Journal
FASEB JOURNAL
Volume 35, Issue 2, Pages -Publisher
WILEY
DOI: 10.1096/fj.202001312R
Keywords
AMPK; glucose uptake; muscle contraction; Rac1; Tiam1
Categories
Funding
- National Natural Science Foundation of China [81670731, 81870547, 81170740, 81161120545]
- Tianjin Municipal Science and Technology Commission [15JCZDJC35500]
- Tianjin Municipal Education Commission [2019ZD028]
- Tianjin Health and Family Planning Commission [15KG102]
- Scientific Research Funding of Tianjin Medical University Chu Hsien-I Memorial Hospital [608]
- Tianjin Research Innovation Project for Postgraduate Students [2019YJSB101]
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Research has shown that Tiam1 protein is part of an AMPK-Tiam1-Rac1 signaling pathway that mediates contraction-stimulated glucose uptake in skeletal muscle cells and tissue.
Contraction-stimulated glucose uptake in skeletal muscle requires Rac1, but the molecular mechanism of its activation is not fully understood. Treadmill running was applied to induce C57BL/6 mouse hind limb skeletal muscle contraction in vivo and electrical pulse stimulation contracted C2C12 myotube cultures in vitro. The protein levels or activities of AMPK or the Rac1-specific GEF, Tiam1, were manipulated by activators, inhibitors, siRNA-mediated knockdown, and adenovirus-mediated expression. Activated Rac1 was detected by a pull-down assay and immunoblotting. Glucose uptake was measured using the 2-NBD-glucose fluorescent analog. Electrical pulse stimulated contraction or treadmill exercise upregulated the expression of Tiam1 in skeletal muscle in an AMPK-dependent manner. Axin1 siRNA-mediated knockdown diminished AMPK activation and upregulation of Tiam1 protein expression by contraction. Tiam1 siRNA-mediated knockdown diminished contraction-induced Rac1 activation, GLUT4 translocation, and glucose uptake. Contraction increased Tiam1 gene expression and serine phosphorylation of Tiam1 protein via AMPK. These findings suggest Tiam1 is part of an AMPK-Tiam1-Rac1 signaling pathway that mediates contraction-stimulated glucose uptake in skeletal muscle cells and tissue.
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