Zhang Haifeng, Wen Junfei, Bigot Anne, Chen Jiacheng, Shang Renjie, Mouly Vincent, Bi Pengpeng
Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA.
Center for Research in Myology UMRS974, Sorbonne Université, INSERM, Myology Institute AIM, Paris, France.
Sci Adv. 2020 Dec 18;6(51). doi: 10.1126/sciadv.abc4062. Print 2020 Dec.
Myoblast fusion is essential for formations of myofibers, the basic cellular and functional units of skeletal muscles. Recent genetic studies in mice identified two long-sought membrane proteins, Myomaker and Myomixer, which cooperatively drive myoblast fusion. It is unknown whether and how human muscles, with myofibers of tremendously larger size, use this mechanism to achieve multinucleations. Here, we report an interesting fusion model of human myoblasts where Myomaker is sufficient to induce low-grade fusion, while Myomixer boosts its efficiency to generate giant myotubes. By CRISPR mutagenesis and biochemical assays, we identified MyoD as the key molecular switch of fusion that is required and sufficient to initiate Myomixer and Myomaker expression. Mechanistically, we defined the E-box motifs on promoters of Myomixer and Myomaker by which MyoD induces their expression for multinucleations of human muscle cells. Together, our study uncovered the key molecular apparatus and the transcriptional control mechanism underlying human myoblast fusion.
成肌细胞融合对于肌纤维的形成至关重要，肌纤维是骨骼肌的基本细胞和功能单位。最近在小鼠身上进行的遗传学研究确定了两种长期寻找的膜蛋白，即成肌素和融合素，它们共同驱动成肌细胞融合。目前尚不清楚人类肌肉中尺寸极大的肌纤维是否以及如何利用这种机制实现多核化。在这里，我们报告了一种有趣的人类成肌细胞融合模型，其中成肌素足以诱导低水平融合，而融合素则提高其效率以生成巨大的肌管。通过CRISPR诱变和生化分析，我们确定肌分化抗原（MyoD）是融合的关键分子开关，它启动融合素和成肌素的表达是必需且充分的。从机制上讲，我们确定了融合素和成肌素启动子上的E-box基序，通过该基序肌分化抗原诱导它们的表达以实现人类肌肉细胞的多核化。总之，我们的研究揭示了人类成肌细胞融合背后的关键分子机制和转录控制机制。
