Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle

Abstract

Alamdari N, Smith IJ, Aversa Z, Hasselgren PO. Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 299: R509 -R520, 2010. First published June 10, 2010 doi:10.1152/ajpregu.00858.2009.-Muscle wasting during sepsis is in part regulated by glucocorticoids. In recent studies, treatment of cultured muscle cells in vitro with dexamethasone upregulated expression and activity of p300, a histone acetyl transferase (HAT), and reduced expression and activity of the histone deacetylases-3 (HDAC3) and -6, changes that favor hyperacetylation. Here, we tested the hypothesis that sepsis and glucocorticoids regulate p300 and HDAC3 and -6 in skeletal muscle in vivo. Because sepsis-induced metabolic changes are particularly pronounced in white, fast-twitch skeletal muscle, most experiments were performed in extensor digitorum longus muscles. Sepsis in rats upregulated p300 mRNA and protein levels, stimulated HAT activity, and reduced HDAC6 expression and HDAC activity. The sepsis-induced changes in p300 and HDAC expression were prevented by the glucocorticoid receptor antagonist RU38486. Treatment of rats with dexamethasone increased expression of p300 and HAT activity, reduced expression of HDAC3 and -6, and inhibited HDAC activity. Finally, treatment with the HDAC inhibitor trichostatin A resulted in increased muscle proteolysis and expression of the ubiquitin ligase atrogin-1. Taken together, our results suggest for the first time that sepsis-induced muscle wasting may be regulated by glucocorticoid-dependent hyperacetylation caused by increased p300 and reduced HDAC expression and activity. The recent development of pharmacological HDAC activators may provide a novel avenue to prevent and treat muscle wasting in sepsis and other catabolic conditions. acetylation; muscle wasting MUSCLE WASTING DURING SEPSIS is, at least in part, regulated by glucocorticoids (15, 50) and is mainly caused by increased degradation of myofibrillar proteins, although inhibited protein synthesis may contribute as well (16,25). Gene transcription is altered in atrophying muscle, and in recent studies in experimental animals, a common set of genes, so called atrogenes, was upregulated in different catabolic conditions (27). Among the atrogenes, the genes for the ubiquitin ligases muscle atrophy F-box, also known as atrogin-1 (MAFbx/atrogin-1) and muscle ring finger 1 (MuRF1) are particularly important (3,14). Because changes in gene transcription play an important role in loss of muscle mass it is likely that transcription factors are involved in muscle wasting. Indeed, recent reports from our and other laboratories suggest that the transcription factors NF-B (4, 44, 59), CCAAT/enhancer-binding protein (C/ EBP)␤ and -␦ (43, 62), AP-1 (41, 44), and forkhead box (FOXO)1 and -3a (11, 12, 21, 22, 52) regulate muscle-wastingrelated genes in sepsis and other catabolic conditions.In addition to transcription factors, gene activation is also regulated by other f...

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