Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal
Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal
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DOI：
10.1074/jbc.m115.686519
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发表时间：
2015-09-25
影响因子：
4.8
通讯作者：
Ren, Hongmei
中科院分区：
文献类型：
--
作者：
Jiang, Weihua;Zhu, Jing;Ren, Hongmei
Lipin1是一种细胞内蛋白，通过其酶活性和核转录功能在控制脂质合成和能量代谢中起关键作用。几种骨骼肌萎缩的小鼠模型与脂质1突变或表达改变有关。最近的人类研究表明，携带LPIN1基因纯合零突变的儿童患有横纹肌溶解症。然而，潜在的病理生理机制仍然知之甚少。在本研究中，我们研究了脂素1是否有助于调节肌肉再生。我们描述了脂素1缺陷小鼠损伤后骨骼肌再生的时间过程。我们发现，与野生型小鼠相比，野生型小鼠在损伤反应中表现出更小的再生肌纤维横截面积。我们的一系列体外实验结果表明，在成肌细胞分化过程中，lipin1被上调并易位到细胞核，并通过调节ERK1/2的胞浆激活，形成复合物和下游效应细胞周期蛋白d3介导的细胞周期退出，在肌发生中发挥关键作用。总的来说，我们的研究揭示了脂素1在骨骼肌再生中的未知作用，并扩展了我们对骨骼肌再生的细胞和分子机制的理解。
Lipin1, an intracellular protein, plays critical roles in controlling lipid synthesis and energy metabolism through its enzymatic activity and nuclear transcriptional functions. Several mouse models of skeletal muscle wasting are associated with lipin1 mutation or altered expression. Recent human studies have suggested that children with homozygous null mutations in the LPIN1 gene suffer from rhabdomyolysis. However, the underlying pathophysiologic mechanism is still poorly understood. In the present study we examined whether lipin1 contributes to regulating muscle regeneration. We characterized the time course of skeletal muscle regeneration in lipin1-deficient fld mice after injury. We found that fld mice exhibited smaller regenerated muscle fiber cross-sectional areas compared with wild-type mice in response to injury. Our results from a series of in vitro experiments suggest that lipin1 is up-regulated and translocated to the nucleus during myoblast differentiation and plays a key role in myogenesis by regulating the cytosolic activation of ERK1/2 to form a complex and a downstream effector cyclin D3-mediated cell cycle withdrawal. Overall, our study reveals a previously unknown role of lipin1 in skeletal muscle regeneration and expands our understanding of the cellular and molecular mechanisms underlying skeletal muscle regeneration.