Dystrophin involvement in peripheral circadian SRF signalling.
Dystrophin involvement in peripheral circadian SRF signalling.
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DOI：
10.26508/lsa.202101014
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发表时间：
2021-10
影响因子：
4.4
通讯作者：
Wood MJ
中科院分区：
文献类型：
--
作者：
Betts CA;Jagannath A;van Westering TL;Bowerman M;Banerjee S;Meng J;Falzarano MS;Cravo L;McClorey G;Meijboom KE;Bhomra A;Lim WF;Rinaldi C;Counsell JR;Chwalenia K;O'Donovan E;Saleh AF;Gait MJ;Morgan JE;Ferlini A;Foster RG;Wood MJ
缺乏完整的肌层蛋白，即肌营养不良蛋白，会破坏骨骼肌中的RhoA-actin-SRF级联，导致srf下游昼夜节律靶点和昼夜节律失调。肌营养不良蛋白是肌肉收缩所必需的一种重要的肌上皮蛋白，缺乏这种蛋白会导致毁灭性的肌肉萎缩疾病杜氏肌营养不良症。肌营养不良蛋白有一个肌动蛋白结合结构域，它结合并稳定丝状-(F)-肌动蛋白，这是rhoa -actin-血清反应因子（SRF）途径的一个组成部分。这条通路在昼夜节律信号传导中起着至关重要的作用，视交叉上核（SCN）将信号传递给外周组织，激活SRF和时钟靶基因的转录。鉴于肌营养不良蛋白与f -肌动蛋白结合，而受到干扰的srf信号传导会扰乱生物钟，我们假设肌营养不良蛋白的缺失会导致昼夜节律缺陷。我们首次在肌营养不良蛋白缺乏的肌管和营养不良小鼠模型中显示了rhoa -actin- srf信号通路的改变。具体来说，我们证明了F/ g -肌动蛋白比率降低，MRTF水平改变，核心时钟和下游靶基因失调，以及在杜氏肌活组织检查中携带一系列突变的关键昼夜节律基因下调。此外，我们发现营养不良小鼠的SCN中缺乏肌营养不良蛋白，这些小鼠表现出昼夜运动行为中断，表明SCN信号传导中断。因此，肌营养不良蛋白是RhoA-actin-SRF通路的重要组成部分，也是外周组织中昼夜节律信号的新型介质，其缺失会导致昼夜节律失调。
Absence of integral sarcolemmal protein, dystrophin, disrupts the RhoA-actin-SRF cascade in skeletal muscle, with subsequent dysregulation of downstream-SRF circadian targets and circadian rhythm. 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.
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