Tianjin Key Laboratory of Exercise Physiology and Sports Medicine, School of Exercise and Health, Tianjin University of Sport, Tianjin, China.
Department of Military Training Medicines, Logistics University of Chinese People's Armed Police Force, Tianjin, China.
Front Endocrinol (Lausanne). 2023 Mar 16;14:1127524. doi: 10.3389/fendo.2023.1127524. eCollection 2023.
Skeletal muscle insulin resistance (IR) plays an important role in the pathogenesis of type 2 diabetes mellitus. Skeletal muscle is a heterogeneous tissue composed of different muscle fiber types that contribute distinctly to IR development. Glucose transport shows more protection in slow-twitch muscles than in fast-twitch muscles during IR development, while the mechanisms involved remain unclear. Therefore, we investigated the role of the mitochondrial unfolded protein response (UPRmt) in the distinct resistance of two types of muscle in IR.
Male Wistar rats were divided into high-fat diet (HFD) feeding and control groups. We measured glucose transport, mitochondrial respiration, UPRmt and histone methylation modification of UPRmt-related proteins to examine the UPRmt in the slow fiber-enriched soleus (Sol) and fast fiber-enriched tibialis anterior (TA) under HFD conditions.
Our results indicate that 18 weeks of HFD can cause systemic IR, while the disturbance of Glut4-dependent glucose transport only occurred in fast-twitch muscle. The expression levels of UPRmt markers, including ATF5, HSP60 and ClpP, and the UPRmt-related mitokine MOTS-c were significantly higher in slow-twitch muscle than in fast-twitch muscle under HFD conditions. Mitochondrial respiratory function is maintained only in slow-twitch muscle. Additionally, in the Sol, histone methylation at the ATF5 promoter region was significantly higher than that in the TA after HFD feeding.
The expression of proteins involved in glucose transport in slow-twitch muscle remains almost unaltered after HFD intervention, whereas a significant decline of these proteins was observed in fast-twitch muscle. Specific activation of the UPRmt in slow-twitch muscle, accompanied by higher mitochondrial respiratory function and MOTS-c expression, may contribute to the higher resistance to HFD in slow-twitch muscle. Notably, the different histone modifications of UPRmt regulators may underlie the specific activation of the UPRmt in different muscle types. However, future work applying genetic or pharmacological approaches should further uncover the relationship between the UPRmt and insulin resistance.
骨骼肌胰岛素抵抗（IR）在 2 型糖尿病的发病机制中起着重要作用。骨骼肌是一种异质性组织，由不同的肌纤维类型组成，这些类型对 IR 的发展有明显的贡献。在 IR 发展过程中，葡萄糖转运在慢肌纤维中比在快肌纤维中表现出更多的保护，而涉及的机制尚不清楚。因此，我们研究了线粒体未折叠蛋白反应（UPRmt）在两种类型肌肉对 IR 不同抗性中的作用。
雄性 Wistar 大鼠分为高脂肪饮食（HFD）喂养组和对照组。我们测量了葡萄糖转运、线粒体呼吸、UPRmt 和 UPRmt 相关蛋白的组蛋白甲基化修饰，以检查 HFD 条件下富含慢肌纤维的比目鱼肌（Sol）和富含快肌纤维的胫骨前肌（TA）中的 UPRmt。
我们的结果表明，18 周的 HFD 可以导致全身 IR，而 Glut4 依赖性葡萄糖转运的紊乱仅发生在快肌纤维中。在 HFD 条件下，慢肌纤维中 UPRmt 标志物，包括 ATF5、HSP60 和 ClpP 以及 UPRmt 相关的促肌因子 MOTS-c 的表达水平明显高于快肌纤维。只有在慢肌纤维中维持线粒体呼吸功能。此外，在 Sol 中，HFD 喂养后 ATF5 启动子区域的组蛋白甲基化明显高于 TA。
在 HFD 干预后，慢肌纤维中参与葡萄糖转运的蛋白质表达几乎不变，而快肌纤维中这些蛋白质的表达明显下降。慢肌纤维中 UPRmt 的特异性激活，伴随着更高的线粒体呼吸功能和 MOTS-c 的表达，可能导致慢肌纤维对 HFD 的更高抗性。值得注意的是，UPRmt 调节因子的不同组蛋白修饰可能是不同肌肉类型中 UPRmt 特异性激活的基础。然而，应用遗传或药理学方法的未来工作应该进一步揭示 UPRmt 与胰岛素抵抗之间的关系。
