Isoform-specific increases in murine skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA in response to β2-adrenergic receptor activation and exercise
Isoform-specific increases in murine skeletal muscle peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA in response to β2-adrenergic receptor activation and exercise
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DOI：
10.1210/en.2008-0466
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发表时间：
2008-09-01
期刊：
影响因子：
4.8
通讯作者：
Ezaki, Osamu
中科院分区：
文献类型：
--
作者：
Miura, Shinji;Kai, Yuko;Ezaki, Osamu
肾上腺素能受体（AR）激活增加过氧化物酶体增殖物激活受体（PPAR）-γ共激活因子1 α（PGC-1 α）mRNA的表达，这可能促进骨骼肌中的线粒体生物合成。在运动中观察到AR激活的PGC-1 α mRNA增加。PGC-1 α mRNA被认为是单一转录物（PGC-1 α-a）;然而，在表达序列标签文库中搜索PGC-1 α的转录物显示，PGC-1 α mRNA的两种新亚型（命名为PGC-1 α-b和PGC-1 α-c）在小鼠组织中表达。与PGC-1 alpha-a mRNA（先前描述的同种型）相比，PGC-1 alpha-b或PGC-1 alpha-c mRNA由PGC-1 alpha基因的不同外显子1转录，并产生略小的蛋白质。PGC-1 alpha-b或PGC-1 alpha-c蛋白是功能性的;这两种异构体都具有转录活性，并且可以共激活PPARs，类似于体外PGC-1 alpha-a中的那些。在骨骼肌中过表达PGC-1 alpha-b或PGC-1 alpha-c的转基因小鼠显示与线粒体生物合成和脂肪酸氧化相关的基因表达增加。在C57 BL/6 J小鼠中，注射β 2-AR激动剂克仑特罗使骨骼肌中的PGC-1 α-b和PGC-1 α- c mRNA表达增加350倍以上，但不增加PGC-1 α-a。单次运动也增加了骨骼肌中的PGC-1 alpha-b和PGC-1 alpha-c mRNA，但没有增加PGC-1 alpha-a。通过使用β 2-AR特异性抑制剂ICI 118，551进行预处理，可抑制骨骼肌对运动的反应增加。然而，在肝脏中，禁食增加PGC-1 α-a mRNA，但不增加PGC-1 α-b和PGC-1 α-c mRNA。这些数据表明，AR激活是骨骼肌中PGC-1 α表达增加的主要机制，并且PGC-1 α mRNA的增加是同种型特异性的。
Adrenergic receptor (AR) activation increases expression of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1 alpha(PGC-1 alpha) mRNA, which may promote mitochondrial biogenesis in skeletal muscles. An AR-activated increase in PGC-1 alpha mRNA was observed in exercise. PGC-1 alpha mRNA is considered a single transcript (PGC-1 alpha-a); however, a transcript search of PGC-1 alpha in expressed sequence tag libraries revealed that two novel isoforms of PGC-1 alpha mRNA, named PGC-1 alpha-b and PGC-1 alpha-c, were expressed in mice tissues. Compared with PGC-1 alpha-a mRNA (a previously described isoform), PGC-1 alpha-b or PGC-1 alpha-c mRNA was transcribed by a different exon 1 of the PGC-1 alpha gene and produced slightly smaller-sized proteins. PGC-1 alpha-b or PGC-1 alpha-c protein was functional; both isoforms possessed transcriptional activity and could coactivate PPARs, similar to those in PGC-1 alpha-a in vitro. Transgenic mice overexpressing PGC-1 alpha-b or PGC-1 alpha-c in skeletal muscles showed increased gene expression related to mitochondrial biogenesis and fatty acid oxidation. In C57BL/6J mice, injection of the beta 2-AR agonist clenbuterol increased PGC-1 alpha-b and PGC-1 alpha- c mRNA expression more than 350-fold, but not PGC-1 alpha-a, in skeletal muscle. A single bout of exercise also increased PGC-1 alpha-b and PGC-1 alpha-c mRNAs, but not PGC-1 alpha-a, in skeletal muscles. The increases in skeletal muscles in response to exercise were inhibited by pretreatment with the beta 2-AR-specific inhibitor ICI 118,551. However, in liver, fasting increased PGC-1 alpha-a mRNA, but not PGC-1 alpha-b and PGC-1 alpha-c mRNAs. These data indicate that AR activation is a major mechanism of an increase in PGC-1 alpha expression in skeletal muscles, and the increase in PGC-1 alpha mRNAs was isoform specific.