Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1

被引:22
作者
de Wendt, Christian [1 ,2 ]
Espelage, Lena [1 ,2 ]
Eickelschulte, Samaneh [1 ,2 ]
Springer, Christian [1 ,2 ]
Toska, Laura [1 ]
Scheel, Anna [1 ,2 ]
Bedou, Awovi Didi [1 ,2 ]
Benninghoff, Tim [1 ]
Cames, Sandra [1 ]
Stermann, Torben [1 ]
Chadt, Alexandra [1 ,2 ]
Al-Hasani, Hadi [1 ,2 ]
机构
[1] Heinrich Heine Univ Dusseldorf, German Diabet Ctr DDZ, Inst Clin Biochem & Pathobiochem, Leibniz Ctr Diabet Res, Dusseldorf, Germany
[2] German Ctr Diabet Res DZD, Partner Dusseldorf, Munich, Germany
关键词
ACTIVATED PROTEIN-KINASE; FATTY-ACID OXIDATION; GLUT4; TRANSLOCATION; INSULIN-RESISTANCE; EXERCISE; AICAR; MICE; KNOCKOUT; AS160; PHOSPHORYLATION;
D O I
10.2337/db21-0587
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The two closely related RabGTPase-activating proteins (RabGAPs) TBC1D1 and TBC1D4, both substrates for AMPK, play important roles in exercise metabolism and contraction-dependent translocation of GLUT4 in skeletal muscle. However, the specific contribution of each RabGAP in contraction signaling is mostly unknown. In this study, we investigated the cooperative AMPK-RabGAP signaling axis in the metabolic response to exercise/contraction using a novel mouse model deficient in active skeletal muscle AMPK combined with knockout of either Tbc1d1, Tbc1d4, or both RabGAPs. AMPK deficiency in muscle reduced treadmill exercise performance. Additional deletion of Tbc1d1 but not Tbc1d4 resulted in a further decrease in exercise capacity. In oxidative soleus muscle, AMPK deficiency reduced contraction-mediated glucose uptake, and deletion of each or both RabGAPs had no further effect. In contrast, in glycolytic extensor digitorum longus muscle, AMPK deficiency reduced contraction-stimulated glucose uptake, and deletion of Tbc1d1, but not Tbc1d4, led to a further decrease. Importantly, skeletal muscle deficient in AMPK and both RabGAPs still exhibited residual contraction-mediated glucose uptake, which was completely abolished by inhibition of the GTPase Rac1. Our results demonstrate a novel mechanistic link between glucose transport and the GTPase signaling framework in skeletal muscle in response to contraction.
引用
收藏
页码:2796 / 2809
页数:14
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