Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Science, Southern Medical University, Guangzhou, 510515, China.
Department of Cell Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Cell Mol Biol Lett. 2023 Feb 27;28(1):15. doi: 10.1186/s11658-023-00429-w.
Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are involved in various muscle pathological states. The IRE1α arm of UPR can affect immunological properties of myofiber through restraining p38 mitogen-activated protein kinases (MAPK) activation under inflammatory milieu. However, the relevant pathway molecules regulating the initiation of the IRE1α arm in myofiber remain unclear. In this work, expression of transforming growth factor-beta (TGF-β) and TGF-β receptor II (TGF-βr2), and UPR pathway activation were examined in cardiotoxin (CTX)-damaged mouse muscle, which revealed the activation of TGF-β signaling and UPR in CTX-damaged muscle and in regenerating myofibers. Using control or transgenic mice with TGF-βr2 deleted in skeletal muscle (SM TGF-βr2) and the derived primary differentiating myogenic precursor cells (MPCs) treated with/without ERS activator or inhibitor, IRE1α pathway inhibitor, or TGF-β signaling activator, this study further revealed an essential role of intrinsic TGF-β signaling in regulating muscle cell to express inflammation-related molecules including H-2K, H2-Eα, TLR3, and special myokines. TGF-β signaling prompted UPR IRE1α arm and restrained p38 MAPK activation in myofiber under inflammatory milieu. This study uncovers a previously unrecognized function of TGF-β signaling acting as an upstream factor controlling myofiber immune capacities in the inflamed state through the UPR-IRE1α-p38 MAPK pathway.
内质网应激（ERS）和未折叠蛋白反应（UPR）参与多种肌肉病理状态。UPR 的 IRE1α 分支可以通过在炎症环境下抑制 p38 丝裂原活化蛋白激酶（MAPK）的激活来影响肌纤维的免疫特性。然而，调节肌纤维中 IRE1α 分支起始的相关途径分子尚不清楚。在这项工作中，研究了心脏毒素（CTX）损伤的小鼠肌肉中转化生长因子-β（TGF-β）和 TGF-β 受体 II（TGF-βr2）的表达以及 UPR 途径的激活情况，结果表明 TGF-β 信号和 UPR 在 CTX 损伤的肌肉和再生肌纤维中被激活。使用在骨骼肌中缺失 TGF-βr2 的对照或转基因小鼠（SM TGF-βr2）和经 ERS 激活剂或抑制剂、IRE1α 途径抑制剂或 TGF-β 信号激活剂处理的衍生原代分化肌前体细胞（MPCs），本研究进一步揭示了内在 TGF-β 信号在调节肌肉细胞表达炎症相关分子（包括 H-2K、H2-Eα、TLR3 和特殊肌因子）中的重要作用。TGF-β 信号促使 UPR IRE1α 分支在炎症环境下抑制肌纤维中 p38 MAPK 的激活。这项研究揭示了 TGF-β 信号作为一种上游因子的新功能，通过 UPR-IRE1α-p38 MAPK 途径控制炎症状态下肌纤维的免疫能力。
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