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FHL3 differentially regulates the expression of MyHC isoforms through interactions with MyoD and pCREB

机译:FHL3通过与MyoD和pCREB的相互作用来差异调节MyHC亚型的表达

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In skeletal muscle, muscle fiber types are defined by four adult myosin heavy chain (MyHC) isoforms. Four and a half LIM domain protein 3 (FHL3) regulates myoblasts differentiation and gene expression by acting as a transcriptional co-activator or co-repressor. However, how FHL3 regulates MyHC expression is currently not clear. In this study, we found that FHL3 down-regulated the expression of MyHC 1/slow and up-regulated the expression of MyHC 2a and MyHC 2b, whereas no significant effect was found on MyHC 2x expression. MyoD and phosphorylated cAMP response element binding protein (pCREB) played important roles in the regulation of MyHC 1/slow and MyHC 2a expression by FHL3, respectively. FHL3 could interact with MyoD, CREB and pCREB in vivo. pCREB had stronger interaction with the cyclic AMP-responsive elements (CRE) of the MyHC 2a promoter compared with CREB, and FHL3 significantly affected the binding capacity of pCREB to CRE. We established a model in which FHL3 promotes the expression of MyHC 2a through CREB-mediated transcription and inhibits the expression of MyHC 1/slow by inhibiting MyoD transcription activity during myogenesis. Our data support the notion that FHL3 plays important roles in the regulation of muscle fiber type composition. (C) 2015 Elsevier Inc. All rights reserved.
机译:在骨骼肌中,肌肉纤维类型由四种成人肌球蛋白重链(MyHC)同工型定义。四个半LIM域蛋白3(FHL3)通过充当转录共激活因子或共抑制因子来调节成肌细胞的分化和基因表达。但是,目前尚不清楚FHL3如何调节MyHC表达。在这项研究中,我们发现FHL3下调MyHC 1 / slow的表达并上调MyHC 2a和MyHC 2b的表达,而对MyHC 2x的表达没有明显影响。 MyoD和磷酸化的cAMP反应元件结合蛋白(pCREB)分别在FHL3调节MyHC 1 / slow和MyHC 2a表达中起重要作用。 FHL3可以在体内与MyoD,CREB和pCREB相互作用。与CREB相比,pCREB与MyHC 2a启动子的环状AMP应答元件(CRE)有更强的相互作用,而FHL3显着影响pCREB与CRE的结合能力。我们建立了一个模型,其中FHL3通过CREB介导的转录促进MyHC 2a的表达,并通过在成肌过程中抑制MyoD转录活性来抑制MyHC 1 / slow的表达。我们的数据支持FHL3在调节肌纤维类型组成中起重要作用的观点。 (C)2015 Elsevier Inc.保留所有权利。

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