Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle
Transcriptional coactivator PGC-1α controls the energy state and contractile function of cardiac muscle
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DOI：
10.1016/j.cmet.2005.03.002
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发表时间：
2005-04-01
期刊：
影响因子：
29
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
--
作者：
Arany, Z;He, HM;Spiegelman, BM
骨骼肌和心肌依赖于线粒体产生的 ATP 的高周转率才能有效收缩。转录共激活因子 PGC-1 α 已被证明是骨骼肌和心肌中线粒体生物发生和呼吸的主要调节因子，但这仅基于功能获得研究。使用基因敲除小鼠，我们在此表明，虽然 PGC-1 α KO 小鼠似乎在两个肌床中保留了正常的线粒体体积，但氧化磷酸化基因的表达明显减弱。这些小鼠的心脏线粒体酶活性降低，ATR 水平降低。重要的是，缺乏 PGC-1 α 的离体心脏响应化学或电刺激而增加功输出的能力减弱。随着缺乏PGC-1α的小鼠年龄的增长，体内心脏功能障碍变得明显。这些数据表明 PGC-1 α 对于心脏满足 ATP 增加的需求并响应生理刺激至关重要。
Skeletal and cardiac muscle depend on high turnover of ATP made by mitochondria in order to contract efficiently. The transcriptional coactivator PGC-1 alpha has been shown to function as a major regulator of mitochondrial biogenesis and respiration in both skeletal and cardiac muscle, but this has been based only on gain-of-function studies. Using genetic knockout mice, we show here that, while PGC-1 alpha KO mice appear to retain normal mitochondrial volume in both muscle beds, expression of genes of oxidative phosphorylation is markedly blunted. Hearts from these mice have reduced mitochondrial enzymatic activities and decreased levels of ATR Importantly, isolated hearts lacking PGC-1 alpha have a diminished ability to increase work output in response to chemical or electrical stimulation. As mice lacking PGC-1 alpha age, cardiac dysfunction becomes evident in vivo. These data indicate that PGC-1 alpha is vital for the heart to meet increased demands for ATP and work in response to physiological stimuli.