Myocardin-related transcription factor-A/serum response factor (MRTF-A/SRF), a well-known transcriptional programme, has been proposed to play crucial roles in skeletal muscle development and function. However, whether MRTF-A participates in muscle regeneration and the molecular mechanisms are not completely understood. Here, we show that MRTF-A levels are highly correlated with myogenic genes using a RNA-seq assay, which reveal that MRTF-A knockdown in C2C12 cells significantly reduces PAX7 expression. Subsequent in vitro and in vivo data show that MRTF-A and PAX7 present identical expression patterns during myoblast differentiation and CTX-induced muscle injury and repair. Remarkably, MRTF-A overexpression promotes myoblast proliferation, while inhibiting cell differentiation and the expression of MyoD and MyoG. MRTF-A loss of function produces the opposite effect. Moreover, mice with lentivirus (MRTF-A) injection possesses more PAX7⁺ satellite cells, but less differentiating MyoD⁺ and MyoG⁺ cells, leading subsequently to diminished muscle regeneration. Our mechanistic results reveal that MRTF-A contributes to PAX7-mediated myoblast self-renewal, proliferation, and differentiation by binding to its distal CArG box. Overall, we propose that MRTF-A functions as a novel PAX7 regulator upon myoblast commitment to differentiation, which could provide pathways for dictating muscle stem cell fate and open new avenues to explore stem cell-based therapy for muscle degenerative diseases.

中文翻译：

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MRTF-A通过在肌肉再生过程中靶向PAX7来调节成肌细胞对分化的承诺

心肌素相关转录因子-A/血清反应因子 (MRTF-A/SRF) 是一种众所周知的转录程序，已被提议在骨骼肌发育和功能中发挥关键作用。然而，MRTF-A是否参与肌肉再生及其分子机制尚不完全清楚。在这里，我们使用 RNA-seq 分析显示 MRTF-A 水平与生肌基因高度相关，这表明 C2C12 细胞中 MRTF-A 的敲低显着降低了 PAX7 的表达。随后的体外和体内数据显示 MRTF-A 和 PAX7 在成肌细胞分化和 CTX 诱导的肌肉损伤和修复过程中呈现相同的表达模式。值得注意的是，MRTF-A 过表达促进成肌细胞增殖，同时抑制细胞分化和 MyoD 和 MyoG 的表达。MRTF-A 功能丧失会产生相反的效果。此外，注射慢病毒 (MRTF-A) 的小鼠拥有更多的 PAX7 ⁺卫星细胞，但较少区分 MyoD ⁺和 MyoG ⁺细胞，随后导致肌肉再生减少。我们的机制结果表明，MRTF-A 通过与其远端 CArG 盒结合，有助于 PAX7 介导的成肌细胞自我更新、增殖和分化。总体而言，我们提出 MRTF-A 作为一种新的 PAX7 调节剂在成肌细胞分化时发挥作用，这可以提供支配肌肉干细胞命运的途径，并为探索基于干细胞的肌肉退行性疾病治疗开辟新途径。