Transcriptional coactivators PGC-1α and PGC-1β control overlapping programs required for perinatal maturation of the heart
Transcriptional coactivators PGC-1α and PGC-1β control overlapping programs required for perinatal maturation of the heart
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DOI：
10.1101/gad.1661708
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发表时间：
2008-07-15
影响因子：
10.5
通讯作者：
Kelly, Daniel P.
中科院分区：
文献类型：
--
作者：
Lai, Ling;Leone, Teresa C.;Kelly, Daniel P.
氧化组织，如心脏，在出生后经历戏剧性的线粒体生物发生，以满足高能需求。PPAR-γ共激活因子-1(PGC-1)α和β参与了细胞能量代谢的转录调控。建立PGC-1α和PGC-1β联合缺陷小鼠(PGC-1αβ(-/-)小鼠)，研究其体内功能的趋同性。在非应激条件下，PGC-1β(-/-)小鼠的表型很少，包括正常的心功能，类似于先前产生的PGC-1α(-/-)小鼠。与单一缺陷的PGC-1品系形成鲜明对比的是，PGC-1α-β(-/-)小鼠出生后不久就死于心脏小、心动过缓、间歇性心脏传导阻滞，心输出量显著减少。在PGC-1α缺陷的背景表型上对PGC-1β基因进行心脏特异性消融，在普适性PGC-1αβ(-/-)小鼠中出现。PGC-1α-β(-/-)小鼠的心脏表现出成熟缺陷的特征，包括生长减慢，线粒体生物发生晚期胎儿停滞，以及持续的胎儿基因表达模式。PGC-1α-β(-/-)小鼠的棕色脂肪组织(BAT)也表现出严重的功能和线粒体密度异常。我们得出结论，PGC-1α和PGC-1β共同参与了心脏和蝙蝠出生后代谢和功能成熟所必需的共同作用。
Oxidative tissues such as heart undergo a dramatic perinatal mitochondrial biogenesis to meet the high-energy demands after birth. PPAR gamma coactivator-1 (PGC-1) alpha and beta have been implicated in the transcriptional control of cellular energy metabolism. Mice with combined deficiency of PGC-1 alpha and PGC-1 beta ( PGC-1 alpha beta(-/-) mice) were generated to investigate the convergence of their functions in vivo. The phenotype of PGC-1 beta(-/-) mice was minimal under nonstressed conditions, including normal heart function, similar to that of PGC-1 alpha(-/-)mice generated previously. In striking contrast to the singly deficient PGC-1 lines, PGC-1 alpha beta(-/-) mice died shortly after birth with small hearts, bradycardia, intermittent heart block, and a markedly reduced cardiac output. Cardiac-specific ablation of the PGC-1 beta gene on a PGC-1 alpha-deficient background phenocopied the generalized PGC-1 alpha beta(-/-) mice. The hearts of the PGC-1 alpha beta(-/-) mice exhibited signatures of a maturational defect including reduced growth, a late fetal arrest in mitochondrial biogenesis, and persistence of a fetal pattern of gene expression. Brown adipose tissue (BAT) of PGC-1 alpha beta(-/-) mice also exhibited a severe abnormality in function and mitochondrial density. We conclude that PGC-1 alpha and PGC-1 beta share roles that collectively are necessary for the postnatal metabolic and functional maturation of heart and BAT.