Multiple muscle wasting-related transcription factors are acetylated in dexamethasone-treated muscle cells
Multiple muscle wasting-related transcription factors are acetylated in dexamethasone-treated muscle cells
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DOI：
10.1139/o11-082
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发表时间：
2012-04-01
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影响因子：
--
通讯作者：
Hasselgren, Per-Olof
中科院分区：
文献类型：
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作者：
Chamberlain, Wei;Gonnella, Patricia;Hasselgren, Per-Olof
最近的研究表明，组蛋白乙酰转移酶p300的表达和活性在分解代谢肌肉中上调，从而允许细胞蛋白质的乙酰化。转录因子的功能受翻译后修饰的影响，包括乙酰化。目前尚不清楚是否参与肌肉质量调节的转录因子在萎缩的肌肉中被乙酰化。我们测定了地塞米松处理的L 6肌细胞中乙酰化C/EBPb、C/EBPd、FOXO 1、FOXO 3a和NF-κ B/p65的细胞水平，这是一种常用的体外肌肉萎缩模型。通过用p300 siRNA转染肌细胞来检测p300在地塞米松诱导的转录因子乙酰化和肌管萎缩中的作用。用地塞米松处理L 6肌管导致乙酰化C/EBP β和δ、FOXO 1和3a以及p65的细胞水平增加。用p300 siRNA下调p300可减少转录因子的乙酰化，降低地塞米松诱导的肌管萎缩和泛素连接酶MuRF 1的表达。结果表明，几个肌肉萎缩相关的转录因子乙酰化支持的概念，调节基因转录的蛋白质的翻译后修饰可能参与肌肉质量的损失。结果还表明，乙酰化的转录因子至少在一定程度上由p300调节，并在糖皮质激素诱导的肌肉萎缩中发挥作用。调节转录因子乙酰化的靶向分子可能有助于减少肌肉萎缩的影响。
Recent studies suggest that the expression and activity of the histone acetyltransferase p300 are upregulated in catabolic muscle allowing for acetylation of cellular proteins. The function of transcription factors is influenced by posttranslational modifications, including acetylation. It is not known if transcription factors involved in the regulation of muscle mass are acetylated in atrophying muscle. We determined cellular levels of acetylated C/EBPb, C/EBPd, FOXO1, FOXO3a, and NF-kB/p65 in dexamethasone-treated L6 muscle cells, a commonly used in vitro model of muscle wasting. The role of p300 in dexamethasone-induced transcription factor acetylation and myotube atrophy was examined by transfecting muscle cells with p300 siRNA. Treatment of L6 myotubes with dexamethasone resulted in increased cellular levels of acetylated C/EBP beta and delta, FOXO1 and 3a, and p65. Downregulation of p300 with p300 siRNA reduced acetylation of transcription factors and decreased dexamethasone-induced myotube atrophy and expression of the ubiquitin ligase MuRF1. The results suggest that several muscle wasting-related transcription factors are acetylated supporting the concept that posttranslational modifications of proteins regulating gene transcription may be involved in the loss of muscle mass. The results also suggest that acetylation of the transcription factors is at least in part regulated by p300 and plays a role in glucocorticoid-induced muscle atrophy. Targeting molecules that regulate acetylation of transcription factors may help reduce the impact of muscle wasting.