FoxO6 and PGC-1α form a regulatory loop in myogenic cells.
FoxO6 and PGC-1α form a regulatory loop in myogenic cells.
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DOI：
10.1042/bsr20130031
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发表时间：
2013-06-13
影响因子：
4
通讯作者：
Chen SL
中科院分区：
文献类型：
--
作者：
Chung SY;Huang WC;Su CW;Lee KW;Chi HC;Lin CT;Chen ST;Huang KM;Tsai MS;Yu HP;Chen SL
FoxO（叉头框O）家族的转录因子调节广泛的细胞生理过程，包括代谢适应和肌源性分化。大多数FoxO成员的转录活性抑制肌源性分化，FoxO 1的过表达抑制体内氧化I型纤维的发育。在这项研究中，我们发现FoxO 6是最后发现的FoxO家族成员，在各种组织中普遍表达，但在氧化组织中表达水平较高，如大脑和氧化肌肉。PGC-1α（过氧化物酶体增殖物激活受体γ共激活因子1α）可以增强FoxO 6的表达水平和启动子活性，从而解释了其在氧化组织中的富集表达。我们进一步证明FoxO 6通过直接结合PGC-1α启动子上游富含A/T的元件（AAGATATCAAAACA，−2228-2215）来抑制PGC-1α的表达。氧化性低强度运动可诱导PGC-1α的表达，但降低了FoxO 6在后肢肌肉中的表达水平，运动也阻止了FoxO 6与PGC-1α启动子的结合。PGC-1α可共同激活FoxO 6启动子，而FoxO 6又可抑制FoxO 6启动子，提示FoxO 6与PGC-1α在骨骼肌氧化代谢水平的调控中形成了一个调控环，运动可诱导骨骼肌氧化代谢水平的变化。
Transcription factors of the FoxO (forkhead box O) family regulate a wide range of cellular physiological processes, including metabolic adaptation and myogenic differentiation. The transcriptional activity of most FoxO members is inhibitory to myogenic differentiation and overexpression of FoxO1 inhibits the development of oxidative type I fibres in vivo. In this study, we found that FoxO6, the last discovered FoxO family member, is expressed ubiquitously in various tissues but with higher expression levels in oxidative tissues, such as brain and oxidative muscles. Both the expression level and promoter activity of FoxO6 were found to be enhanced by PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α), thus explained its enriched expression in oxidative tissues. We further demonstrated that FoxO6 represses the expression of PGC-1α via direct binding to an upstream A/T-rich element (AAGATATCAAAACA,−2228–2215) in the PGC-1α promoter. Oxidative low-intensity exercise induced PGC-1α but reduced FoxO6 expression levels in hind leg muscles, and the binding of FoxO6 to PGC-1α promoter was also prevented by exercise. As FoxO6 promoter can be co-activated by PGC-1α and its promoter in turn can be repressed by FoxO6, it suggests that FoxO6 and PGC-1α form a regulatory loop for setting oxidative metabolism level in the skeletal muscle, which can be entrained by exercise.