title: Trichostatin A, a histone deacetylase inhibitor, modulates unloaded-induced skeletal muscle atrophy.
abstract: Skeletal muscle atrophy is commonly associated with immobilization, ageing, and catabolic diseases such as diabetes and cancer cachexia. Epigenetic regulation of gene expression resulting from chromatin remodeling through histone acetylation has been implicated in muscle disuse. The present work was designed to test the hypothesis that treatment with trichostatin A (TSA), a histone deacetylase inhibitor, would partly counteract unloading-induced muscle atrophy. Soleus muscle atrophy (-38%) induced by 14 days of rat hindlimb suspension was reduced to only 25% under TSA treatment. TSA partly prevented the loss of type I and IIa fiber size and reversed the transitions of slow-twitch to fast-twitch fibers in soleus muscle. Unloading or TSA treatment did not affect myostatin gene expression and follistatin protein. Soleus protein carbonyl content remained unchanged, whereas the decrease in glutathione vs. glutathione disulfide ratio and the increase in catalase activity (biomarkers of oxidative stress) observed after unloading were abolished by TSA treatment. The autophagy-lysosome pathway (Bnip3 and microtubule-associated protein 1 light chain 3 proteins, Atg5, Gabarapl1, Ulk1, and cathepsin B and L mRNA) was not activated by unloading or TSA treatment. However, TSA suppressed the rise in muscle-specific RING finger protein 1 (MuRF1) caused by unloading without affecting the forkhead box (Foxo3) transcription factor. Prevention of muscle atrophy by TSA might be due to the regulation of the skeletal muscle atrophy-related MuRF1 gene. Our findings suggest that TSA may provide a novel avenue to treat unloaded-induced muscle atrophy.
authors.affiliation: Université de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France; CNRS, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Villeurbanne, France;
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dupré-Aucouturier
authors.affiliation: Université de Lyon, Lyon, France; Université de Lyon, Lyon, France;
authors.forename: Josiane
authors.initials: J
authors.lastname: Castells
authors.affiliation: Université de Lyon, Lyon, France; Laboratoire de Physiologie de l'Exercice, Université de Lyon, St Etienne, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Freyssenet
authors.affiliation: Université de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Villeurbanne, France; CNRS, Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Villeurbanne, France; dominique.desplanches@univ-lyon1.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Desplanches
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D019417:Hindlimb Suspension; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013997:Time Factors; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009124:Muscle Proteins; D012333:RNA, Messenger; D000070584:Tripartite Motif Proteins; C012589:trichostatin A; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases
keywords: histone acetylation; hypokinesia; oxidative stress; proteolysis