Wnt/β-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy

β-Catenin is a transcriptional activator shown to regulate the embryonic, postnatal, and oncogenic growth of many tissues. In most research to date, β-catenin activation has been the unique downstream function of the Wnt signaling pathway. However, in the heart, a Wnt-independent mechanism involving Akt-mediated phosphorylation of glycogen synthase kinase (GSK)-3β was recently shown to activate β-catenin and regulate cardiomyocyte growth. In this study, results have identified the activation of the Wnt/β-catenin pathway during hypertrophy of mechanically overloaded skeletal muscle. Significant increases in β-catenin were determined during skeletal muscle hypertrophy. In addition, the Wnt receptor, mFrizzled (mFzd)-1, the signaling mediator disheveled-1, and the transcriptional co-activator, lymphocyte enhancement factor (Lef)-1, are all increased during hypertrophy of the overloaded mouse plantaris muscle. Experiments also determined an increased association between GSK-3β and the inhibitory frequently rearranged in advanced T cell-1 protein with no increase in GSK-3β phosphorylation (Ser9). Finally, skeletal muscle overload resulted in increased nuclear β-catenin/Lef-1 expression and induction of the transcriptional targets c-Myc, cyclin D1, and paired-like homeodomain transcription factor 2. Thus this study provides the first evidence that the Wnt signaling pathway induces β-catenin/Lef-1 activation of growth-control genes during overload induced skeletal muscle hypertrophy.

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A divergent canonical WNT-signaling pathway regulates microtubule dynamics

The Journal of Cell Biology ◽

10.1083/jcb.200309096 ◽

2004 ◽

Vol 164 (2) ◽

pp. 243-253 ◽

Cited By ~ 125

Author(s):

Lorenza Ciani ◽

Olga Krylova ◽

Matthew J. Smalley ◽

Trevor C. Dale ◽

Patricia C. Salinas

Keyword(s):

Wnt Signaling ◽

Signaling Pathway ◽

Transcriptional Activation ◽

Glycogen Synthase ◽

Wnt Signaling Pathway ◽

Negative Regulator ◽

Canonical Wnt Signaling ◽

Microtubule Stability ◽

Gsk 3Β ◽

Canonical Wnt

Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β). In the canonical WNT pathway, the negative regulator Axin forms a complex with β-catenin and GSK-3β, resulting in β-catenin degradation. Inhibition of GSK-3β by DVL increases β-catenin stability and TCF transcriptional activation. Here, we show that Axin associates with microtubules and unexpectedly stabilizes microtubules through DVL. In turn, DVL stabilizes microtubules by inhibiting GSK-3β through a transcription- and β-catenin–independent pathway. More importantly, axonal microtubules are stabilized after DVL localizes to axons. Increased microtubule stability is correlated with a decrease in GSK-3β–mediated phosphorylation of MAP-1B. We propose a model in which Axin, through DVL, stabilizes microtubules by inhibiting a pool of GSK-3β, resulting in local changes in the phosphorylation of cellular targets. Our data indicate a bifurcation in the so-called canonical WNT-signaling pathway to regulate microtubule stability.

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ROLE OF GSK-3 IN Wnt/β-CATENIN SIGNALING PATHWAY IN OBESITY

Medical Immunology (Russia) ◽

10.15789/1563-0625-rog-2287 ◽

2021 ◽

Vol 23 (4) ◽

pp. 775-780

Author(s):

A. S. Kulakova ◽

I. A. Snimshchikova ◽

M. O. Plotnikova

Keyword(s):

Serum Level ◽

Wnt Signaling ◽

Signaling Pathway ◽

Glycogen Synthase ◽

Wnt Signaling Pathway ◽

Obese Patients ◽

Healthy Individuals ◽

Gsk 3Β ◽

The Impact

The complexity of the adipogenesis mechanism results from the impact of multiple cues, among which an important place is held by the components of the Wnt signaling pathway. The search for potential markers of the development of diseases related to obesity aroused an interest in the study of GSK-3 (glycogen synthase kinase), β-catenin. GSK-3β is an intracellular serine / threonine kinase found in the cytoplasm, nucleus, mitochondria, synthesized in all body tissues and involved in regulating metabolic processes, cell proliferation, apoptosis etc. The first of the discovered functions of GSK-3β was the regulation of glycogen synthesis. Active GSK-3β phosphorylates and thereby inhibits glycogen synthase. As a result of the insulin binding to the cell receptor via inositol-3-phosphate, protein kinase B (Akt1) is activated, which, in turn, phosphorylates and inhibits GSK-3β. In addition, GSK-3β is involved in the regulating glucose metabolism. The most important function of GSK-3β is the inhibition of the β-catenin protein. In a resting cell, GSK-3β in complex with the APC and Axin proteins binds and phosphorylates the β-catenin transcription factor, which leads to its ubiquitination and degradation. When Wnt proteins act on the cell, the Dvl protein is activated, which, by binding to GSK-3β, releases β-catenin, preventing its degradation, however, the role of GSK3α/β in the adipocyte inflammatory response has not yet been fully investigated, therefore it seems promising to study the role of GSK-3 in the Wnt/β-catenin signaling pathway in obesityThe aim of the study was to assess the activity of the components of the Wnt signaling pathway in obese patients by measuring the serum level of GSK-3 and β-catenin. There were enrolled 32 patients with progressive forms of I-III degree obesity in the absence of diabetes mellitus. The concentration of serum GSK-3α, GSK-3β, and β-catenin was measured by enzyme-linked immunoassay. Data are presented as absolute and relative (%) number of patients; arithmetic mean; medians, 1 and 3 quartiles – Ме (Q0.25-Q0.75). Obese patients contained a 7.5-fold increased serum level of GSK-3α (785 (371-1317.5) pg/ml) compared to healthy individuals 105 (102.5-110) pg/ml, (p < 0.001), paralleled with increased amount of GSK-3β, which level in obese patients was 295 (190-695) pg/ml, which is by 18.3% higher than those in healthy individuals 241 (218.75-287.5) pg/ml, p = 0.111. Amount of GSK-3 depending on the degree of obesity tended to increase, most often coupled to decreased β-catenin level which is consistent with the literature data and can be considered as a prognostic criterion for the course of pathological processes in obesity.

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Regulation of Dishevelled and β-catenin in rat skeletal muscle: an alternative exercise-induced GSK-3β signaling pathway

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00180.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. E152-E158 ◽

Cited By ~ 25

Author(s):

William G. Aschenbach ◽

Richard C. Ho ◽

Kei Sakamoto ◽

Nobuharu Fujii ◽

Yangfeng Li ◽

...

Keyword(s):

Skeletal Muscle ◽

Signaling Pathway ◽

Glycogen Synthase ◽

Wnt Signaling Pathway ◽

Treadmill Running ◽

Glycogen Depletion ◽

Multifunctional Protein ◽

Highly Correlated ◽

Gsk 3Β

β-catenin is a multifunctional protein involved in cell-cell adhesion and the Wnt signaling pathway. β-Catenin is activated upon its dephosphorylation, an event triggered by Dishevelled (Dvl)-mediated phosphorylation and deactivation of glycogen synthase kinase-3β (GSK-3β). In skeletal muscle, both insulin and exercise decrease GSK-3β activity, and we tested the hypothesis that these two stimuli regulate β-catenin. Immunoblotting demonstrated that Dvl, Axin, GSK-3β, and β-catenin proteins are expressed in rat red and white gastrocnemius muscles. Treadmill running exercise in vivo significantly decreased β-catenin phosphorylation in both muscle types, with complete dephosphorylation being elicited by maximal exercise. β-Catenin dephosphorylation was intensity dependent, as dephosphorylation was highly correlated with muscle glycogen depletion during exercise ( r2 = 0.84, P < 0.001). β-Catenin dephosphorylation was accompanied by increases in GSK-3β Ser9 phosphorylation and Dvl-GSK-3β association. In contrast to exercise, maximal insulin treatment (1 U/kg body wt) had no effect on skeletal muscle β-catenin phosphorylation or Dvl-GSK-3β interaction. In conclusion, exercise in vivo, but not insulin, increases the association between Dvl and GSK-3β in skeletal muscle, an event paralleled by β-catenin dephosphorylation.

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MicroRNA-140 inhibits skeletal muscle glycolysis and atrophy in endotoxin-induced sepsis in mice via the WNT signaling pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00419.2018 ◽

2019 ◽

Vol 317 (2) ◽

pp. C189-C199 ◽

Cited By ~ 3

Author(s):

Li Liu ◽

Tian-Mei Li ◽

Xue-Ru Liu ◽

Yi-Ping Bai ◽

Jie Li ◽

...

Keyword(s):

Skeletal Muscle ◽

Lactic Acid ◽

Wnt Signaling ◽

Signaling Pathway ◽

Acid Production ◽

Lactic Acid Production ◽

Wnt Signaling Pathway ◽

Serum Levels ◽

Cross Sectional

Sepsis is a systemic inflammatory response syndrome resulting from infection. This study aimed at exploring the role of microRNA-140 (miR-140) in septic mice. Wnt family member 11 (WNT11) was verified to be a target gene of miR-140 after bioinformatic prediction and dual luciferase reporter gene assay. Importantly, miR-140 negatively regulated WNT11. We initially induced the model of sepsis by endotoxin, and then ectopic expression and knockdown experiments were performed to explore the functional role of miR-140 in sepsis. Additionally, cross-sectional areas of muscle fiber, lactic acid production, 3-methylhistidine (3-MH) and tyrosine (Tyr) production in extensor digitorium longus (EDL) muscles, and serum levels of inflammatory factors were examined. The effect of miR-140 on the expression of WNT signaling pathway-related and apoptosis-related factors in skeletal muscle tissue was determined. The experimental results indicated that upregulated miR-140 or silenced WNT11 increased cross-sectional areas of muscle fiber while decreasing lactic acid production, skeletal muscle cell apoptosis [corresponding to downregulated B cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and caspase-3 and upregulated Bcl-2], and the proteolytic rate of Tyr and 3-MH. Also, overexpressed miR-140 or silenced WNT11 reduced inflammation as reflected by decreased serum levels of IL-6, IL-10, and TNF-α. Furthermore, overexpression of miR-140 was shown to suppress the activation of the WNT signaling pathway, accompanied by decreased expression of WNT11, β-catenin, and GSK-3β. Taken together, upregulation of miR-140 could potentially inhibit skeletal muscle lactate release, an indirect measure of glycolysis, and atrophy in septic mice through suppressing the WNT signaling pathway via inhibiting WNT11 expression.

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AMPKγ3 is dispensable for skeletal muscle hypertrophy induced by functional overload

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00387.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. E461-E472 ◽

Cited By ~ 4

Author(s):

Isabelle Riedl ◽

Megan E. Osler ◽

Marie Björnholm ◽

Brendan Egan ◽

Gustavo A. Nader ◽

...

Keyword(s):

Skeletal Muscle ◽

Signaling Pathways ◽

Muscle Hypertrophy ◽

Muscle Growth ◽

Mammalian Target Of Rapamycin ◽

Growth Control ◽

Mass Gain ◽

Mtor Signaling ◽

Wild Type ◽

Skeletal Muscle Hypertrophy

Mechanisms regulating skeletal muscle growth involve a balance between the activity of serine/threonine protein kinases, including the mammalian target of rapamycin (mTOR) and 5′-AMP-activated protein kinase (AMPK). The contribution of different AMPK subunits to the regulation of cell growth size remains inadequately characterized. Using AMPKγ3 mutant-overexpressing transgenic Tg-Prkag3 225Q and AMPKγ3-knockout ( Prkag3−/−) mice, we investigated the requirement for the AMPKγ3 isoform in functional overload-induced muscle hypertrophy. Although the genetic disruption of the γ3 isoform did not impair muscle growth, control sham-operated AMPKγ3-transgenic mice displayed heavier plantaris muscles in response to overload hypertrophy and underwent smaller mass gain and lower Igf1 expression compared with wild-type littermates. The mTOR signaling pathway was upregulated with functional overload but unchanged between genetically modified animals and wild-type littermates. Differences in AMPK-related signaling pathways between transgenic, knockout, and wild-type mice did not impact muscle hypertrophy. Glycogen content was increased following overload in wild-type mice. In conclusion, our functional, transcriptional, and signaling data provide evidence against the involvement of the AMPKγ3 isoform in the regulation of skeletal muscle hypertrophy. Thus, the AMPKγ3 isoform is dispensable for functional overload-induced muscle growth. Mechanical loading can override signaling pathways that act as negative effectors of mTOR signaling and consequently promote skeletal muscle hypertrophy.

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