Lee Eun Ju, Jan Arif Tasleem, Baig Mohammad Hassan, Ashraf Jalaluddin Mohammad, Nahm Sang-Soep, Kim Yong-Woon, Park So-Young, Choi Inho
School of Biotechnology, Yeungnam University, Gyeongsan, South Korea;
College of Veterinary Medicine, Konkuk University, Seoul, South Korea; and.
FASEB J. 2016 Aug;30(8):2708-19. doi: 10.1096/fj.201500133R. Epub 2016 Apr 11.
Differentiation of muscle satellite cells (MSCs) involves interaction of the proteins present in the extracellular matrix (ECM) with MSCs to regulate their activity, and therefore phenotype. Herein, we report fibromodulin (FMOD), a member of the proteoglycan family participating in the assembly of ECM, as a novel regulator of myostatin (MSTN) during myoblast differentiation. In addition to having a pronounced effect on the expression of myogenic marker genes [myogenin (MYOG) and myosin light chain 2 (MYL2)], FMOD was found to maintain the transcriptional activity of MSTN Moreover, coimmunoprecipitation and in silico studies performed to investigate the interaction of FMOD helped confirm that it antagonizes MSTN function by distorting its folding and preventing its binding to activin receptor type IIB. Furthermore, in vivo studies revealed that FMOD plays an active role in healing by increasing satellite cell recruitment to sites of injury. Together, these findings disclose a hitherto unrecognized regulatory role for FMOD in MSCs and highlight new mechanisms whereby FMOD circumvents the inhibitory effects of MSTN and triggers myoblast differentiation. These findings offer a basis for the design of novel MSTN inhibitors that promote muscle regeneration after injury or for the development of pharmaceutical agents for the treatment of different muscle atrophies.-Lee, E. J., Jan, A. T., Baig, M. H., Ashraf, J. M., Nahm, S.-S., Kim, Y.-W., Park, S.-Y., Choi, I. Fibromodulin: a master regulator of myostatin controlling progression of satellite cells through a myogenic program.
肌肉卫星细胞（MSC）的分化涉及细胞外基质（ECM）中存在的蛋白质与MSC相互作用以调节其活性，进而调控其表型。在此，我们报告纤调蛋白（FMOD），一种参与ECM组装的蛋白聚糖家族成员，是成肌细胞分化过程中肌肉生长抑制素（MSTN）的新型调节因子。除了对成肌标记基因[肌细胞生成素（MYOG）和肌球蛋白轻链2（MYL2）]的表达有显著影响外，还发现FMOD可维持MSTN的转录活性。此外，为研究FMOD的相互作用而进行的免疫共沉淀和计算机模拟研究有助于证实，它通过扭曲MSTN的折叠并阻止其与IIB型激活素受体结合来拮抗MSTN的功能。此外，体内研究表明，FMOD通过增加卫星细胞向损伤部位的募集，在愈合过程中发挥积极作用。总之，这些发现揭示了FMOD在MSC中迄今未被认识的调节作用，并突出了FMOD规避MSTN抑制作用并触发成肌细胞分化的新机制。这些发现为设计促进损伤后肌肉再生的新型MSTN抑制剂或开发治疗不同肌肉萎缩的药物提供了依据。-李，E.J.，扬，A.T.，贝格，M.H.，阿什拉夫，J.M.，纳姆，S.-S.，金，Y.-W.，朴，S.-Y.，崔，I.纤调蛋白：通过成肌程序控制卫星细胞进展的肌肉生长抑制素的主要调节因子。
