Phospholipase D1 facilitates second-phase myoblast fusion and skeletal muscle regeneration.
Phospholipase D1 facilitates second-phase myoblast fusion and skeletal muscle regeneration.
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DOI：
10.1091/mbc.e14-03-0802
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发表时间：
2015-02-01
影响因子：
3.3
通讯作者：
Huang P
中科院分区：
文献类型：
--
作者：
Teng S;Stegner D;Chen Q;Hongu T;Hasegawa H;Chen L;Kanaho Y;Nieswandt B;Frohman MA;Huang P
磷脂酶D1及其产物磷脂酸在体内促进肌纤维再生，并且在体外第二阶段成肌细胞融合期间单核肌细胞需要与新生肌管融合。成肌细胞的分化和融合是一个精心策划的多步骤过程，对骨骼肌的发育和再生至关重要。磷脂酶D1（PLD1）已被牵连在体外成肌细胞分化的启动。然而，PLD1是否在成肌细胞融合中发挥额外的作用，并在体内肌发生中发挥作用仍然未知。在这里，我们表明，PLD1的表达上调，在心肌细胞再生心脏毒素损伤后，PLD1的基因消融延迟肌纤维再生的结果。来自PLD1缺失小鼠或用PLD1特异性抑制剂处理的成肌细胞不能形成成熟的肌管，表明第二阶段成肌细胞融合缺陷。伴随地，PLD 1产物磷脂酸在分化中的肌细胞的质膜上被瞬时检测到，并且其产生被PLD 1敲低抑制。外源性溶血磷脂酰胆碱，融合孔形成的关键膜脂质，部分拯救PLD1抑制导致的融合缺陷。因此，这些研究证明了PLD 1在肌发生期间成肌细胞融合中的作用，其中PLD 1促进单核肌细胞与新生肌管的融合。
Phospholipase D1 and its product, phosphatidic acid, facilitate muscle fiber regeneration in vivo and are required by mononuclear myocytes to fuse with nascent myotubes during second-phase myoblast fusion in vitro. Myoblast differentiation and fusion is a well-orchestrated multistep process that is essential for skeletal muscle development and regeneration. Phospholipase D1 (PLD1) has been implicated in the initiation of myoblast differentiation in vitro. However, whether PLD1 plays additional roles in myoblast fusion and exerts a function in myogenesis in vivo remains unknown. Here we show that PLD1 expression is up-regulated in myogenic cells during muscle regeneration after cardiotoxin injury and that genetic ablation of PLD1 results in delayed myofiber regeneration. Myoblasts derived from PLD1-null mice or treated with PLD1-specific inhibitor are unable to form mature myotubes, indicating defects in second-phase myoblast fusion. Concomitantly, the PLD1 product phosphatidic acid is transiently detected on the plasma membrane of differentiating myocytes, and its production is inhibited by PLD1 knockdown. Exogenous lysophosphatidylcholine, a key membrane lipid for fusion pore formation, partially rescues fusion defect resulting from PLD1 inhibition. Thus these studies demonstrate a role for PLD1 in myoblast fusion during myogenesis in which PLD1 facilitates the fusion of mononuclear myocytes with nascent myotubes.