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.

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.

scholarly journals Protein Breakdown in Muscle from Burned Rats Is Blocked by Insulin-Like Growth Factor I and Glycogen Synthase Kinase-3β Inhibitors

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 3141-3149 ◽  
Author(s):  
Cheng-Hui Fang ◽  
Bing-Guo Li ◽  
J. Howard James ◽  
Jy-Kung King ◽  
Amy R. Evenson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factors ◽  
Signaling Pathway ◽  
Lithium Chloride ◽  
Glycogen Synthase ◽  
Mammalian Target Of Rapamycin ◽  
Glycogen Synthase Kinase 3Β ◽  
Protein Breakdown ◽  
Igf I ◽  
Gsk 3Β

Abstract We reported previously that IGF-I inhibits burn-induced muscle proteolysis. Recent studies suggest that activation of the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway with downstream phosphorylation of Forkhead box O transcription factors is an important mechanism of IGF-I-induced anabolic effects in skeletal muscle. The potential roles of other mechanisms in the anabolic effects of IGF-I are less well understood. In this study we tested the roles of mammalian target of rapamycin and glycogen synthase kinase-3β (GSK-3β) phosphorylation as well as MAPK- and calcineurin-dependent signaling pathways in the anticatabolic effects of IGF-I by incubating extensor digitorum longus muscles from burned rats in the presence of IGF-I and specific signaling pathway inhibitors. Surprisingly, the PI3K inhibitors LY294002 and wortmannin reduced basal protein breakdown. No additional inhibition by IGF-I was noticed in the presence of LY294002 or wortmannin. Inhibition of proteolysis by IGF-I was associated with phosphorylation (inactivation) of GSK-3β. In addition, the GSK-3β inhibitors, lithium chloride and thiadiazolidinone-8, reduced protein breakdown in a similar fashion as IGF-I. Lithium chloride, but not thiadiazolidinone-8, increased the levels of phosphorylated Foxo 1 in incubated muscles from burned rats. Inhibitors of mammalian target of rapamycin, MAPK, and calcineurin did not prevent the IGF-I-induced inhibition of muscle proteolysis. Our results suggest that IGF-I inhibits protein breakdown at least in part through a PI3K/Akt/GSK3β-dependent mechanism. Additional experiments showed that similar mechanisms were responsible for the effect of IGF-I in muscle from nonburned rats. Taken together with recent reports in the literature, the present results suggest that IGF-I inhibits protein breakdown in skeletal muscle by multiple mechanisms, including PI3K/Akt-mediated inactivation of GSK-3β and Foxo transcription factors.

Fam83d modulates MAP kinase and AKT signaling and is induced during neurogenic skeletal muscle atrophy

2020 ◽  
Vol 70 ◽  
pp. 109576 ◽  
Author(s):  
Lisa M. Cooper ◽  
Abby Hanson ◽  
Jack A. Kavanagh ◽  
David S. Waddell
Keyword(s):  
Skeletal Muscle ◽  
Map Kinase ◽  
Muscle Atrophy ◽  
Akt Signaling ◽  
Skeletal Muscle Atrophy

Resistance exercise and growth hormone as countermeasures for skeletal muscle atrophy in hindlimb-suspended rats

1994 ◽  
Vol 267 (2) ◽  
pp. R365-R371 ◽  
Author(s):  
J. K. Linderman ◽  
K. L. Gosselink ◽  
F. W. Booth ◽  
V. R. Mukku ◽  
R. E. Grindeland
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone ◽  
Resistance Exercise ◽  
Protein Content ◽  
Muscle Atrophy ◽  
Myofibrillar Protein ◽  
Hindlimb Suspension ◽  
Skeletal Muscle Atrophy ◽  
Plantar Flexor ◽  
Fast Twitch

Unweighting of rat hindlimb muscles results in skeletal muscle atrophy, decreased protein synthesis, and reduced growth hormone (GH) secretion. Resistance exercise (ladder climbing) and GH treatment partially attenuate skeletal muscle atrophy in hypophysectomized hindlimb-suspended rats. It was hypothesized that a combination of multiple bouts of daily resistance exercise and GH (1 mg.kg-1.day-1) would prevent skeletal muscle atrophy in growing nonhypophysectomized hindlimb-suspended rats. Hindlimb suspension decreased the absolute (mg/pair) and relative (mg/100 g body wt) weights of the soleus, a slow-twitch plantar flexor, by 30 and 21%, respectively, and the absolute and relative weights of the gastrocnemius, a predominantly fast-twitch plantar flexor, by 20 and 11%, respectively (P < 0.05). Exercise did not increase soleus mass but attenuated loss of relative wet weight in the gastrocnemius muscles of hindlimb-suspended rats (P < 0.05). Hindlimb suspension decreased gastrocnemius myofibrillar protein content and synthesis (mg/day) by 26 and 64%, respectively (P < 0.05). The combination of exercise and GH attenuated loss of gastrocnemius myofibrillar protein content and synthesis by 70 and 23%, respectively (P < 0.05). Results of the present investigation indicate that a combination of GH and resistance exercise attenuates atrophy of unweighted fast-twitch skeletal muscles.

scholarly journals Protective Effect of Pyropia yezoensis Peptide on Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 284 ◽  
Author(s):  
Min-Kyeong Lee ◽  
Jeong-Wook Choi ◽  
Youn Hee Choi ◽  
Taek-Jeong Nam
Keyword(s):  
Skeletal Muscle ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Protective Effects ◽  
Factor I ◽  
Igf I ◽  
Foxo Signaling Pathway

Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling pathway. To elucidate the molecular mechanisms underlying the effects of PYP15 on DEX-induced myotube atrophy, C2C12 myotubes were treated for 24 h with 100 μM DEX in the presence or absence of 500 ng/mL PYP15. Cell viability assays revealed no PYP15 toxicity in C2C12 myotubes. PYP15 activated the insulin-like growth factor-I receptor (IGF-IR) and Akt-mTORC1 signaling pathway in DEX-induced myotube atrophy. In addition, PYP15 markedly downregulated the nuclear translocation of transcription factors FoxO1 and FoxO3a, and inhibited 20S proteasome activity. Furthermore, PYP15 inhibited the autophagy-lysosomal pathway in DEX-stimulated myotube atrophy. Our findings suggest that PYP15 treatment protected against myotube atrophy by regulating IGF-I and the Akt-mTORC1-FoxO signaling pathway in skeletal muscle. Therefore, PYP15 treatment appears to exert protective effects against skeletal muscle atrophy.

Ectopic expression of IGF‐I and Shh by skeletal muscle inhibits disuse‐mediated skeletal muscle atrophy and bone osteopenia in vivo

2003 ◽  
Vol 18 (1) ◽  
pp. 221-223 ◽  
Author(s):  
Mohammed Borhan Alzghoul ◽  
Dave Gerrard ◽  
Bruce A. Watkins ◽  
Kevin Hannon
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ectopic Expression ◽  
Skeletal Muscle Atrophy ◽  
Igf I

Myogenic differentiation during regrowth of atrophied skeletal muscle is associated with inactivation of GSK-3β

2007 ◽  
Vol 292 (5) ◽  
pp. C1636-C1644 ◽  
Author(s):  
Jos L. J. van der Velden ◽  
Ramon C. J. Langen ◽  
Marco C. J. M. Kelders ◽  
Jodil Willems ◽  
Emiel F. M. Wouters ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Glycogen Synthase ◽  
Myogenic Differentiation ◽  
Hindlimb Suspension ◽  
Akt Phosphorylation ◽  
Proliferation And Differentiation ◽  
Igf I ◽  
Myoblast Proliferation ◽  
Gsk 3Β ◽  
First Time

Muscle atrophy contributes to morbidity and mortality in aging and chronic disease, emphasizing the need to gain understanding of the mechanisms involved in muscle atrophy and (re)growth. We hypothesized that the magnitude of muscle regrowth during recovery from atrophy determines whether myonuclear accretion and myogenic differentiation are required and that insulin-like growth factor (IGF)-I/Akt/glycogen synthase kinase (GSK)-3β signaling differs between regrowth responses. To address this hypothesis we subjected mice to hindlimb suspension (HS) to induce atrophy of soleus (−40%) and plantaris (−27%) muscle. Reloading-induced muscle regrowth was complete after 14 days and involved an increase in IGF-IEa mRNA expression that coincided with Akt phosphorylation in both muscles. In contrast, phosphorylation and inactivation of GSK-3β were observed during soleus regrowth only. Furthermore, soleus but not plantaris regrowth involved muscle regeneration based on a transient increase in expression of histone 3.2 and myosin heavy chain-perinatal, which are markers of myoblast proliferation and differentiation, and a strong induction of muscle regulatory factor (MRF) expression. Experiments in cultured muscle cells showed that IGF-I-induced MRF expression is facilitated by inactivation of GSK-3β and selectively occurs in the myoblast population. This study suggests that induction of IGF-I expression and Akt phosphorylation during recovery from muscle atrophy is independent of the magnitude of muscle regrowth. Moreover, our data demonstrate for the first time that the regenerative response characterized by myoblast proliferation, differentiation, and increased MRF expression in recovering muscle is associated with the magnitude of regrowth and may be regulated by inactivation of GSK-3β.

Sign in / Sign up

Export Citation Format

Share Document