Loss of T‐type calcium channel (TCC) function has been reported to result in decreased cell viability and impaired muscle regeneration, but the underlying mechanisms remain largely unknown. We previously found that expression of TCC is reduced in aged pelvic floor muscle of multiple vaginal delivery mice, and this is related to endoplasmic reticulum stress (ERS) activation and autophagy flux blockade. In the present work, we further investigated the effects of TCC function loss on C2C12 myotubes and skeletal muscle, which is mediated by promotion of ERS and ultimately contributes to mitochondrial‐related apoptotic cell death. We found that application of a TCC inhibitor induced mitochondria‐related apoptosis in a dose‐dependent manner and also reduced mitochondrial transmembrane potential (MMP), induced mito‐ROS generation, and enhanced expression of mitochondrial apoptosis proteins. Functional inhibition of TCC induced ERS, resulting in disorder of Ca²⁺ homeostasis in endoplasmic reticulum, and ultimately leading to cell apoptosis in C2C12 myotubes. Tibialis anterior muscles of T‐type α1H channel knockout mice displayed a smaller skeletal muscle fiber size and elevated ERS‐mediated apoptosis signaling. Our data point to a novel mechanism whereby TCC blockade leads to ERS activation and terminal mitochondrial‐related apoptotic events in C2C12 myotubes and skeletal muscles.

中文翻译：

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T 型钙通道阻断通过内质网应激激活诱导 C2C12 肌管和骨骼肌细胞凋亡。

据报道，T 型钙通道 (TCC) 功能的丧失会导致细胞活力降低和肌肉再生受损，但其潜在机制仍然很大程度上未知。我们之前发现，多只阴道分娩小鼠的老年盆底肌肉中 TCC 的表达降低，这与内质网应激 (ERS) 激活和自噬通量阻断有关。在目前的工作中，我们进一步研究了 TCC 功能丧失对 C2C12 肌管和骨骼肌的影响，其通过促进 ERS ​​介导并最终导致线粒体相关的凋亡细胞死亡。我们发现 TCC 抑制剂的应用以剂量依赖性方式诱导线粒体相关的细胞凋亡，并且还降低了线粒体跨膜电位 (MMP)，诱导线粒体活性氧的产生，并增强线粒体凋亡蛋白的表达。功能性抑制 TCC 诱导的 ERS，导致 Ca 紊乱^{内质网中的2+}稳态，最终导致 C2C12 肌管中的细胞凋亡。T 型 α1H 通道敲除小鼠的胫骨前肌显示出更小的骨骼肌纤维尺寸和升高的 ERS ​​介导的细胞凋亡信号。我们的数据指出了一种新的机制，即 TCC 阻断导致 C2C12 肌管和骨骼肌中的 ERS ​​激活和末端线粒体相关的凋亡事件。