S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt

Di, Ruo-Min; Wu, Xiangqi; Chang, Zai; Zhao, Xia; Feng, Qiuting; Lu, Shuangshuang; Luan, Qing; Hemmings, Brian A.; Li, Xinli; Yang, Zhongzhou

doi:10.1042/bj20110033

Cited by 53 publications

(55 citation statements)

References 46 publications

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“…This may explain the preferential effect of PF-4708671 on Akt S473 and not Akt T308-as revealed by immunoblot analysis of Akt phosphorylation sites in FAO cells and insulin target tissues of HF-fed obese mice. In line with these results, PF-4708671 has been also shown to be cardioprotective against myocardial infarction in mice by increasing Akt phosphorylation [37]. Thus, increased Akt activity likely plays a major role in the beneficial metabolic outcomes of S6K1 inhibition by PF-4708671.…”

Section: Discussionsupporting

confidence: 66%

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

et al. 2016

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Aims/hypothesis The mammalian target of rapamycin complex 1 (mTORC1)/p70 ribosomal S6 kinase (S6K)1 pathway is overactivated in obesity, leading to inhibition of phosphoinositide 3-kinase (PI3K)/Akt signalling and insulin resistance. However, chronic mTORC1 inhibition by rapamycin impairs glucose homeostasis because of robust induction of liver gluconeogenesis. Here, we compared the effect of rapamycin with that of the selective S6K1 inhibitor, PF-4708671, on glucose metabolism in vitro and in vivo. Methods We used L6 myocytes and FAO hepatocytes to explore the effect of PF-4708671 on the regulation of glucose uptake, glucose production and insulin signalling. We also treated high-fat (HF)-fed obese mice for 7 days with PF-4708671 in comparison with rapamycin to assess glucose tolerance, insulin resistance and insulin signalling in vivo. Results Chronic rapamycin treatment induced insulin resistance and impaired glucose metabolism in hepatic and muscle cells. Conversely, chronic S6K1 inhibition with PF-4708671 reduced glucose production in hepatocytes and enhanced glucose uptake in myocytes. Whereas rapamycin treatment inhibited Akt phosphorylation, PF-4708671 increased Akt phosphorylation in both cell lines. These opposite effects of the mTORC1 and S6K1 inhibitors were also observed in vivo. Indeed, while rapamycin treatment induced glucose intolerance and failed to improve Akt phosphorylation in liver and muscle of HF-fed mice, PF-4708671 treatment improved glucose tolerance and increased Akt phosphorylation in metabolic tissues of these obese mice. Conclusions/interpretation Chronic S6K1 inhibition by PF-4708671 improves glucose homeostasis in obese mice through enhanced Akt activation in liver and muscle. Our results suggest that specific S6K1 blockade is a valid pharmacological approach to improve glucose disposal in obese diabetic individuals.

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Section: Discussionsupporting

confidence: 66%

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

et al. 2016

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“…Rapamycin treatment of mice was as previously described (20). Potassium bisperoxo(1,10-phenanthroline)oxovanadate [bpV(phen)] was purchased from Santa Cruz (sc-221378A) and was administered to mice intraperitoneally at 2 weeks after birth for 7 days at a dose of 6.6 mg/kg body weight.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we found that long-term treatment of mice with rapamycin abolished Akt S473 in the heart while enhancing Akt T308 phosphorylation, which is cardiac protective (20). This study suggests that mTOR is responsible for Akt S473 phosphorylation.…”

mentioning

confidence: 96%

Phosphoinositide-Dependent Kinase 1 and mTORC2 Synergistically Maintain Postnatal Heart Growth and Heart Function in Mice

Zhao

Nie

et al. 2014

Molecular and Cellular Biology

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eThe protein kinase Akt plays a critical role in heart function and is activated by phosphorylation of threonine 308 (T308) and serine 473 (S473). While phosphoinositide-dependent kinase 1 (PDK1) is responsible for Akt T308 phosphorylation, the identities of the kinases for Akt S473 phosphorylation in the heart remain controversial. Here, we disrupted mTOR complex 2 (mTORC2) through deletion of Rictor in the heart and found normal heart growth and function. Rictor deletion caused significant reduction of Akt S473 phosphorylation but enhanced Akt T308 phosphorylation, suggesting that a high level of Akt T308 phosphorylation maintains Akt activity and heart function. Deletion of Pdk1 in the heart caused significantly enhanced Akt S473 phosphorylation that was suppressed by removal of Rictor, leading to worsened dilated cardiomyopathy (DCM) and accelerated heart failure in Pdk1-deficient mice. In addition, we found that increasing Akt S473 phosphorylation through deletion of Pten or chemical inhibition of PTEN reversed DCM and heart failure in Pdk1-deficient mice. Investigation of heart samples from human DCM patients revealed changes similar to those in the mouse models. These results demonstrated that PDK1 and mTORC2 synergistically promote postnatal heart growth and maintain heart function in postnatal mice.

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“…The previously described mouse strains used in this study included Pten conditional mice (Suzuki et al, 2001), Mesp1-Cre and Mef2c-AHF-Cre mice (Klaus and Birchmeier, 2009;Saga et al, 1999;Verzi et al, 2005), β-cateninfloxed mice (Huelsken et al, 2001) and Akt1 and Pdk1 conditional mice (Di et al, 2012;Feng et al, 2010;Zhao et al, 2014). All mouse lines were maintained in a B6 genetic background.…”

Section: Micementioning

confidence: 99%

Akt1 signaling coordinates BMP signaling and β-catenin activity to regulate second heart field progenitor development

et al. 2015

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Second heart field (SHF) progenitors exhibit continued proliferation and delayed differentiation, which are modulated by FGF4/8/10, BMP and canonical Wnt/β-catenin signaling. PTEN-Akt signaling regulates the stem cell/progenitor cell homeostasis in several systems, such as hematopoietic stem cells, intestinal stem cells and neural progenitor cells. To address whether PTEN-Akt signaling is involved in regulating cardiac progenitors, we deleted Pten in SHF progenitors. Deletion of Pten caused SHF expansion and increased the size of the SHF derivatives, the right ventricle and the outflow tract. Cell proliferation of cardiac progenitors was enhanced, whereas cardiac differentiation was unaffected by Pten deletion. Removal of Akt1 rescued the phenotype and early lethality of Pten deletion mice, suggesting that Akt1 was the key downstream target that was negatively regulated by PTEN in cardiac progenitors. Furthermore, we found that inhibition of FOXO by Akt1 suppressed the expression of the gene encoding the BMP ligand (BMP7), leading to dampened BMP signaling in the hearts of Pten deletion mice. Cardiac activation of Akt also increased the Ser552 phosphorylation of β-catenin, thus enhancing its activity. Reducing β-catenin levels could partially rescue heart defects of Pten deletion mice. We conclude that Akt signaling regulates the cell proliferation of SHF progenitors through coordination of BMP signaling and β-catenin activity.

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S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt

Cited by 53 publications

References 46 publications

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

Pharmacological inhibition of S6K1 increases glucose metabolism and Akt signalling in vitro and in diet-induced obese mice

Phosphoinositide-Dependent Kinase 1 and mTORC2 Synergistically Maintain Postnatal Heart Growth and Heart Function in Mice

Akt1 signaling coordinates BMP signaling and β-catenin activity to regulate second heart field progenitor development

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