Joshi Aniket S, Castillo Micah B, Tomaz da Silva Meiricris, Vuong Anh Tuan, Gunaratne Preethi H, Darabi Radbod, Liu Yu, Kumar Ashok
Institute of Muscle Biology and Cachexia, University of Houston College of Pharmacy, Houston, TX 77204, USA.
Department of Pharmacological and Pharmaceutical Sciences, University of Houston College of Pharmacy, Houston, TX 77204, USA.
iScience. 2024 Nov 12;27(12):111372. doi: 10.1016/j.isci.2024.111372. eCollection 2024 Dec 20.
Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is activated in skeletal muscle under multiple conditions. However, the role of the UPR in the regulation of muscle regeneration remains less understood. We demonstrate that gene expression of various markers of the UPR is induced in both myogenic and non-myogenic cells in regenerating muscle. Genetic ablation of X-box binding protein 1 (XBP1), a downstream target of the Inositol requiring enzyme 1α (IRE1α) arm of the UPR, in myofibers attenuates muscle regeneration in adult mice. Single nucleus RNA sequencing (snRNA-seq) analysis showed that deletion of XBP1 in myofibers perturbs proteolytic systems and mitochondrial function in myogenic cells. Trajectory analysis of snRNA-seq dataset showed that XBP1 regulates the abundance of satellite cells and the formation of new myofibers in regenerating muscle. In addition, ablation of XBP1 disrupts the composition of non-myogenic cells in injured muscle microenvironment. Collectively, our study suggests that myofiber XBP1 regulates muscle regeneration through both cell-autonomous and -non-autonomous mechanisms.
内质网（ER）应激诱导的未折叠蛋白反应（UPR）在多种条件下的骨骼肌中被激活。然而，UPR在肌肉再生调节中的作用仍不太清楚。我们证明，再生肌肉中的成肌细胞和非成肌细胞中均诱导了UPR各种标志物的基因表达。在肌纤维中，UPR的肌醇需求酶1α（IRE1α）臂的下游靶点X盒结合蛋白1（XBP1）的基因缺失会减弱成年小鼠的肌肉再生。单核RNA测序（snRNA-seq）分析表明，肌纤维中XBP1的缺失会扰乱成肌细胞中的蛋白水解系统和线粒体功能。snRNA-seq数据集的轨迹分析表明，XBP1调节再生肌肉中卫星细胞的丰度和新肌纤维的形成。此外，XBP1的缺失会破坏受伤肌肉微环境中非成肌细胞的组成。总体而言，我们的研究表明，肌纤维XBP1通过细胞自主和非自主机制调节肌肉再生。
