Inducible deletion of skeletal muscle AMPKα reveals that AMPK is required for nucleotide balance but dispensable for muscle glucose uptake and fat oxidation during exercise
Inducible deletion of skeletal muscle AMPKα reveals that AMPK is required for nucleotide balance but dispensable for muscle glucose uptake and fat oxidation during exercise
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诱导缺失骨骼肌AMPKα表明AMPK在核苷酸平衡中是必需的，但在运动过程中肌肉葡萄糖摄取和脂肪氧化中是不必要的
DOI：
10.1016/j.molmet.2020.101028
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发表时间：
2020-10-01
影响因子：
8.1
通讯作者：
Wojtaszewski, Jorgen F. P.
中科院分区：
文献类型：
--
作者：
Hingst, Janne R.;Kjobsted, Rasmus;Wojtaszewski, Jorgen F. P.
目的：AMP激活蛋白激酶(AMPK)介导的运动中骨骼肌代谢调节的证据主要基于AMPK功能慢性(终生)中断的转基因小鼠模型。基于这类模型的研究结果可能会受到与慢性AMPK功能缺乏有关的次要影响的影响。为了研究AMPK对运动过程中肌肉代谢的直接影响(S)，我们建立了成年小鼠肌肉特异性AMPKα催化亚单位可诱导缺失的新模型。方法：采用CRE/loxP系统建立他莫昔芬诱导和肌肉特异性AMPKα1/α2双KO小鼠(AMPKαimdKO)，CRE由人骨骼肌肌动蛋白(HSA)启动子控制。结果：在相同的相对运动强度下，AMPKαimdKO小鼠表现出更大的肌肉ATP消耗，这与脱氨产物IMP的积累有关。成年小鼠肌肉特异性AMPKα的缺失迅速降低了最大跑步速度和肌肉糖原含量，并与糖原合成途径的关键成分UGP2的表达减少有关。成年小鼠肌肉中AMPKα亚基的特异性缺失不影响肌肉线粒体呼吸、全身底物利用以及肌肉收缩活动中的葡萄糖摄取和脂肪酸(FA)氧化。结论：AMPKα亚基的可诱导缺失揭示了AMPK在运动中维持肌肉ATP水平和核苷酸平衡所必需的，但对调节运动中肌肉葡萄糖摄取、FA氧化和底物利用是不必要的。(C)2020作者。由Elsevier GmbH出版。
Objective: Evidence for AMP-activated protein kinase (AMPK)-mediated regulation of skeletal muscle metabolism during exercise is mainly based on transgenic mouse models with chronic (lifelong) disruption of AMPK function. Findings based on such models are potentially biased by secondary effects related to a chronic lack of AMPK function. To study the direct effect(s) of AMPK on muscle metabolism during exercise, we generated a new mouse model with inducible muscle-specific deletion of AMPK alpha catalytic subunits in adult mice.Methods: Tamoxifen-inducible and muscle-specific AMPK alpha 1/alpha 2 double KO mice (AMPK alpha imdKO) were generated by using the Cre/loxP system, with the Cre under the control of the human skeletal muscle actin (HSA) promoter. Results: During treadmill running at the same relative exercise intensity, AMPK alpha imdKO mice showed greater depletion of muscle ATP, which was associated with accumulation of the deamination product IMP. Muscle-specific deletion of AMPK alpha in adult mice promptly reduced maximal running speed and muscle glycogen content and was associated with reduced expression of UGP2, a key component of the glycogen synthesis pathway. Muscle mitochondrial respiration, whole-body substrate utilization, and muscle glucose uptake and fatty acid (FA) oxidation during muscle contractile activity remained unaffected by muscle-specific deletion of AMPK alpha subunits in adult mice.Conclusions: Inducible deletion of AMPK alpha subunits in adult mice reveals that AMPK is required for maintaining muscle ATP levels and nucleotide balance during exercise but is dispensable for regulating muscle glucose uptake, FA oxidation, and substrate utilization during exercise. (C) 2020 The Authors. Published by Elsevier GmbH.