiber size when its expression is enhanced by histone deacetylase inhibitors.
Purpose of the Study:
- To investigate if valproic acid or trichostatin-A can restore muscle mass in C26 tumor-bearing mice.
- To determine the effects of these histone deacetylase inhibitors on myostatin signaling and muscle-specific ubiquitin ligases in cancer cachexia.
Main Methods:
- C26 tumor-bearing mice were treated with valproic acid or trichostatin-A.
- Muscle mass, myostatin levels, follistatin expression, ubiquitin ligase expression, and GSK-3beta phosphorylation were assessed.
Main Results:
- Tumor growth led to significant loss of body and muscle weight, with elevated myostatin and ubiquitin ligase expression.
- Valproic acid treatment reduced muscle myostatin levels and increased follistatin expression and GSK-3beta inactivating phosphorylation.
- Trichostatin-A did not affect these parameters.
- Neither valproic acid nor trichostatin-A counteracted the muscle atrophy or the hyperexpression of ubiquitin ligases.
Conclusions:
- Modulating the myostatin/follistatin axis alone is insufficient to reverse muscle atrophy in cancer cachexia.
- Targeting histone deacetylases may not be an effective strategy for treating muscle wasting in cancer cachexia.
