The Nuclear Receptor and Clock Repressor Rev-erbaα Suppresses Myogenesis
The Nuclear Receptor and Clock Repressor Rev-erbaα Suppresses Myogenesis
复制标题
DOI：
10.1038/s41598-019-41059-7
复制
发表时间：
2019-03-14
影响因子：
4.6
通讯作者：
Ma, Ke
中科院分区：
文献类型：
--
作者：
Chatterjee, Somik;Yin, Hongshan;Ma, Ke
rev - erbb α是一种依赖配体的核受体，也是分子时钟转录网络的关键抑制因子。越来越多的证据表明，生物钟机制支配着骨骼肌的多种生物过程，包括肌肉生长、修复和大量维持。Rev-erb α在肌生成调节中的生理功能在很大程度上仍然未知。在这里，我们发现Rev-erb α对肌原性前体细胞的增殖和分化具有细胞自主抑制作用，这些作用协同抑制体内肌肉再生。机制研究揭示Rev-erb α直接转录控制两种主要的肌生成机制，即增殖途径和Wnt信号级联。与这一发现一致，缺乏rev - erbb α的原代成肌细胞表现出显著增强的增殖生长和成肌进展。此外，Rev-erb α活性的药理学激活减弱，而拮抗剂对其的抑制促进了这些过程。值得注意的是，在肌肉损伤后，体内rev - erbb α的功能丧失增强了卫星细胞在再生过程中的增殖扩张和再生进展。总的来说，我们的研究确定rev - erbb α是一种新的抑制肌源性祖细胞特性的抑制因子，可以抑制出生后的肌发生。抑制Rev-erb α活性的药物干预可能对增强肌肉疾病的再生能力有潜在的效用。
Rev-erb alpha is a ligand-dependent nuclear receptor and a key repressor of the molecular clock transcription network. Accumulating evidence indicate that the circadian clock machinery governs diverse biological processes in skeletal muscle, including muscle growth, repair and mass maintenance. The physiological function of Rev-erb alpha in myogenic regulation remains largely unknown. Here we show that Rev-erb alpha exerts cell-autonomous inhibitory effects on proliferation and differentiation of myogenic precursor cells, and these actions concertedly inhibit muscle regeneration in vivo. Mechanistic studies reveal Rev-erb alpha direct transcriptional control of two major myogenic mechanisms, proliferative pathway and the Wnt signaling cascade. Consistent with this finding, primary myoblasts lacking Rev-erb alpha display significantly enhanced proliferative growth and myogenic progression. Furthermore, pharmacological activation of Rev-erb alpha activity attenuates, whereas its inhibition by an antagonist promotes these processes. Notably, upon muscle injury, the loss-of-function of Rev-erb alpha in vivo augmented satellite cell proliferative expansion and regenerative progression during regeneration. Collectively, our study identifies Rev-erb alpha as a novel inhibitory regulator of myogenic progenitor cell properties that suppresses postnatal myogenesis. Pharmacological interventions to dampen Rev-erb alpha activity may have potential utilities to enhance regenerative capacity in muscle diseases.