Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle
Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle
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DOI：
10.1152/ajpregu.00858.2009
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发表时间：
2010-08-01
影响因子：
2.8
通讯作者：
Hasselgren, Per-Olof
中科院分区：
文献类型：
--
作者：
Alamdari, Nima;Smith, Ira J.;Hasselgren, Per-Olof
Alamdari N，Smith IJ，阿韦萨Z，Hasselgren PO.脓毒症和糖皮质激素上调p300和下调HDAC 6表达和活性在骨骼肌。Am J Physiol Regul Integr Comp Physiol 299：R509-R520，2010年。首次发表于2010年6月10日; doi：10.1152/ajpregu.00858.2009。脓毒症期间的肌肉消耗部分受糖皮质激素调节。在最近的研究中，用地塞米松处理体外培养的肌细胞上调了p300（一种组蛋白乙酰转移酶（HAT））的表达和活性，并降低了组蛋白脱乙酰酶-3（HDAC 3）和-6（HDAC 3和HDAC 6）的表达和活性，这些变化有利于超乙酰化。在这里，我们测试的假设，脓毒症和糖皮质激素调节p300和HDAC 3和-6在体内骨骼肌。由于脓毒症诱导的代谢变化在白色快速收缩的骨骼肌中特别明显，因此大多数实验在趾长伸肌中进行。脓毒症大鼠上调p300 mRNA和蛋白水平，刺激HAT活性，降低HDAC 6表达和HDAC活性。脓毒症诱导的p300和HDAC表达的变化被糖皮质激素受体拮抗剂RU 38486阻止。地塞米松处理大鼠增加了p300的表达和HAT活性，减少了HDAC 3和-6的表达，并抑制了HDAC活性。最后，用HDAC抑制剂阿曲他汀A治疗导致肌肉蛋白水解和泛素连接酶atrogin-1的表达增加。两者合计，我们的研究结果表明，脓毒症引起的肌肉萎缩可能是由糖皮质激素依赖性的过度乙酰化引起的p300增加和HDAC的表达和活性降低调节。药理学HDAC激活剂的最新发展可能为预防和治疗脓毒症和其他分解代谢疾病中的肌肉萎缩提供新的途径。
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.