NRF2/KEAP1-mediated antioxidant defence pathway regulates skeletal muscle circadian clock function
NRF2/KEAP1-mediated antioxidant defence pathway regulates skeletal muscle circadian clock function
复制标题
NRF2/KEAP1介导的抗氧化防御途径调节骨骼肌生物钟功能
DOI：
10.1016/j.freeradbiomed.2017.04.174
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发表时间：
2017
影响因子：
7.4
通讯作者：
Horton N
中科院分区：
文献类型：
--
作者：
Horton N
生物钟是一种内在的计时机制，它调节着人体内的大多数生理过程。昼夜节律的破坏已被确定为改变氧化还原控制的几种慢性疾病的危险因素。我们研究了这样的假设：NRF 2是抗氧化防御的主要调节因子，是骨骼肌中的一个时钟控制基因，可以调节生物钟功能。利用遗传学、药理学和实时成像方法，我们确定了生物钟机制和NRF 2/KEAP 1抗氧化途径之间的反馈机制。NRF 2的药理学操作对生物钟振荡的幅度和周期性都产生了强大的影响。此外，单个肌纤维分离证实了来自Nrf 2 KO小鼠的纤维中核心时钟基因表达的细胞自主变化。有趣的是，对时钟基因表达的类似影响在从老年野生型小鼠分离的肌纤维中也很明显。Nrf 2的丢失或衰老导致生物钟基因周期减少，但激活了参与炎症和抗应激的基因的节律性基因周期。总之，这些发现暗示NRF 2是一个重要的治疗靶点，未来可能会用于重置或重新调整与肌肉萎缩相关的几种慢性疾病（包括COPD和肌肉减少症）中出现的昼夜节律紊乱。
The circadian clock is an intrinsic timing mechanism which regulates most physiological processes within the body. Disruption of circadian rhythms has been identified as a risk factor for several chronic diseases with altered redox control. We investigated the hypothesis that NRF2, a master regulator of antioxidant defence, is a clock-controlled gene in skeletal muscle, which can modulate the circadian clock function. Using genetic, pharmacological and real-time imaging approaches, we identified a feedback mechanism between the circadian clock machinery and the NRF2/KEAP1 antioxidant pathway. Pharmacological manipulation of NRF2 exerted robust effects on both the amplitude and periodicity of circadian clock oscillations. Moreover, single muscle fibre isolation has confirmed cell-autonomous changes in core clock gene expression in fibres from Nrf2 KO mice. Interestingly, similar effects on clock gene expression were also evident in muscle fibres isolated from old wild-type mice. Loss of Nrf2, or ageing led to diminished clock gene cycles but activated rhythmic gene cycles of genes involved in inflammation and stress resistance. All together, these findings implicate NRF2 as an important therapeutic target which may be utilised in future to reset or re-align disrupted circadian rhythms seen in several chronic diseases associated with muscle wasting including COPD and sarcopenia.