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

Yue, Yingying; Zhang, Chang; Zhang, Xuejiao; Zhang, Shitian; Liu, Qian; Hu, Fang; Lv, Xiaoting; Li, Hanqi; Yang, Jianming; Wang, Xinli; Chen, Liming; Yao, Zhi; Duan, Hong‐Quan; Niu, Wenyan

doi:10.1152/ajpendo.00272.2019

Cited by 21 publications

(49 citation statements)

References 38 publications

(81 reference statements)

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“…A recent study reported that AMPK activation by electrical stimulation in C2C12 myotubes and exercise in mouse gastrocnemius muscle stimulated AXIN1‐dependent GTP‐loading of the small GTPase Rac1, GLUT4 translocation and glucose uptake (Yue et al . 2020). Furthermore, insulin‐stimulated stabilization of AXIN1 may be required for insulin‐dependent kinesin KIF3A‐mediated GLUT4 translocation in 3T3‐L1 adipocytes and C2C12 muscle cells (Guo et al .…”

Section: Introductionmentioning

confidence: 99%

AXIN1 knockout does not alter AMPK/mTORC1 regulation and glucose metabolism in mouse skeletal muscle

Knudsen

Henríquez‐Olguín

et al. 2021

The Journal of Physiology

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Key points Tamoxifen‐inducible skeletal muscle‐specific AXIN1 knockout (AXIN1 imKO) in mouse does not affect whole‐body energy substrate metabolism. AXIN1 imKO does not affect AICAR or insulin‐stimulated glucose uptake in adult skeletal muscle. AXIN1 imKO does not affect adult skeletal muscle AMPK or mTORC1 signalling during AICAR/insulin/amino acid incubation, contraction and exercise. During exercise, α2/β2/γ3AMPK and AMP/ATP ratio show greater increases in AXIN1 imKO than wild‐type in gastrocnemius muscle. Abstract AXIN1 is a scaffold protein known to interact with >20 proteins in signal transduction pathways regulating cellular development and function. Recently, AXIN1 was proposed to assemble a protein complex essential to catabolic‐anabolic transition by coordinating AMPK activation and inactivation of mTORC1 and to regulate glucose uptake‐stimulation by both AMPK and insulin. To investigate whether AXIN1 is permissive for adult skeletal muscle function, a phenotypic in vivo and ex vivo characterization of tamoxifen‐inducible skeletal muscle‐specific AXIN1 knockout (AXIN1 imKO) mice was conducted. AXIN1 imKO did not influence AMPK/mTORC1 signalling or glucose uptake stimulation at rest or in response to different exercise/contraction protocols, pharmacological AMPK activation, insulin or amino acids stimulation. The only genotypic difference observed was in exercising gastrocnemius muscle, where AXIN1 imKO displayed elevated α2/β2/γ3 AMPK activity and AMP/ATP ratio compared to wild‐type mice. Our work shows that AXIN1 imKO generally does not affect skeletal muscle AMPK/mTORC1 signalling and glucose metabolism, probably due to functional redundancy of its homologue AXIN2.

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Section: Introductionmentioning

confidence: 99%

AXIN1 knockout does not alter AMPK/mTORC1 regulation and glucose metabolism in mouse skeletal muscle

Knudsen

Henríquez‐Olguín

et al. 2021

The Journal of Physiology

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“…Contractions were induced by electrical stimulation every 15 sec with 2-sec trains of 0.2 msec pulses delivered at 100 Hz (∼35V) for 15 minutes. 2DG transport was measured together with 1 mM 2DG during the last 10 min of the contraction stimulation period using 0.60-0.75 µCi mL -1 [ 3 H]-2DG and 0.180-0.225 µCi mL -1 [ 14 C]-mannitol radioactive tracers (Perkin Elmer) as described previously 31 . Tissue-specific [ 3 H]-2DG accumulation with [ 14 C]-mannitol as an extracellular marker was determined as previously described 32 .…”

Section: Methodsmentioning

confidence: 99%

“…Redundant Ca +2 -dependent signalling, metabolic stress signalling, and mechanical stress signalling are proposed to regulate distinct steps important for glucose transport in response to muscle contraction 12 . The group I p21-activated kinase (PAK)-1 and PAK2 are activated in response to electrical pulse stimulation in C2C12 myotubes 13,14 and muscle contraction/acute exercise in mouse and human skeletal muscle 15 . Group I PAKs (PAK1-3) are downstream targets of the Rho family GTPases Cdc42 and Rac1 16 .…”

Section: Introductionmentioning

confidence: 99%

The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

Llv

Nielsen

et al. 2020

Preprint

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20Aim: Muscle contraction stimulates skeletal muscle glucose transport. Since it occurs inde-21 pendently of insulin, it is an important alternative pathway to increase glucose uptake in insu-22 lin-resistant states, but the intracellular signalling mechanisms are not fully understood. Muscle 23 contraction activates group I p21-activated kinases (PAKs) in mouse and human skeletal mus-24 cle. PAK1 and PAK2 are downstream targets of Rac1, which is a key regulator of contraction-25 stimulated glucose transport. Thus, PAK1 and PAK2 could be downstream effectors of Rac1 26 in contraction-stimulated glucose transport. The current study aimed to test the hypothesis that 27 PAK1 and/or PAK2 regulate contraction-induced glucose transport. Methods: Glucose 28 transport was measured in isolated soleus and extensor digitorum longus (EDL) mouse skeletal 29 muscle incubated either in the presence or absence of a pharmacological inhibitor (IPA-3) of 30 group I PAKs or originating from whole-body PAK1 knockout (KO), muscle-specific PAK2 31 (m)KO or double whole-body PAK1 and muscle-specific PAK2 knockout mice. Results: IPA-32 3 attenuated (-22%) the increase in muscle glucose transport in response to electrically-stimu-33 lated contraction. PAK1 was dispensable for contraction-stimulated glucose uptake in both so-34 leus and EDL muscle. Lack of PAK2, either alone (-13%) or in combination with PAK1 (-35 14%), reduced contraction-stimulated glucose transport compared to control littermates in 36 EDL, but not soleus muscle. Conclusion: Contraction-stimulated glucose transport in isolated 37 glycolytic mouse EDL muscle is partly dependent on PAK2, but not PAK1. 38 Keywords 39 Contraction; Glucose uptake, Metabolism; p21-activated kinase; Skeletal muscle.40 41Muscle contraction increases skeletal muscle glucose uptake independently of insulin 1-3 . Ac-42 cordingly, muscle contraction increases glucose uptake in both insulin-sensitive and insulin-43 resistant skeletal muscle 4-6 . Additionally, insulin sensitivity is improved after cessation of 44 muscle contraction 7-10 , making muscle contraction during acute exercise a non-pharmacolog-45 ical treatment for insulin resistance 11 . However, while muscle contraction is known to promote 46 the translocation of the glucose transporter (GLUT)-4 to the plasma membrane, which facili-47 tates glucose entry into the muscle, the intracellular signalling regulating this process is not 48 completely understood. 49Upon muscle contraction, multiple intracellular signalling pathways are activated that promote 50 GLUT4 translocation and a subsequent increase in muscle glucose transport. Redundant Ca +2 -51 dependent signalling, metabolic stress signalling, and mechanical stress signalling are proposed 52 to regulate distinct steps important for glucose transport in response to muscle contraction 12 . 53The group I p21-activated kinase (PAK)-1 and PAK2 are activated in response to electrical 54 pulse stimulation in C2C12 myotubes 13,14 and muscle contraction/acute exercise in mouse and 55 human sk...

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“…8 Recently, we demonstrated that Rac1 activation in electrically contracted myotubes or treadmill exercised mouse muscle is dependent on AMPK activity placing AMPK activation upstream of Rac1 during contraction. 10 Rac1 alternates between a GTP-bound active form and a GDP-bound inactive form and the status of Rac1 activation is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), or GDP-dissociation inhibitors (GDIs). [11][12][13] P-Rex1, FLJ00068, Tiam1, VAV2, and Trio are known Rac-GEF proteins.…”

Section: Introductionmentioning

confidence: 99%

Tiam1 mediates Rac1 activation and contraction‐induced glucose uptake in skeletal muscle cells

et al. 2020

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

Cited by 21 publications

References 38 publications

AXIN1 knockout does not alter AMPK/mTORC1 regulation and glucose metabolism in mouse skeletal muscle

AXIN1 knockout does not alter AMPK/mTORC1 regulation and glucose metabolism in mouse skeletal muscle

The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

Tiam1 mediates Rac1 activation and contraction‐induced glucose uptake in skeletal muscle cells

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