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

Abstract

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.

• Authors: Yingying Yue, Chang Zhang, Xuejiao Zhang, Shitian Zhang, Qian Liu, Fang Hu, Xiaoting Lv, Hanqi Li, Jianming Yang, Xinli Wang, Liming Chen, Zhi Yao, Hongquan Duan, Wenyan Niu
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 318 Issue 3 Pg. E330-E342 (03 01 2020) ISSN: 1522-1555 [Electronic] United States
• PMID: 31846370 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Axin Protein
• Axin1 protein, mouse
• Neuropeptides
• RNA, Small Interfering
• Rac1 protein, mouse
• AMP-Activated Protein Kinases
• rac1 GTP-Binding Protein
• Glucose

Topics

• AMP-Activated Protein Kinases (genetics, physiology)
• Animals
• Axin Protein (genetics, physiology)
• Cell Line
• Electric Stimulation
• Gene Knockdown Techniques
• Glucose (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Muscle Contraction (physiology)
• Muscle Fibers, Skeletal (metabolism, physiology)
• Neuropeptides (genetics, physiology)
• RNA, Small Interfering (pharmacology)
• Signal Transduction (genetics, physiology)
• rac1 GTP-Binding Protein (genetics, physiology)