Osteocalcin Induces Proliferation via Positive Activation of the PI3K/Akt, P38 MAPK Pathways and Promotes Differentiation Through Activation of the GPRC6A-ERK1/2 Pathway in C2C12 Myoblast Cells

Liu, Sui-Feng; Gao, Feng; Wen, Lei; Ouyang, Ming; Wang, Yi; Wang, Qiong; Luo, Liping; Jian, Zaijin

doi:10.1159/000481752

Cited by 72 publications

(70 citation statements)

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“…(20,28) The ucOC effect on muscle cells appears to involve the enhancement of GPRC6A expression. (18) In support, the expression of GPRC6A was increased by ucOC + insulin treatment in placebo EDL muscle compared with insulin alone. However, ucOC did not change GPRC6A expression in muscle from CS-treated animals, suggesting that the alteration of GPRC6A abundance is unlikely to be involved in the rescuing effect of ucOC.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 83%

“…Furthermore, it was reported that the effect is also likely via an increase in the abundance of these signaling proteins, including the postulated ucOC receptor G protein‐coupled receptor, class C, group 6, member A (GPRC6A) (Supplemental Fig. S1) . However, the exact molecular mechanisms of ucOC on muscle insulin resistance, particularly GC‐induced insulin resistance, are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…S1). (14,15,18) However, the exact molecular mechanisms of ucOC on muscle insulin resistance, particularly GC-induced insulin resistance, are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Lin

Parker

McLennan

et al. 2019

Journal of Bone and Mineral Research

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Short‐term administration of glucocorticoids (GCs) impairs muscle insulin sensitivity at least in part via the reduction of undercarboxylated osteocalcin (ucOC). However, whether ucOC treatment reverses the GC‐induced muscle insulin resistance remains unclear. To test the hypothesis that ucOC directly ameliorates impaired insulin‐stimulated glucose uptake (ISGU) induced by short‐term GC administration in mice muscle and to identify the molecular mechanisms, mice were implanted with placebo or corticosterone (CS) slow‐release pellets. Two days post‐surgery, insulin‐tolerance tests (ITTs) were performed. On day 3, serum was collected and extensor digitorum longus (EDL) and soleus muscles were isolated and treated ex vivo with vehicle, ucOC (30 ng/mL), insulin (60 µU/mL), or both. Circulating hormone levels, muscle glucose uptake, and muscle signaling proteins were assessed. CS administration reduced both serum osteocalcin and ucOC levels, whole‐body insulin sensitivity, and muscle ISGU in EDL. Ex vivo ucOC treatment restored ISGU in CS‐affected muscle, without increasing non‐insulin‐stimulated glucose uptake. In CS‐affected EDL muscle, ucOC enhanced insulin action on phosphorylated (p‐)protein kinase B (Akt)Ser473and the p‐extracellular signal‐regulated kinase isoform 2 (ERK2)Thr202/Tyr204/total (t)ERK2 ratio, which correlated with ISGU. In CS‐affected soleus muscle, ucOC enhanced insulin action on p‐mammalian target of rapamycin (mTOR)Ser2481, the p‐mTORSer2481/tmTOR ratio, p‐Akt substrate of 160kD (AS160)Thr642, and p‐protein kinase C (PKC) (pan)Thr410, which correlated with ISGU. Furthermore, p‐PKC (pan)Thr410 correlated with p‐AktSer473 and p‐AS160Thr642. ucOC exerts direct insulin‐sensitizing effects on CS‐affected mouse muscle, likely through an enhancement in activity of key proteins involved in both insulin and ucOC signaling pathways. Furthermore, these effects are muscle type‐dependent. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.

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Section: Journal Of Bone and Mineral Researchmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Lin

Parker

McLennan

et al. 2019

Journal of Bone and Mineral Research

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“…In our study, we found that the COPS3 was overexpressed in bone metastasis tissues by immunohistochemistry, and the levels of phosphorylated p38 MAPK reduced in the COPS3‐knockdown cells. MAPK families, which had identified at least three major signaling pathway in mammals including MAPK/ERK, stress‐activated kinase/c‐Jun N‐terminal kinase, and p38 MAPK were responsible for regulating complex cellular processes such as proliferation, differentiation, and apoptosis . The decreased level of p‐p38 MAPK induced by COPS3 knockdown indicated that COPS3 may promote the PCa cells proliferation by activating the p38 MAPK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of COPS3 inhibits the progress of prostate cancer through reducing phosphorylated p38 MAPK expression and impairs the epithelial‐mesenchymal transition process

et al. 2019

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Background The amplification of gene COPS3 is closely related to the development of osteosarcoma and hepatocellular carcinoma. However, the effects of COPS3 on prostate cancer (PCa) are poorly understood. Methods In this study, the protein expression of COPS3 in PCa tissues, adjacent normal tissues, and bone metastasis tissues of PCa was analyzed by immunohistochemistry. Furthermore, cell proliferation, colony formation, migration, and invasion assay were performed in 22rv1 and PC‐3 cells after knocking down COPS3 by small interfering RNAs. Furthermore, we performed western blot analysis to explore the potential mechanisms underlying it. Results This study found that the overall survival of the COPS3 high‐expression group was significantly shorter than the low‐expression group. This study discovered that the protein expression of COPS3 in PCa tissues was higher than that in the matched nontumor prostate tissues. In addition, tissues from bone metastasis of PCa had a high percentage of overexpressing COPS3. After knockdown of the COPS3 gene in 22rv1 and PC3 cells, two classic human PCa cell lines which had a high level of COPS3, the abilities of migration, invasion, and proliferation were inhibited. Finally, protein levels of phosphorylated P38 mitogen‐activated protein kinase (MAPK) and N‐cadherin were significantly decreased after knocking down the expression of COPS3, and the protein levels of E‐cadherin were significantly increased. Conclusions In conclusion, COPS3 may be closely related to the progress of PCa. Knockdown of COPS3 inhibited the progress of PCa through reducing the levels of phosphorylated P38 MAPK and impaired the epithelial‐mesenchymal transition process.

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“…Previous studies have shown that PIK3IP1 acts as a negative regulator of PI3K (He et al, ; DeFrances et al, ). In addition, the PI3K/AKT signaling pathway plays an important role in cell proliferation (Ohashi et al, ; Liu et al, ). Therefore, we hypothesized that WDR13 may affect the differentiation of bovine MDSCs by affecting the PI3K/AKT signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

WDR13 promotes the differentiation of bovine skeletal muscle‐derived satellite cells by affecting PI3K/AKT signaling

Tong

et al. 2019

Cell Biology International

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Muscle satellite cells are usually at rest, and when externally stimulated or regulated, they can be further differentiated by cell fusion to form new myotubes and muscle fibers. WD repeat domain 13 (WDR13) is highly conserved in vertebrates. Studies have shown that mice lacking the Wdr13 gene develop mild obesity, hyperinsulinemia, and increased islet β cell proliferation. However, the role of WDR13 in bovine cells is unclear. Here, we investigated the effect of WDR13 on bovine skeletal muscle‐derived satellite cells (MDSCs). We found that WDR13 was upregulated in bovine MDSCs using western blotting and immunofluorescence experiments. Moreover, activation and inhibition of WDR13 expression increased and decreased cell differentiation, respectively, suggesting that WDR13 promotes bovine MDSC differentiation. To further understand the mechanism of action of WDR13, we examined changes in the PI3K/AKT signaling pathway following WDR13 activation or inhibition. In addition, cells were treated with a phosphoinositide kinase 3 (PI3K) inhibitor, LY294004, to observe cell differentiation. The results showed that activation of WDR13 inhibited the PI3K/AKT signaling pathway and enhanced cell differentiation. These data suggest that WDR13 can promote the differentiation of bovine MDSCs by affecting the PI3K/AKT signaling pathway.

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Osteocalcin Induces Proliferation via Positive Activation of the PI3K/Akt, P38 MAPK Pathways and Promotes Differentiation Through Activation of the GPRC6A-ERK1/2 Pathway in C2C12 Myoblast Cells

Cited by 72 publications

References 35 publications

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Undercarboxylated Osteocalcin Improves Insulin-Stimulated Glucose Uptake in Muscles of Corticosterone-Treated Mice

Knockdown of COPS3 inhibits the progress of prostate cancer through reducing phosphorylated p38 MAPK expression and impairs the epithelial‐mesenchymal transition process

WDR13 promotes the differentiation of bovine skeletal muscle‐derived satellite cells by affecting PI3K/AKT signaling

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