Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1

Wendt, Christian de; Espelage, Lena; Eickelschulte, Samaneh; Springer, Christian; Toska, Laura; Scheel, Anna; Bedou, Awovi Didi; Benninghoff, Tim; Cames, Sandra; Stermann, Torben; Chadt, Alexandra; Al-Hasani, Hadi

doi:10.2337/db21-0587

Cited by 21 publications

(20 citation statements)

References 53 publications

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“…AMPK activation occurs mainly through activation of the upstream liver kinase B1(kinase LKB1) through Thr172 phosphorylation of its catalytic domain in response to increased cellular AMP:ATP ratio ( Hawley et al, 2003 ; Woods et al, 2003 ). Activated AMPK inactivates its downstream target TBC1D1 ( Kramer et al, 2006 ; Treebak et al, 2006 ; Taylor et al, 2008 ; Ferrari et al, 2019 ; de Wendt et al, 2021 ) by phosphorylation (an interaction also known as “AMPK-TBC1D1 signaling nexus”; Chavez et al, 2008 ; Taylor et al, 2008 ; Vichaiwong et al, 2010 ; Treebak et al, 2014 ; Kjøbsted et al, 2016 ; Ferrari et al, 2019 ). TBC1D1 inactivation during exercise has been reported in mouse skeletal muscles ( Taylor et al, 2008 ; Vichaiwong et al, 2010 ; de Wendt et al, 2021 ) and in human skeletal muscles ( Jessen et al, 2011 ; Tobias et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…Activated AMPK inactivates its downstream target TBC1D1 ( Kramer et al, 2006 ; Treebak et al, 2006 ; Taylor et al, 2008 ; Ferrari et al, 2019 ; de Wendt et al, 2021 ) by phosphorylation (an interaction also known as “AMPK-TBC1D1 signaling nexus”; Chavez et al, 2008 ; Taylor et al, 2008 ; Vichaiwong et al, 2010 ; Treebak et al, 2014 ; Kjøbsted et al, 2016 ; Ferrari et al, 2019 ). TBC1D1 inactivation during exercise has been reported in mouse skeletal muscles ( Taylor et al, 2008 ; Vichaiwong et al, 2010 ; de Wendt et al, 2021 ) and in human skeletal muscles ( Jessen et al, 2011 ; Tobias et al, 2020 ). Activation of AMPK-TBC1D1 signaling nexus results in increased GLUT4 expression and translocation from the cytosol to the plasma membrane enabling increased glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

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Enhanced Oxygen Utilization Efficiency With Concomitant Activation of AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knockout Mice

2021

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We have previously reported in HEK 293 T cells and in constitutive cyclophilin-D (Cyp-D) knockout (KO) mice that Cyp-D ablation downregulates oxygen consumption (VO2) and triggers an adaptive response that manifest in higher exercise endurance with less VO2. This adaptive response involves a metabolic switch toward preferential utilization of glucose via AMPK-TBC1D1 signaling nexus. We now investigated whether a similar response could be triggered in mice after acute ablation of Cyp-D using tamoxifen-induced ROSA26-Cre-mediated (i.e., conditional KO, CKO) by subjecting them to treadmill exercise involving five running sessions. At their first treadmill running session, CKO mice and controls had comparable VO2 (208.4 ± 17.9 vs. 209.1 ± 16.8 ml/kg min−1), VCO2 (183.6 ± 17.2 vs. 184.8 ± 16.9 ml/kg min−1), and RER (0.88 ± 0.043 vs. 0.88 ± 0.042). With subsequent sessions, CKO mice displayed more prominent reduction in VO2 (genotype & session interaction p = 0.000) with less prominent reduction in VCO2 resulting in significantly increased RER (genotype and session interaction p = 0.013). The increase in RER was consistent with preferential utilization of glucose as respiratory substrate (4.6 ± 0.8 vs. 4.0 ± 0.9 mg/min, p = 0.003). CKO mice also performed a significantly higher treadmill work for given VO2 expressed as a power/VO2 ratio (7.4 ± 0.2 × 10−3 vs. 6.7 ± 0.2 10−3 ratio, p = 0.025). Analysis of CKO skeletal muscle tissue after completion of five treadmill running sessions showed enhanced AMPK activation (0.669 ± 0.06 vs. 0.409 ± 0.11 pAMPK/β-tubulin ratio, p = 0.005) and TBC1D1 inactivation (0.877 ± 0.16 vs. 0.565 ± 0.09 pTBC1D1/β-tubulin ratio, p < 0.05) accompanied by increased glucose transporter-4 levels consistent with activation of the AMPK-TBC1D1 signaling nexus enabling increased glucose utilization. Taken together, our study demonstrates that like constitutive Cyp-D ablation, acute Cyp-D ablation also induces a state of increased O2 utilization efficiency, paving the way for exploring the use of pharmacological approach to elicit the same response, which could be beneficial under O2 limiting conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhanced Oxygen Utilization Efficiency With Concomitant Activation of AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knockout Mice

2021

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“…Multiple upstream mechanisms including Rac1/actin and Ca 2+ /calmodulin-dependent protein kinase (CAMK) signaling are activated via muscle contraction [ 21 ]. These two signaling networks share downstream key proteins such as AMP-activated protein kinase (AMPK) and PI3K while also relying on novel targets such as TBC1D1/4 [ 22 , 23 ]. While GLUT4 is the most highly expressed glucose transport protein in skeletal muscle, there are other GLUT isoforms with physiological significance, notably GLUT1, which is constitutively present on the surface of skeletal muscle [ 24 ].…”

Section: Role Of Skeletal Muscle In Blood Glucose Regulationmentioning

confidence: 99%

Glucose Uptake by Skeletal Muscle within the Contexts of Type 2 Diabetes and Exercise: An Integrated Approach

2022

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Type 2 diabetes continues to negatively impact the health of millions. The inability to respond to insulin to clear blood glucose (insulin resistance) is a key pathogenic driver of the disease. Skeletal muscle is the primary tissue for maintaining glucose homeostasis through glucose uptake via insulin-dependent and -independent mechanisms. Skeletal muscle is also responsive to exercise-meditated glucose transport, and as such, exercise is a cornerstone for glucose management in people with type 2 diabetes. Skeletal muscle glucose uptake requires a concert of events. First, the glucose-rich blood must be transported to the skeletal muscle. Next, the glucose must traverse the endothelium, extracellular matrix, and skeletal muscle membrane. Lastly, intracellular metabolic processes must be activated to maintain the diffusion gradient to facilitate glucose transport into the cell. This review aims to examine the physiology at each of these steps in healthy individuals, analyze the dysregulation affecting these pathways associated with type 2 diabetes, and describe the mechanisms by which exercise acts to increase glucose uptake.

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“…Importantly, cytoskeletal rearrangements are critical events for insulin-stimulated glucose uptake in adipocytes and skeletal muscle. 41 Marcusohn reported that Rac1 does not participate in insulin signalling in adipocytes. 106 However, a recent finding of Balamatsias with co-workers 107 suggests that Rac1 is involved in glucose uptake in adipocytes.…”

Section: Mechanisms By Which the Rac1 Gene Polymorphisms May Contribu...mentioning

confidence: 99%

Association between RAC1 gene variation, redox homeostasis and type 2 diabetes mellitus

Azarova

Klyosova

Полоников

2022

Eur J Clin Investigation

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Background Increased production of reactive oxygen species (ROS) and oxidative stress are known to play a key role in the pathogenesis of type 2 diabetes (T2D); however, the relationship between genes encoding a multi‐subunit ROS‐generated enzyme NADPH oxidase and disease susceptibility remains unexplored. Aims The present pilot study investigated whether single‐nucleotide polymorphisms (SNP) at the RAC1 gene (Rac family small GTPase 1), a molecular switcher of NADPH oxidase, are associated with the risk of T2D, glucose metabolism and redox homeostasis. Materials & Methods DNA samples from 3206 unrelated Russian subjects (1579 T2D patients and 1627 controls) were genotyped for six common SNPs rs4724800, rs7784465, rs10951982, rs10238136, rs836478 and rs9374 of RAC1 using the MassArray‐4 system. Results SNP rs7784465 was associated with an increased risk of T2D (p = .0003), and significant differences in the RAC1 haplotypes occurred between the cases and controls (p = .005). Seventeen combinations of RAC1 genotypes showed significant associations with T2D risk (FDR <0.05). Associations of RAC1 polymorphisms with T2D were modified by environmental factors such as sedentary lifestyle, psychological stresses, a dietary deficit of fresh fruits/vegetables and increased carbohydrate intake. RAC1 polymorphisms were associated with biochemical parameters in diabetics: rs7784465 (p = .015) and rs836478 (p = .028) with increased glycated haemoglobin, rs836478 (p = .005) with increased fasting blood glucose, oxidized glutathione (p = .012) and uric acid (p = .034). Haplotype rs4724800A–rs7784465C–rs10951982G–rs10238136A–rs836478C–rs9374G was strongly associated with increased levels of hydrogen peroxide (p < .0001). Conclusion Thus, polymorphisms in the RAC1 gene represent novel genetic markers of type 2 diabetes, and their link with glucose metabolism and disease pathogenesis is associated with the changes in redox homeostasis.

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Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1

Cited by 21 publications

References 53 publications

Enhanced Oxygen Utilization Efficiency With Concomitant Activation of AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knockout Mice

Enhanced Oxygen Utilization Efficiency With Concomitant Activation of AMPK-TBC1D1 Signaling Nexus in Cyclophilin-D Conditional Knockout Mice

Glucose Uptake by Skeletal Muscle within the Contexts of Type 2 Diabetes and Exercise: An Integrated Approach

Association between RAC1 gene variation, redox homeostasis and type 2 diabetes mellitus

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