Dipartimento di Medicina Sperimentale Clinica, University of Florence, Florence, Italy.
Dipartimento di Scienze Mediche, University of Turin, Turin, Italy.
Dig Liver Dis. 2019 Oct;51(10):1400-1408. doi: 10.1016/j.dld.2019.03.002. Epub 2019 Apr 18.
BACKGROUND & AIMS: Myostatin is mainly expressed in skeletal muscle, where it negatively regulates trophism. This myokine is implicated in the pathophysiology of nonalcoholic steatohepatitis, an emerging cause of liver fibrosis. In this study we explored the effects of myostatin on the biology of hepatic stellate cells.
The effects of myostatin were assessed both in LX-2 and in human primary stellate cells. Cell migration was determined in Boyden chambers. Activation of intracellular pathways was evaluated by Western blotting. Procollagen type 1 secretion was measured by enzyme immunoassay. The role of c-Jun N-terminal kinase was assessed by pharmacologic and genetic inhibition.
Activin receptor-2B was up-regulated in livers of mice with experimental fibrosis, and detectable in human stellate cells. Serum myostatin levels increased in a model of acute liver injury. Myostatin reduced HSC proliferation, induced cell migration, and increased expression of procollagen type1, tissue inhibitor of metalloproteinase-1, and transforming growth factor-β1. Myostatin activated different signaling pathways, including c-Jun N-terminal kinase and Smad3. Genetic and/or pharmacologic inhibition of c-Jun N-terminal kinase activity significantly reduced cell migration and procollagen secretion in response to myostatin.
Activation of activin receptor-2B by myostatin modulates the fibrogenic phenotype of human stellate cells, indicating that a myokine may be implicated in the pathogenesis of hepatic fibrosis.
肌肉生长抑制素（Myostatin）主要在骨骼肌中表达，在那里它负调控营养作用。这种肌肉因子与非酒精性脂肪性肝炎的病理生理学有关，后者是肝纤维化的一个新兴病因。在这项研究中，我们探讨了肌肉生长抑制素对肝星状细胞生物学的影响。
在 LX-2 和人原代星状细胞中评估肌肉生长抑制素的作用。在 Boyden 室中测定细胞迁移。通过 Western blot 评估细胞内途径的激活。通过酶免疫测定法测量前胶原 1 型的分泌。通过药理学和遗传抑制评估 c-Jun N 端激酶的作用。
在实验性纤维化小鼠的肝脏中上调了激活素受体 2B，并且在人星状细胞中可检测到。急性肝损伤模型中血清肌肉生长抑制素水平升高。肌肉生长抑制素降低 HSC 增殖，诱导细胞迁移，并增加前胶原 1 型、金属蛋白酶组织抑制剂 1 和转化生长因子-β1 的表达。肌肉生长抑制素激活了不同的信号通路，包括 c-Jun N 端激酶和 Smad3。c-Jun N 端激酶活性的遗传和/或药理学抑制显著减少了对肌肉生长抑制素的细胞迁移和前胶原分泌。
肌肉生长抑制素激活激活素受体 2B 可调节人星状细胞的纤维生成表型，表明肌肉因子可能与肝纤维化的发病机制有关。
