Deacetylase inhibitors modulate the myostatin/follistatin axis without improving cachexia in tumor-bearing mice.
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.
Bonetto
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A
Department of Experimental Medicine and Oncology, University of Torino, 10125 Torino, Italy.
Penna
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F
Minero
V G
VG
Reffo
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P
Bonelli
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G
Baccino
F M
FM
Costelli
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D000818:Animals; D002100:Cachexia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D003110:Colonic Neoplasms / Q000150:complications; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D038681:Follistatin / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism; D009133:Muscular Atrophy / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D055435:Myostatin / Q000378:metabolism*; D009368:Neoplasm Transplantation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D038681:Follistatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D055435:Myostatin; C012589:trichostatin A; D014635:Valproic Acid; D044767:Ubiquitin-Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3