Involvement of the protein kinase Akt2 in insulin-stimulated Rac1 activation leading to glucose uptake in mouse skeletal muscle

Takenaka, Nobuyuki; Araki, Natsumi; Satoh, Takaya

doi:10.1371/journal.pone.0212219

Cited by 14 publications

(28 citation statements)

References 34 publications

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“…The specific signalling pathways and events which regulate β-catenin's role in actin cytoskeleton remodelling are not fully elucidated, and it is possible that β-catenin integrates with the established actin-cytoskeleton regulating pathways via interactions with Rac1 [ 7 ]. While our data suggest that β-catenin is downstream of Akt in the insulin signalling cascade, and Rac1 has been suggested to be involved in insulin-stimulated actin cytoskeleton reorganisation independent of Akt [ 7 ], this conflicts with reports that Rac1 may also be downstream of Akt [ 8 ]. Whether and how these pathways work together to regulate actin reorganisation during GLUT4 trafficking and therefore how β-catenin fits into the system requires further attention.…”

Section: Discussioncontrasting

confidence: 99%

“…The best characterised of these pathways involves PI3k/Akt mediated phosphorylation of Akt-substrate of 160 kD (AS160/TBC1D4) [ 2 , 3 ], which results in the inhibition of GTPase activity, triggering translocation and fusion of GLUT4-containing vesicles (GCVs). The second involves remodelling of the actin cytoskeleton at the cell membrane, thereby providing the physical structure to facilitate the movement of GCV within the cell [ [4] , [5] , [6] , [7] , [8] , [9] ]. While localised actin remodelling is critical for optimal insulin-stimulated glucose uptake in skeletal muscle [ 6 ], many putative insulin-induced actin regulators, such as PAK1 [ 10 ] appear to be somewhat dispensable suggesting that there are alternative regulators of insulin-dependent GLUT4 trafficking.…”

Section: Introductionmentioning

confidence: 99%

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β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

Masson

Sorrenson

Shepherd

et al. 2020

Molecular Metabolism

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Objective Skeletal muscle glucose disposal following a meal is mediated through insulin-stimulated movement of the GLUT4-containing vesicles to the cell surface. The highly conserved scaffold-protein β-catenin is an emerging regulator of vesicle trafficking in other tissues. Here, we investigated the involvement of β-catenin in skeletal muscle insulin-stimulated glucose transport. Methods Glucose homeostasis and transport was investigated in inducible muscle specific β-catenin knockout (BCAT-mKO) mice. The effect of β-catenin deletion and mutation of β-catenin serine 552 on signal transduction, glucose uptake and protein–protein interactions were determined in L6-G4-myc cells, and β-catenin insulin-responsive binding partners were identified via immunoprecipitation coupled to label-free proteomics. Results Skeletal muscle specific deletion of β-catenin impaired whole-body insulin sensitivity and insulin-stimulated glucose uptake into muscle independent of canonical Wnt signalling. In response to insulin, β-catenin was phosphorylated at serine 552 in an Akt-dependent manner, and in L6-G4-myc cells, mutation of β-catenin S552 impaired insulin-induced actin-polymerisation, resulting in attenuated insulin-induced glucose transport and GLUT4 translocation. β-catenin was found to interact with M-cadherin in an insulin-dependent β-catenin S552 -phosphorylation dependent manner, and loss of M-cadherin in L6-G4-myc cells attenuated insulin-induced actin-polymerisation and glucose transport. Conclusions Our data suggest that β-catenin is a novel mediator of glucose transport in skeletal muscle and may contribute to insulin-induced actin-cytoskeleton remodelling to support GLUT4 translocation.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

Masson

Sorrenson

Shepherd

et al. 2020

Molecular Metabolism

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“…Here, we examined the effect of ectopic expression of constitutively activated Akt2 on the activation state of Rac1. A polypeptide that specifically recognizes Rac1·GTP, designated glutathione S -transferase (GST)-POSH(251–489)-V5×3 [12,20,21,22,24,25], was used as a probe. When ectopically expressed, Myr-Akt2 actually induced the formation of Rac1·GTP as detected by the binding of GST-POSH(251–489)-V5×3, but not the control peptide GST-V5×3 (Figure 5).…”

Section: Resultsmentioning

confidence: 99%

A Crucial Role for the Small GTPase Rac1 Downstream of the Protein Kinase Akt2 in Insulin Signaling that Regulates Glucose Uptake in Mouse Adipocytes

Takenaka

Nakao

Matsui

et al. 2019

IJMS

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Insulin-stimulated glucose uptake is mediated by translocation of the glucose transporter GLUT4 to the plasma membrane in adipocytes and skeletal muscle cells. In both types of cells, phosphoinositide 3-kinase and the protein kinase Akt2 have been implicated as critical regulators. In skeletal muscle, the small GTPase Rac1 plays an important role downstream of Akt2 in the regulation of insulin-stimulated glucose uptake. However, the role for Rac1 in adipocytes remains controversial. Here, we show that Rac1 is required for insulin-dependent GLUT4 translocation also in adipocytes. A Rac1-specific inhibitor almost completely suppressed GLUT4 translocation induced by insulin or a constitutively activated mutant of phosphoinositide 3-kinase or Akt2. Constitutively activated Rac1 also enhanced GLUT4 translocation. Insulin-induced, but not constitutively activated Rac1-induced, GLUT4 translocation was abrogated by inhibition of phosphoinositide 3-kinase or Akt2. On the other hand, constitutively activated Akt2 caused Rac1 activation, and insulin-induced Rac1 activation was suppressed by an Akt2-specific inhibitor. Moreover, GLUT4 translocation induced by a constitutively activated mutant of Akt2 or Rac1 was diminished by knockdown of another small GTPase RalA. RalA was activated by a constitutively activated mutant of Akt2 or Rac1, and insulin-induced RalA activation was suppressed by an Akt2- or Rac1-specific inhibitor. Collectively, these results suggest that Rac1 plays an important role in the regulation of insulin-dependent GLUT4 translocation downstream of Akt2, leading to RalA activation in adipocytes.

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“…However, when investigating the Akt-Rac1 interplay in the insulin-resistant whole-body Akt2 knockout mice, the authors report a tissue specific effect on Rac1 activity by Akt, as insulin fails to stimulate Rac1 in the EDL but not soleus muscles from Akt2 knockout mice [64]. In addition, acute knockdown experiments for Akt2 performed by the Satoh group have suggested Rac1 lies downstream of the PI3K-Akt signaling in the regulation of glucose uptake by insulin in gastrocnemius muscle [69], [70], [71]. Therefore, the molecular hierarchy and potential interplay between Akt and Rac1 in skeletal muscle remain ill-defined.…”

Section: Discussionmentioning

confidence: 99%

The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis

Jaiswal

Gavin

Quinn

et al. 2019

Molecular Metabolism

133

109

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ObjectiveSkeletal muscle insulin signaling is a major determinant of muscle growth and glucose homeostasis. Protein kinase B/Akt plays a prominent role in mediating many of the metabolic effects of insulin. Mice and humans harboring systemic loss-of-function mutations in Akt2, the most abundant Akt isoform in metabolic tissues, are glucose intolerant and insulin resistant. Since the skeletal muscle accounts for a significant amount of postprandial glucose disposal, a popular hypothesis in the diabetes field suggests that a reduction in Akt, specifically in skeletal muscle, leads to systemic glucose intolerance and insulin resistance. Despite this common belief, the specific role of skeletal muscle Akt in muscle growth and insulin sensitivity remains undefined.MethodsWe generated multiple mouse models of skeletal muscle Akt deficiency to evaluate the role of muscle Akt signaling in vivo. The effects of these genetic perturbations on muscle mass, glucose homeostasis and insulin sensitivity were assessed using both in vivo and ex vivo assays.ResultsSurprisingly, mice lacking Akt2 alone in skeletal muscle displayed normal skeletal muscle insulin signaling, glucose tolerance, and insulin sensitivity despite a dramatic reduction in phosphorylated Akt. In contrast, deletion of both Akt isoforms (M-AktDKO) prevented downstream signaling and resulted in muscle atrophy. Despite the absence of Akt signaling, in vivo and ex vivo insulin-stimulated glucose uptake were normal in M-AktDKO mice. Similar effects on insulin sensitivity were observed in mice with prolonged deletion (4 weeks) of both skeletal muscle Akt isoforms selectively in adulthood. Conversely, short term deletion (2 weeks) of skeletal muscle specific Akt in adult muscles impaired insulin tolerance paralleling the effect observed by acute pharmacological inhibition of Akt in vitro. Mechanistically, chronic ablation of Akt induced mitochondrial dysfunction and activation of AMPK, which was required for insulin-stimulated glucose uptake in the absence of Akt.ConclusionsTogether, these data indicate that chronic reduction in Akt activity alone in skeletal muscle is not sufficient to induce insulin resistance or prevent glucose uptake in all conditions. Therefore, since insulin-stimulated glucose disposal in skeletal muscle is markedly impaired in insulin-resistant states, we hypothesize that alterations in signaling molecules in addition to skeletal muscle Akt are necessary to perturb glucose tolerance and insulin sensitivity in vivo.

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Involvement of the protein kinase Akt2 in insulin-stimulated Rac1 activation leading to glucose uptake in mouse skeletal muscle

Cited by 14 publications

References 34 publications

β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

β-catenin regulates muscle glucose transport via actin remodelling and M-cadherin binding

A Crucial Role for the Small GTPase Rac1 Downstream of the Protein Kinase Akt2 in Insulin Signaling that Regulates Glucose Uptake in Mouse Adipocytes

The role of skeletal muscle Akt in the regulation of muscle mass and glucose homeostasis

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