改善胰岛素耐药性:针对骨肌肉线粒体功能所需的新型PAK1信号通路
Rekha Balakrishnan1, Pablo A Garcia1, Rajakrishnan Veluthakal1
1Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Beckman Research Institute, 1500 E Duarte Road, Duarte, CA 91010, USA.
Antioxidants (Basel, Switzerland)
|September 28, 2023
概括
激活p21激酶1 (PAK1) 调节骨肌肉的线粒体功能和胰岛素敏感性. PAK1的枯竭会损害线粒体呼吸和PGC1α的表达,而其丰富会改善这些功能,这表明PAK1是p38MAPK/ATF2/PGC1α通路的上游.
科学领域:
- 细胞生物学 细胞生物学
- 代谢过程中的代谢.
- 分子生物学分子生物学
背景情况:
- 21激活激酶1 (PAK1) 对于胰岛素刺激的骨肌肉中的葡萄糖吸收至关重要.
- 在调节骨肌肉线粒体功能的PAK1的作用,胰岛素敏感性的关键因素,仍然不清楚.
研究的目的:
- 为了研究调节PAK1对骨肌细胞中线粒体功能的影响.
- 阐明通过PAK1影响线粒体生物发生和氧化代谢的信号通路.
主要方法:
- 在老鼠L6.GLUT4myc和人类LHCN-M2神经管中使用siRNA (敲击) 和腺病毒转导 (过度表达) 来调节PAK1水平.
- 评估了线粒体功能,包括副本数和呼吸.
- 分析了PGC1α,p38MAPK和ATF2的表达.
- 实验包括胰岛素耐药肌管和人类2型糖尿病 (T2D) 和非糖尿病 (ND) 骨肌样本.
主要成果:
- 由于PAK1的枯竭,线粒体拷贝数,呼吸和PGC1α的表达,以及其激活剂p38MAPK和ATF2.2,都降低了.
- 在抗胰岛素肌管中PAK1丰富改善了线粒体功能,并恢复了PGC1α水平.
- 当p38MAPK被抑制时,PAK1活性局部化到细胞质,其丰富并没有挽救PGC1α水平.
- 人类T2D样本显示PGC1α减少,人体肌管中PAK1耗尽减少了线粒体呼吸.
结论:
- PAK1在调节骨肌肉线粒体功能方面发挥着重要作用.
- PAK1在p38MAPK/ATF2/PGC1α通路上游作用,控制线粒体生物发生和氧化代谢.
- 调节PAK1活性可能是改善2型糖尿病等疾病中的胰岛素敏感性的治疗点.
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