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

Author:

Yue Yingying123,Zhang Chang1234,Zhang Xuejiao123,Zhang Shitian123,Liu Qian123,Hu Fang123,Lv Xiaoting123,Li Hanqi123,Yang Jianming123,Wang Xinli123,Chen Liming123,Yao Zhi123,Duan Hongquan4,Niu Wenyan123

Affiliation:

1. Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Ministry of Education, Tianjin Medical University, Tianjin, China

2. NHC Key Laboratory of Hormones and Development, Tianjin Medical University, Tianjin, China

3. Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China

4. School of Pharmacy, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China

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.

Funder

National Natural Science Foundation of China

Tianjin Municipal Science and Technology Commission

Tianjin Health and Family Planning Commission

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

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