Life-and-death decisions of myoblast cells during differentiation

内质网应激是由内质网内未折叠蛋白的积累引起的，这种情况在多种条件下发生。我们最近证明了内质网应激信号在体内成肌细胞分化过程中发生。这种信号传导导致成肌细胞亚群中的细胞凋亡。为了进一步研究内质网应激在肌发生过程中的作用，我们将培养的成肌细胞暴露于内质网应激诱导剂中，使其从增殖过渡到分化。内质网应激增强成肌细胞分化相关凋亡。我们发现存活的成肌细胞能有效地分化成收缩肌纤维，这在培养中是很少发现的。我们的观察表明，内质网应激对肌纤维形成有积极影响，可能模仿体内驱动细胞凋亡和分化的信号的作用。先前的研究表明，培养基中分泌的胰岛素样生长因子II （IGF-II）调节成肌细胞的分化。我们发现内质网应激诱导剂预处理后的细胞外IGF-II水平低于未预处理的分化成肌细胞分泌的IGF-II水平。IGF-II水平较低至少部分是由于其合成减少。在培养基中添加重组IGF-II，无论预处理与否，几乎完全阻止分化成肌细胞的凋亡。细胞外IGF-II的水平可以通过IGF-II/甘露糖-6-磷酸（Man-6-P）受体内化而调节。预处理后细胞外man -6- p修饰的原athepsin B减少，这可能促进了IGF-II及其受体的关联。这些结果表明，用内质网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。Bc1-xL在凋亡细胞中的表达水平低于增殖细胞和存活细胞。这一结果表明，基于Bcl-xL水平的负选择在成肌细胞分化过程中特异性地起作用。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