Department of Exercise and Health Sciences, College of Nursing and Health Sciences, University of Massachusetts Boston, Boston, MA, USA.
School of Sports Medicine and Health, Chengdu Sport Institute, Chengdu, China.
Physiol Rep. 2021 Apr;9(7):e14808. doi: 10.14814/phy2.14808.
Dynamin-related protein-1 (Drp1) is a key regulator in mitochondrial fission. Excessive Drp1-mediated mitochondrial fission in skeletal muscle under the obese condition is associated with impaired insulin action. However, it remains unknown whether pharmacological inhibition of Drp1, using the Drp1-specific inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), is effective in alleviating skeletal muscle insulin resistance and improving whole-body metabolic health under the obese and insulin-resistant condition. We subjected C57BL/6J mice to a high-fat diet (HFD) or low-fat diet (LFD) for 5-weeks. HFD-fed mice received Mdivi-1 or saline injections for the last week of the diet intervention. Additionally, myotubes derived from obese insulin-resistant humans were treated with Mdivi-1 or saline for 12 h. We measured glucose area under the curve (AUC) from a glucose tolerance test (GTT), skeletal muscle insulin action, mitochondrial dynamics, respiration, and H O content. We found that Mdivi-1 attenuated impairments in skeletal muscle insulin signaling and blood glucose AUC from a GTT induced by HFD feeding (p < 0.05). H O content was elevated in skeletal muscle from the HFD group (vs. LFD, p < 0.05), but was reduced with Mdivi-1 treatment, which may partially explain the improvement in skeletal muscle insulin action. Similarly, Mdivi-1 enhanced the mitochondrial network structure, reduced reactive oxygen species, and improved insulin action in myotubes from obese humans (vs. saline, p < 0.05). In conclusion, inhibiting Drp1 with short-term Mdivi-1 administration attenuates the impairment in skeletal muscle insulin signaling and improves whole-body glucose tolerance in the setting of obesity-induced insulin resistance. Targeting Drp1 may be a viable approach to treat obesity-induced insulin resistance.
动力相关蛋白 1（Drp1）是线粒体裂变的关键调节因子。肥胖状态下骨骼肌中过多的 Drp1 介导的线粒体裂变与胰岛素作用受损有关。然而，尚不清楚使用 Drp1 特异性抑制剂线粒体分裂抑制剂 1（Mdivi-1）抑制 Drp1 是否能有效缓解肥胖和胰岛素抵抗状态下骨骼肌胰岛素抵抗并改善整体代谢健康。我们使 C57BL/6J 小鼠接受高脂肪饮食（HFD）或低脂饮食（LFD）5 周。HFD 喂养的小鼠在饮食干预的最后一周接受 Mdivi-1 或生理盐水注射。此外，来自肥胖胰岛素抵抗患者的肌管用 Mdivi-1 或生理盐水处理 12 小时。我们测量了葡萄糖耐量试验（GTT）的葡萄糖曲线下面积（AUC）、骨骼肌胰岛素作用、线粒体动力学、呼吸和 H 2 O 含量。我们发现 Mdivi-1 减轻了 HFD 喂养引起的骨骼肌胰岛素信号和 GTT 血糖 AUC 的损伤（p<0.05）。H 2 O 含量在 HFD 组的骨骼肌中升高（与 LFD 相比，p<0.05），但用 Mdivi-1 处理后降低，这可能部分解释了骨骼肌胰岛素作用的改善。同样，Mdivi-1 增强了肌管的线粒体网络结构，减少了活性氧，并改善了肥胖患者肌管的胰岛素作用（与生理盐水相比，p<0.05）。总之，短期用 Mdivi-1 抑制 Drp1 可减轻肥胖诱导的胰岛素抵抗状态下骨骼肌胰岛素信号的损伤，并改善全身葡萄糖耐量。靶向 Drp1 可能是治疗肥胖诱导的胰岛素抵抗的一种可行方法。
