An AMPK/Axin1-Rac1 signaling pathway mediates contraction-regulated glucose uptake in skeletal muscle cells

Contraction stimulates skeletal muscle glucose uptake predominantly through activation of AMP-activated protein kinase (AMPK) and Rac1. However, the molecular details of how contraction activates these signaling proteins are not clear. Recently, Axin1 has been shown to form a complex with AMPK and l...

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Published in:American journal of physiology: endocrinology and metabolism 2020-03, Vol.318 (3), p.E330-E342
Main Authors: Yue, Yingying, Zhang, Chang, Zhang, Xuejiao, Zhang, Shitian, Liu, Qian, Hu, Fang, Lv, Xiaoting, Li, Hanqi, Yang, Jianming, Wang, Xinli, Chen, Liming, Yao, Zhi, Duan, Hongquan, Niu, Wenyan
Format: Article
Language:English
Subjects:
Activation
AMP
AMP-activated protein kinase
Axin1 protein
Gastrocnemius muscle
Glucose
Guanosine triphosphate
Kinases
Lysates
Muscle contraction
Muscles
Musculoskeletal system
Myotubes
p21-activated kinase
Phosphorylation
Proteins
Rac1 protein
Signal transduction
Signaling
siRNA
Skeletal muscle
Treadmills
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Summary:Contraction stimulates skeletal muscle glucose uptake predominantly through activation of AMP-activated protein kinase (AMPK) and Rac1. However, the molecular details of how contraction activates these signaling proteins are not clear. Recently, Axin1 has been shown to form a complex with AMPK and liver kinase B1 during glucose starvation-dependent activation of AMPK. Here, we demonstrate that electrical pulse-stimulated (EPS) contraction of C2C12 myotubes or treadmill exercise of C57BL/6 mice enhanced reciprocal coimmunoprecipitation of Axin1 and AMPK from myotube lysates or gastrocnemius muscle tissue. Interestingly, EPS or exercise upregulated total cellular Axin1 levels in an AMPK-dependent manner in C2C12 myotubes and gastrocnemius mouse muscle, respectively. Also, direct activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide treatment of C2C12 myotubes or gastrocnemius muscle elevated Axin1 protein levels. On the other hand, siRNA-mediated Axin1 knockdown lessened activation of AMPK in contracted myotubes. Further, AMPK inhibition with compound C or siRNA-mediated knockdown of AMPK or Axin1 blocked contraction-induced GTP loading of Rac1, p21-activated kinase phosphorylation, and contraction-stimulated glucose uptake. In summary, our results suggest that an AMPK/Axin1-Rac1 signaling pathway mediates contraction-stimulated skeletal muscle glucose uptake.
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00272.2019