Xue Siwen, Benvie Abigail M, Blum Jamie E, Kolba Nikolai J, Cosgrove Benjamin D, Thalacker-Mercer Anna, Berry Daniel C
The Divisional of Nutritional Sciences at Cornell University, Ithaca, NY.
Current address: Department of Chemical Engineering; Stanford University; Stanford, CA.
bioRxiv. 2024 Oct 18:2024.10.15.618247. doi: 10.1101/2024.10.15.618247.
Muscle cell fusion is critical for forming and maintaining multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identify platelet-derived growth factor receptor beta (PDGFRβ) signaling as a key modulator of myocyte fusion in adult muscle cells. Our findings demonstrate that genetic deletion of enhances muscle regeneration and increases myofiber size, whereas PDGFRβ activation impairs muscle repair. Inhibition of PDGFRβ activity promotes myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalls myotube development by preventing cell spreading to limit fusion potential. Transcriptomics analysis show that PDGFRβ signaling cooperates with TGFβ signaling to direct myocyte size and fusion. Mechanistically, PDGFRβ signaling requires STAT1 activation, and blocking STAT1 phosphorylation enhances myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to rapidly boost skeletal muscle repair.
在骨骼肌发育和再生过程中，肌细胞融合对于形成和维持多核肌管至关重要。然而，指导细胞间融合的分子机制尚未完全明确。在此，我们确定血小板衍生生长因子受体β（PDGFRβ）信号传导是成年肌细胞中肌细胞融合的关键调节因子。我们的研究结果表明，基因缺失可增强肌肉再生并增加肌纤维大小，而PDGFRβ激活则会损害肌肉修复。抑制PDGFRβ活性可促进小鼠和人类肌管中的肌核增加，而PDGFRβ激活则通过阻止细胞铺展以限制融合潜能来阻碍肌管发育。转录组学分析表明，PDGFRβ信号传导与TGFβ信号传导协同作用以指导肌细胞大小和融合。从机制上讲，PDGFRβ信号传导需要STAT1激活，而阻断STAT1磷酸化可增强再生过程中的肌纤维修复和大小。总体而言，PDGFRβ信号传导作为一个再生检查点，代表了一个快速促进骨骼肌修复的潜在临床靶点。
