No muscle atrophy without GSK-3β. Focus on “Glycogen synthase kinase-3β is required for the induction of skeletal muscle atrophy”

2011 ◽  
Vol 301 (5) ◽  
pp. C980-C981 ◽  
Author(s):  
Esther E. Dupont-Versteegden ◽  
Christine Waters
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Skeletal Muscle Atrophy ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β

Inhibition of glycogen synthase kinase-3β activity is sufficient to stimulate myogenic differentiation

2006 ◽  
Vol 290 (2) ◽  
pp. C453-C462 ◽  
Author(s):  
Jos L. J. van der Velden ◽  
Ramon C. J. Langen ◽  
Marco C. J. M. Kelders ◽  
Emiel F. M. Wouters ◽  
Yvonne M. W. Janssen-Heininger ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Glycogen Synthase ◽  
Muscle Growth ◽  
Glycogen Synthase Kinase ◽  
Skeletal Muscle Atrophy ◽  
Glycogen Synthase Kinase 3Β ◽  
Igf I ◽  
Gsk 3Β ◽  
Stimulation Of

Skeletal muscle atrophy is a prominent and disabling feature of chronic wasting diseases. Prevention or reversal of muscle atrophy by administration of skeletal muscle growth (hypertrophy)-stimulating agents such as insulin-like growth factor I (IGF-I) could be an important therapeutic strategy in these diseases. To elucidate the IGF-I signal transduction responsible for muscle formation (myogenesis) during muscle growth and regeneration, we applied IGF-I to differentiating C2C12 myoblasts and evaluated the effects on phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK-3β) signaling and myogenesis. IGF-I caused phosphorylation and inactivation of GSK-3β activity via signaling through the PI3K/Akt pathway. We assessed whether pharmacological inhibition of GSK-3β with lithium chloride (LiCl) was sufficient to stimulate myogenesis. Addition of IGF-I or LiCl stimulated myogenesis, evidenced by increased myotube formation, muscle creatine kinase (MCK) activity, and troponin I (TnI) promoter transactivation during differentiation. Moreover, mRNAs encoding MyoD, Myf-5, myogenin, TnI-slow, TnI-fast, MCK, and myoglobin were upregulated in myoblasts differentiated in the presence of IGF-I or LiCl. Importantly, blockade of GSK-3β inhibition abrogated IGF-I- but not LiCl-dependent stimulation of myogenic mRNA accumulation, suggesting that the promyogenic effects of IGF-I require GSK-3β inactivation and revealing an important negative regulatory role for GSK-3β in myogenesis. Therefore, this study identifies GSK-3β as a potential target for pharmacological stimulation of muscle growth.

Glycogen synthase kinase-3β is required for the induction of skeletal muscle atrophy

2011 ◽  
Vol 301 (5) ◽  
pp. C995-C1007 ◽  
Author(s):  
Koen J. P. Verhees ◽  
Annemie M. W. J. Schols ◽  
Marco C. J. M. Kelders ◽  
Céline M. H. Op den Kamp ◽  
Jos L. J. van der Velden ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Glycogen Synthase ◽  
Akt Signaling ◽  
Myofibrillar Protein ◽  
Skeletal Muscle Atrophy ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Loss ◽  
Igf I ◽  
Gsk 3Β

Skeletal muscle atrophy commonly occurs in acute and chronic disease. The expression of the muscle-specific E3 ligases atrogin-1 (MAFbx) and muscle RING finger 1 (MuRF1) is induced by atrophy stimuli such as glucocorticoids or absence of IGF-I/insulin and subsequent Akt signaling. We investigated whether glycogen synthase kinase-3β (GSK-3β), a downstream molecule in IGF-I/Akt signaling, is required for basal and atrophy stimulus-induced expression of atrogin-1 and MuRF1, and myofibrillar protein loss in C2C12 skeletal myotubes. Abrogation of basal IGF-I signaling, using LY294002, resulted in a prominent induction of atrogin-1 and MuRF1 mRNA and was accompanied by a loss of myosin heavy chain fast (MyHC-f) and myosin light chains 1 (MyLC-1) and -3 (MyLC-3). The synthetic glucocorticoid dexamethasone (Dex) also induced the expression of both atrogenes and likewise resulted in the loss of myosin protein abundance. Genetic ablation of GSK-3β using small interfering RNA resulted in specific sparing of MyHC-f, MyLC-1, and MyLC-3 protein levels after Dex treatment or impaired IGF-I/Akt signaling. Interestingly, loss of endogenous GSK-3β suppressed both basal and atrophy stimulus-induced atrogin-1 and MuRF1 expression, whereas pharmacological GSK-3β inhibition, using CHIR99021 or LiCl, only reduced atrogin-1 mRNA levels in response to LY294002 or Dex. In conclusion, our data reveal that myotube atrophy and myofibrillar protein loss are GSK-3β dependent, and demonstrate for the first time that basal and atrophy stimulus-induced atrogin-1 mRNA expression requires GSK-3β enzymatic activity, whereas MuRF1 expression depends solely on the physical presence of GSK-3β.

scholarly journals Inactivation of glycogen synthase kinase-3β (GSK-3β) enhances skeletal muscle oxidative metabolism

2017 ◽  
Vol 1863 (12) ◽  
pp. 3075-3086 ◽  
Author(s):  
W.F. Theeuwes ◽  
H.R. Gosker ◽  
R.C.J. Langen ◽  
K.J.P. Verhees ◽  
N.A.M. Pansters ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Metabolism ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β

scholarly journals Dextromethorphan Attenuates NADPH Oxidase-Regulated Glycogen Synthase Kinase 3β and NF-κB Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection

2018 ◽  
Vol 62 (6) ◽  
pp. e02045-17 ◽  
Author(s):  
Chia-Ling Chen ◽  
Miao-Huei Cheng ◽  
Chih-Feng Kuo ◽  
Yi-Lin Cheng ◽  
Ming-Han Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nadph Oxidase ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Streptococcal Toxic Shock Syndrome ◽  
Glycogen Synthase Kinase 3Β ◽  
Diphenylene Iodonium ◽  
Group A ◽  
Gsk 3Β

ABSTRACTGroup AStreptococcus(GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47phoxand subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3β (GSK-3β) activation, and subsequent NF-κB nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3β/NF-κB/NO signaling pathway.

scholarly journals Glycogen Synthase Kinase 3β Promotes Postoperative Cognitive Dysfunction by Inducing the M1 Polarization and Migration of Microglia

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Jingjin Li ◽  
Chonglong Shi ◽  
Zhengnian Ding ◽  
Wenjie Jin
Keyword(s):  
Cognitive Dysfunction ◽  
Lithium Chloride ◽  
Glycogen Synthase ◽  
Postoperative Cognitive Dysfunction ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Central Nervous System Complication ◽  
Proinflammatory Mediators ◽  
M1 Polarization ◽  
Gsk 3Β

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system complication, especially in the elderly. It has been consistently reported that the pathological process of this clinical syndrome is related to neuroinflammation and microglial proliferation. Glycogen synthase kinase 3β (GSK-3β) is a widely expressed kinase with distinct functions in different types of cells. The role of GSK-3β in regulating innate immune activation has been well documented, but as far as we know, its role in POCD has not been fully elucidated. Lithium chloride (LiCl) is a widely used inhibitor of GSK-3β, and it is also the main drug for the treatment of bipolar disorder. Prophylactic administration of lithium chloride (2 mM/kg) can inhibit the expression of proinflammatory mediators in the hippocampus, reduce the hippocampal expression of NF-κB, and increase both the downregulation of M1 microglial-related genes (inducible nitric oxide synthase and CD86) and upregulation of M2 microglial-related genes (IL-10 and CD206), to alleviate the cognitive impairment caused by orthopedic surgery. In vitro, LiCl reversed LPS-induced production of proinflammatory mediators and M1 polarization of microglia. To sum up these results, GSK-3β is a key contributor to POCD and a potential target of neuroprotective strategies.

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