PPARγ coactivator-1α expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations
PPARγ coactivator-1α expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations
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DOI：
10.1152/ajpcell.00409.2002
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发表时间：
2003-06-01
影响因子：
5.5
通讯作者：
Hood, DA
中科院分区：
文献类型：
--
作者：
Irrcher, I;Adhihetty, PJ;Hood, DA
转录辅激活因子-过氧化物酶体增殖体激活受体γ辅激活因子-1 α (pgc -1 α)已被确定为线粒体生物发生的重要介质，基于其与激活编码线粒体蛋白的核基因的转录因子相互作用的能力。在引起线粒体生物发生的条件下，如收缩活动或甲状腺激素（T-3）治疗，pgc -1 α蛋白表达的诱导尚未完全确定。因此，我们将pgc -1 α蛋白表达与细胞色素c氧化酶（COX）活性联系起来：1)不同氧化能力的组织，2)经T-3处理的动物组织，以及3)细胞培养和体内均具有收缩活性的骨骼肌。我们的研究结果表明，PGC-1α的变化与COX活性之间存在很强的正相关（r = 0.74; P < 0.05）， COX活性被用作线粒体适应性的指标。PGC-1α的组成水平在心脏中最高，而在快速收缩的白肌和肝脏中最低。T-3增加PGC-1α含量在快肌和慢肌以及肝脏中相似，但在心脏中没有。T-3还诱导早期（6小时）amp活化蛋白激酶（AMPKα）活性增加，以及后期（5天）慢抽搐肌肉中p38 MAP激酶活性增加，但在快速抽搐肌肉中没有。收缩活动引起PGC-1α的早期升高，与线粒体转录因子A （Tfam）和核呼吸因子-1 （NRF-1）蛋白表达的升高一致，表明PGC-1α在协调核和线粒体基因组表达方面具有重要的生理作用。Ca2+离子团处理肌肉细胞导致PGC-1α蛋白增加约三倍，收缩活性诱导p38 MAP激酶和AMPKα活性快速显著增加。5-氨基咪唑-4-羧酰胺-1-β- d -核呋喃苷（AICAR）处理肌肉细胞也导致AMPKα活性和PGC-1α蛋白水平平行增加。这些数据与观察结果一致，表明PGC-1α蛋白的增加受Ca2+信号机制、AMPKα活性以及增加PGC-1α蛋白稳定性的翻译后磷酸化事件的影响。我们的数据支持PGC-1α在多种组织中线粒体含量的生理调节中的作用，并表明PGC-1α表达的增加是促进T-3和收缩活动诱导的线粒体适应的统一途径的一部分。
The transcriptional coactivator the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been identified as an important mediator of mitochondrial biogenesis based on its ability to interact with transcription factors that activate nuclear genes encoding mitochondrial proteins. The induction of PGC-1alpha protein expression under conditions that provoke mitochondrial biogenesis, such as contractile activity or thyroid hormone (T-3) treatment, is not fully characterized. Thus we related PGC-1alpha protein expression to cytochrome c oxidase (COX) activity in 1) tissues of varying oxidative capacities, 2) tissues from animals treated with T-3, and 3) skeletal muscle subject to contractile activity both in cell culture and in vivo. Our results demonstrate a strong positive correlation (r = 0.74; P < 0.05) between changes in PGC-1α and COX activity, used as an index of mitochondrial adaptations. The highest constitutive levels of PGC-1α were found in the heart, whereas the lowest were measured in fast-twitch white muscle and liver. T-3 increased PGC-1α content similarly in both fast- and slow-twitch muscle, as well as in the liver, but not in heart. T-3 also induced early (6 h) increases in AMP-activated protein kinase (AMPKα) activity, as well as later (5 day) increases in p38 MAP kinase activity in slow-twitch, but not in fast- twitch, muscle. Contractile activity provoked early increases in PGC-1α, coincident with increases in mitochondrial transcription factor A (Tfam), and nuclear respiratory factor-1 (NRF-1) protein expression, suggesting that PGC-1α is physiologically important in coordinating the expression of the nuclear and mitochondrial genomes. Ca2+ ionophore treatment of muscle cells led to an approximately threefold increase in PGC-1α protein, and contractile activity induced rapid and marked increases in both p38 MAP kinase and AMPKα activities. 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) treatment of muscle cells also led to parallel increases in AMPKα activity and PGC-1α protein levels. These data are consistent with observations that indicate that increases in PGC-1α protein are affected by Ca2+ signaling mechanisms, AMPKα activity, as well as posttranslational phosphorylation events that increase PGC-1α protein stability. Our data support a role for PGC-1α in the physiological regulation of mitochondrial content in a variety of tissues and suggest that increases in PGC-1α expression form part of a unifying pathway that promotes both T-3- and contractile activity-induced mitochondrial adaptations.