The role of Nrf2 in skeletal muscle contractile and mitochondrial function
The role of Nrf2 in skeletal muscle contractile and mitochondrial function
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DOI：
10.1152/japplphysiol.00042.2016
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发表时间：
2016-09-01
影响因子：
3.3
通讯作者：
Hood, David A.
中科院分区：
文献类型：
--
作者：
Crilly, Matthew J.;Tryon, Liam D.;Hood, David A.
核因子红细胞2相关因子2（Nrf 2）是一种转录因子，其通过响应于氧化应激上调抗氧化酶来赋予细胞保护。然而，Nrf 2在骨骼肌中的功能仍有待进一步阐明。我们使用年轻（3个月）和老年（12个月）Nrf 2野生型（WT）和敲除（KO）小鼠研究了Nrf 2在确定肌肉表型中的作用。基本上，Nrf 2的缺乏不影响线粒体含量。在肌原纤维间线粒体中，Nrf 2的缺乏导致状态4呼吸减少40%，这与活性氧（ROS）排放增加68%相吻合。nrf 2废除原位肌肉性能受损，其特征在于在刺激的第一个5分钟内，疲劳率增加48%，力降低35%。急性跑步机运动通过增强WT动物的DNA结合导致Nrf 2活化增加1.5倍。作为对训练的响应，WT动物的细胞色素c氧化酶活性增加了20%;然而，KO小鼠的这种响应减弱。Nrf 2蛋白通过训练降低了30%。尽管如此，运动训练使KO小鼠的呼吸、ROS产生和肌肉表现正常化。我们的研究结果表明，Nrf 2的转录活性增加运动和Nrf 2所需的基础线粒体功能的维护，以及在特定的线粒体蛋白的正常增加，在响应训练。尽管如此，运动训练可以挽救Nrf 2 KO肌肉中线粒体功能的下降，这表明这种恢复功能通过独立于Nrf 2的途径发挥作用。
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that confers cellular protection by upregulating antioxidant enzymes in response to oxidative stress. However, Nrf2 function within skeletal muscle remains to be further elucidated. We examined the role of Nrf2 in determining muscle phenotype using young (3 mo) and older (12 mo) Nrf2 wild-type (WT) and knockout (KO) mice. Basally, the absence of Nrf2 did not impact mitochondrial content. In intermyofibrillar mitochondria, lack of Nrf2 resulted in a 40% reduction in state 4 respiration, which coincided with a 68% increase in reactive oxygen species (ROS) emission. Nrf2 abrogation impaired in situ muscle performance, characterized by a 48% greater rate of fatigue and a 35% decrease in force within the first 5 min of stimulation. Acute treadmill exercise resulted in a 1.5-fold increase in Nrf2 activation via enhanced DNA binding in WT animals. In response to training, cytochrome-c oxidase activity increased by 20% in the WT animals; however, this response was attenuated in KO mice. Nrf2 protein was reduced 30% by training. Despite this, exercise training normalized respiration, ROS production, and muscle performance in KO mice. Our results suggest that Nrf2 transcriptional activity is increased by exercise and that Nrf2 is required for the maintenance of basal mitochondrial function as well as for the normal increase in specific mitochondrial proteins in response to training. Nonetheless, the decrements in mitochondrial function in Nrf2 KO muscle can be rescued by exercise training, suggesting that this restorative function operates via a pathway independent of Nrf2.