Department of Paediatrics, University of Oxford, South Parks Road, Oxford, UK
Sleep and Circadian Neuroscience Institute (SCNi), Nuffield Department of Clinical Neurosciences, Oxford Molecular Pathology Institute, Dunn School of Pathology, University of Oxford, Oxford, UK.
Life Sci Alliance. 2021 Aug 13;4(10). doi: 10.26508/lsa.202101014. Print 2021 Oct.
Absence of dystrophin, an essential sarcolemmal protein required for muscle contraction, leads to the devastating muscle-wasting disease Duchenne muscular dystrophy. Dystrophin has an actin-binding domain, which binds and stabilises filamentous-(F)-actin, an integral component of the RhoA-actin-serum-response-factor-(SRF) pathway. This pathway plays a crucial role in circadian signalling, whereby the suprachiasmatic nucleus (SCN) transmits cues to peripheral tissues, activating SRF and transcription of clock-target genes. Given dystrophin binds F-actin and disturbed SRF-signalling disrupts clock entrainment, we hypothesised dystrophin loss causes circadian deficits. We show for the first time alterations in the RhoA-actin-SRF-signalling pathway, in dystrophin-deficient myotubes and dystrophic mouse models. Specifically, we demonstrate reduced F/G-actin ratios, altered MRTF levels, dysregulated core-clock and downstream target-genes, and down-regulation of key circadian genes in muscle biopsies from Duchenne patients harbouring an array of mutations. Furthermore, we show dystrophin is absent in the SCN of dystrophic mice which display disrupted circadian locomotor behaviour, indicative of disrupted SCN signalling. Therefore, dystrophin is an important component of the RhoA-actin-SRF pathway and novel mediator of circadian signalling in peripheral tissues, loss of which leads to circadian dysregulation.
缺乏肌营养不良蛋白（一种肌肉收缩所必需的重要肌膜蛋白）会导致毁灭性的肌肉消耗疾病——杜氏肌营养不良症。肌营养不良蛋白具有肌动蛋白结合域，该域可结合并稳定丝状肌动蛋白（F-肌动蛋白），这是 RhoA-肌动蛋白-血清反应因子（SRF）通路的一个组成部分。该通路在昼夜节律信号转导中起着至关重要的作用，其中视交叉上核（SCN）向周围组织传递信号，激活 SRF 和时钟靶基因的转录。鉴于肌营养不良蛋白结合 F-肌动蛋白，并且 SRF 信号转导紊乱会破坏时钟同步，我们假设肌营养不良蛋白缺失会导致昼夜节律紊乱。我们首次显示肌营养不良蛋白缺失会改变肌管和 DMD 小鼠模型中的 RhoA-肌动蛋白-SRF 信号通路。具体而言，我们证明 F/G-肌动蛋白比值降低、MRTF 水平改变、核心时钟和下游靶基因失调，以及 Duchenne 患者肌肉活检中的关键生物钟基因下调，这些患者携带多种突变。此外，我们还证明在 DMD 小鼠的 SCN 中缺乏肌营养不良蛋白，这些小鼠表现出昼夜节律运动行为紊乱，表明 SCN 信号转导受损。因此，肌营养不良蛋白是 RhoA-肌动蛋白-SRF 通路的重要组成部分，也是周围组织昼夜节律信号转导的新介质，其缺失会导致昼夜节律失调。
