State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China.
Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing 210006, China.
Clin Sci (Lond). 2020 Sep 18;134(17):2381-2398. doi: 10.1042/CS20191320.
Skeletal muscle is responsible for the majority of glucose disposal in the body. Insulin resistance in the skeletal muscle accounts for 85-90% of the impairment of total glucose disposal in patients with type 2 diabetes (T2D). However, the mechanism remains controversial. The present study aims to investigate whether AKT2 deficiency causes deficits in skeletal muscle development and metabolism, we analyzed the expression of molecules related to skeletal muscle development, glucose uptake and metabolism in mice of 3- and 8-months old. We found that AMP-activated protein kinase (AMPK) phosphorylation and myocyte enhancer factor 2 (MEF2) A (MEF2A) expression were down-regulated in AKT2 knockout (KO) mice, which can be inverted by AMPK activation. We also observed reduced mitochondrial DNA (mtDNA) abundance and reduced expression of genes involved in mitochondrial biogenesis in the skeletal muscle of AKT2 KO mice, which was prevented by AMPK activation. Moreover, AKT2 KO mice exhibited impaired AMPK signaling in response to insulin stimulation compared with WT mice. Our study establishes a new and important function of AKT2 in regulating skeletal muscle development and glucose metabolism via AMPK-dependent signaling.
骨骼肌负责身体内大部分葡萄糖的摄取。在 2 型糖尿病（T2D）患者中，骨骼肌的胰岛素抵抗导致总葡萄糖摄取受损的 85-90%。然而，其机制仍存在争议。本研究旨在探讨 AKT2 缺乏是否导致骨骼肌发育和代谢缺陷，我们分析了 3 月龄和 8 月龄 AKT2 敲除（KO）小鼠骨骼肌中与骨骼肌发育、葡萄糖摄取和代谢相关分子的表达。我们发现 AKT2 KO 小鼠的 AMP 激活蛋白激酶（AMPK）磷酸化和肌细胞增强因子 2A（MEF2A）表达下调，这可以通过 AMPK 激活来逆转。我们还观察到 AKT2 KO 小鼠骨骼肌中线粒体 DNA（mtDNA）丰度降低，参与线粒体生物发生的基因表达减少，而 AMPK 激活可预防这种情况。此外，与 WT 小鼠相比，AKT2 KO 小鼠对胰岛素刺激的 AMPK 信号转导反应受损。我们的研究确立了 AKT2 通过 AMPK 依赖性信号转导在调节骨骼肌发育和葡萄糖代谢方面的新的和重要功能。
