Qiaoli Chen1, Bingxian Xie1, Sangsang Zhu1, Ping Rong1, Yang Sheng1, Serge Ducommun2, Liang Chen1, Chao Quan1, Min Li1, Kei Sakamoto2, Carol MacKintosh3, Shuai Chen4,5, Hong Yu Wang6,7. 1. MOE Key Laboratory of Model Animal for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Pukou District, Nanjing, 210061, China. 2. Nestlé Institute of Health Sciences SA, Campus EPFL, Quartier de l'Innovation, Bâtiment G, Lausanne, Switzerland. 3. Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, Scotland, UK. 4. MOE Key Laboratory of Model Animal for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Pukou District, Nanjing, 210061, China. schen6@163.com. 5. Collaborative Innovation Center of Genetics and Development, Shanghai, China. schen6@163.com. 6. MOE Key Laboratory of Model Animal for Disease Study and State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Pukou District, Nanjing, 210061, China. wanghy@nicemice.cn. 7. Collaborative Innovation Center of Genetics and Development, Shanghai, China. wanghy@nicemice.cn.
Abstract
AIMS/HYPOTHESIS: TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab GTPase-activating protein (RabGAP) that has been implicated in regulating GLUT4 trafficking. TBC1D1 can be phosphorylated by the AMP-activated protein kinase (AMPK) on Ser231, which consequently interacts with 14-3-3 proteins. Given the key role for AMPK in regulating insulin-independent muscle glucose uptake, we hypothesised that TBC1D1-Ser231 phosphorylation and/or 14-3-3 binding may mediate AMPK-governed glucose homeostasis. METHODS: Whole-body glucose homeostasis and muscle glucose uptake were assayed in mice bearing a Tbc1d1 Ser231Ala-knockin mutation or harbouring skeletal muscle-specific Ampkα1/α2 (also known as Prkaa1/2) double-knockout mutations in response to an AMPK-activating agent, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Exercise-induced muscle glucose uptake and exercise capacity were also determined in the Tbc1d1 Ser231Ala-knockin mice. RESULTS: Skeletal muscle-specific deletion of Ampkα1/a2 in mice prevented AICAR-induced hypoglycaemia and muscle glucose uptake. The Tbc1d1 Ser231Ala-knockin mutation also attenuated the glucose-lowering effect of AICAR in mice. Glucose uptake and cell surface GLUT4 content were significantly lower in muscle isolated from the Tbc1d1 Ser231Ala-knockin mice upon stimulation with a submaximal dose of AICAR. However, this Tbc1d1 Ser231Ala-knockin mutation neither impaired exercise-induced muscle glucose uptake nor affected exercise capacity in mice. CONCLUSIONS/ INTERPRETATION: TBC1D1-Ser231 phosphorylation and/or 14-3-3 binding partially mediates AMPK-governed glucose homeostasis and muscle glucose uptake in a context-dependent manner.
AIMS/HYPOTHESIS: TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab GTPase-activating protein (RabGAP) that has been implicated in regulating GLUT4 trafficking. TBC1D1 can be phosphorylated by the AMP-activated protein kinase (AMPK) on Ser231, which consequently interacts with 14-3-3 proteins. Given the key role for AMPK in regulating insulin-independent muscle glucose uptake, we hypothesised that TBC1D1-Ser231 phosphorylation and/or 14-3-3 binding may mediate AMPK-governed glucose homeostasis. METHODS: Whole-body glucose homeostasis and muscle glucose uptake were assayed in mice bearing a Tbc1d1Ser231Ala-knockin mutation or harbouring skeletal muscle-specific Ampkα1/α2 (also known as Prkaa1/2) double-knockout mutations in response to an AMPK-activating agent, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Exercise-induced muscle glucose uptake and exercise capacity were also determined in the Tbc1d1Ser231Ala-knockin mice. RESULTS: Skeletal muscle-specific deletion of Ampkα1/a2 in mice prevented AICAR-induced hypoglycaemia and muscle glucose uptake. The Tbc1d1Ser231Ala-knockin mutation also attenuated the glucose-lowering effect of AICAR in mice. Glucose uptake and cell surface GLUT4 content were significantly lower in muscle isolated from the Tbc1d1Ser231Ala-knockin mice upon stimulation with a submaximal dose of AICAR. However, this Tbc1d1Ser231Ala-knockin mutation neither impaired exercise-induced muscle glucose uptake nor affected exercise capacity in mice. CONCLUSIONS/ INTERPRETATION:TBC1D1-Ser231 phosphorylation and/or 14-3-3 binding partially mediates AMPK-governed glucose homeostasis and muscle glucose uptake in a context-dependent manner.
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