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TBC1D4-S711 controls skeletal muscle insulin sensitization after exercise and contraction
Diabetes ( IF 7.7 ) Pub Date : 2023-04-19 , DOI: 10.2337/db22-0666
Rasmus Kjøbsted 1 , Jonas M Kristensen 1 , Nicolas O Eskesen 1 , Kohei Kido 1 , Klara Fjorder 1 , Ditte F Damgaard 1 , Jeppe K Larsen 1, 2 , Nicoline R Andersen 1 , Jesper B Birk 1 , Anders Gudiksen 3 , Jonas T Treebak 2 , Peter Schjerling 4, 5 , Henriette Pilegaard 3 , Jørgen F P Wojtaszewski 1
Affiliation  

The ability of insulin to stimulate glucose uptake in skeletal muscle is important for whole-body glycemic control. Insulin-stimulated skeletal muscle glucose uptake is improved in the period after a single bout of exercise and accumulating evidence suggests that phosphorylation of TBC1D4 by the protein kinase AMPK is the primary mechanism responsible for this phenomenon. To investigate this, we generated a TBC1D4 knock-in mouse model with a serine-to-alanine point mutation at residue 711 that is phosphorylated in response to both insulin and AMPK activation. Female TBC1D4-S711A mice exhibited normal growth and eating behavior as well as intact wholebody glycemic control on chow and high-fat diets. Moreover, muscle contraction increased glucose uptake, glycogen utilization and AMPK activity similarly in wild-type and TBC1D4-S711A mice. In contrast, improvements in whole-body and muscle insulin sensitivity after exercise and contractions were only evident in wild-type mice and occurred concomitantly with enhanced phosphorylation of TBC1D4-S711. These results provide genetic evidence to support that TBC1D4-S711 serves as a major point of convergence for AMPK- and insulin-induced signaling that mediates the insulin-sensitizing effect of exercise and contractions on skeletal muscle glucose uptake.

中文翻译:

TBC1D4-S711 控制运动和收缩后骨骼肌胰岛素敏感性

胰岛素刺激骨骼肌葡萄糖摄取的能力对于全身血糖控制很重要。胰岛素刺激的骨骼肌葡萄糖摄取在单次运动后得到改善,越来越多的证据表明,蛋白激酶 AMPK 对 TBC1D4 的磷酸化是造成这种现象的主要机制。为了研究这一点,我们构建了 TBC1D4 敲入小鼠模型,该模型在残基 711 处具有丝氨酸至丙氨酸点突变,该突变响应胰岛素和 AMPK 激活而磷酸化。雌性 TBC1D4-S711A 小鼠表现出正常的生长和饮食行为,以及对食物和高脂肪饮食的完整全身血糖控制。此外,在野生型和 TBC1D4-S711A 小鼠中,肌肉收缩增加了葡萄糖摄取、糖原利用率和 AMPK 活性。相比之下,运动和收缩后全身和肌肉胰岛素敏感性的改善仅在野生型小鼠中明显,并且伴随着 TBC1D4-S711 磷酸化的增强。这些结果提供了遗传证据,支持 TBC1D4-S711 是 AMPK 和胰岛素诱导信号的主要汇聚点,介导运动和收缩对骨骼肌葡萄糖摄取的胰岛素增敏作用。
更新日期:2023-04-19
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