Life-and-death decisions of myoblast cells during differentiation

内质网（ER）应激是由内质网中未折叠蛋白的积累引起的，其在多种条件下发生。我们最近证明，ER应激信号发生在体内成肌细胞分化。这种信号传导导致成肌细胞亚群的凋亡。为了进一步研究ER应激在肌发生过程中的作用，我们将培养的成肌细胞在从增殖到分化的过渡过程中暴露于ER应激诱导剂。增加内质网应激增强分化相关的成肌细胞凋亡。我们发现，存活的成肌细胞有效地分化成收缩肌纤维，很少发现在文化。我们的观察结果表明，内质网应激对肌纤维形成产生积极影响，可能模仿体内驱动凋亡和分化的信号的作用。以前的研究表明，胰岛素样生长因子II（IGF-II）在培养基中分泌调节成肌细胞分化， ...更多信息 我们发现用ER应激诱导剂预处理后细胞外IGF-II的水平低于未经预处理的分化成肌细胞分泌的IGF-II。IGF-II水平较低至少部分是由于其合成减少。添加重组IGF-II的培养基几乎完全阻止分化成肌细胞的凋亡，有或没有预处理。细胞外IGF-II的水平可以通过IGF-II/甘露糖-6-磷酸（Man-6-P）受体的内化来调节。预处理后细胞外Man-6-P修饰的组织蛋白酶原B减少，这可能有助于IGF-II与其受体的结合。这些结果表明，用ER应激诱导剂预处理成肌细胞可减少IGF-II的合成，并通过IGF-II/Man-6-P受体增强细胞外IGF-II的内化。我们还发现凋亡细胞中Bc1-xL的水平低于增殖细胞和存活细胞。这一结果表明，负选择，Bcl-xL水平的基础上，专门在成肌细胞分化。少

Endoplasmic reticulum (ER) stress is caused by the accumulation of unfolded proteins in the ER, which occurs under a variety of conditions. We recently demonstrated that ER stress signaling occurs during myoblast differentiation in vivo. This signaling results in apoptosis in a subpopulation of myoblasts. To further examine the role of ER stress during myogenesis, we exposed cultured myoblasts to ER stress inducers during the transition from proliferation to differentiation. Increased ER stress enhanced differentiation-associated apoptosis of myoblasts. We found that the surviving myoblast cells efficiently differentiated into contracting myofibers that are rarely found in culture. Our observations suggest that ER stress exerts a positive effect on myofiber formation, possibly mimicking the action of signals that drive apoptosis and differentiation in vivo. Previous studies have revealed that insulin-like growth factor II (IGF-II) secreted in the medium regulates myoblast differentiati … More on. We found that levels of extracellular IGF-II after pretreatment with ER stress inducers were lower than those IGF-II secreted from differentiating myoblasts without pretreatment. The lower levels of IGF-II is at least partly due to a decrease in its synthesis. Addition of recombinant IGF-II to the medium nearly completely prevented apoptosis of differentiating myoblasts with or without pretreatment. The level of extracellular IGF-II can be modulated as a result of its internalization by the IGF-II/mannose-6-phosphate (Man-6-P) receptor. Extracellular Man-6-P-modified procathepsin B decreased after pretreatment that may facilitate the association of IGF-II and its receptor. These results suggest that pretreatment of myoblasts with ER stress inducers reduces IGF-II synthesis and enhances internalization of extracellular IGF-II by the IGF-II/Man-6-P receptor. We also found that the level of Bc1-xL in apoptotic cells was lower than that in proliferating cells and surviving cells. This result suggests that negative selection, based on Bcl-xL level, operates specifically during myoblast differentiation. Less