Canonical signaling and nuclear activity of <scp>mTOR</scp>—a teamwork effort to regulate metabolism and cell growth

Giguère, Vincent

doi:10.1111/febs.14384

Cited by 57 publications

(56 citation statements)

References 124 publications

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“…It is tempting to speculate that mTORmKOKI muscles are mechanistically unable to induce FGF21. In support of this notion, FGF21 has been shown to be under mTORC1 control because its transcriptional induction is rapamycin‐sensitive and is directly mediated by transcription factors themselves regulated by mTOR, such as PPARs, ATF4, and ChREBP …”

Section: Discussionmentioning

confidence: 94%

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

Zhang

Conjard-Duplany

Moncollin

et al. 2018

J cachexia sarcopenia muscle

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Background The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age‐related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown. Methods We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle‐specific mTOR knockout (mTORmKO) littermates. Results In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice ( P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% ( P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down‐regulation of glycogen phosphorylase expression (0.16‐fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V. Conclusions Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole‐body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole‐body homeostasis.

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Section: Discussionmentioning

confidence: 94%

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

Zhang

Conjard-Duplany

Moncollin

et al. 2018

J cachexia sarcopenia muscle

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“…An important and promising target for metastatic RCC to date is mTOR, which is a pivotal regulator of the metabolic pathway of a cell. mTOR receives input from sensors of energy, nutrients, and stress and produces output that regulates protein synthesis and cell growth . The activation of class I PI3K could lead to activation of Akt‐mTOR signaling pathway, which in turn inhibits autophagy .…”

Section: Discussionmentioning

confidence: 99%

“…Although several types of vascular endothelial growth factor‐ and mechanistic target of rapamycin (mTOR)‐targeted drugs have been approved as first‐line therapies for the treatment of metastatic RCC, more than 40% of patients do not respond to these agents . In particular, mTOR signaling pathway is a pivotal regulator of cellular growth, differentiation, survival, metabolism, and stress response . mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E‐BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis.…”

Section: Introductionmentioning

confidence: 99%

“…mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E‐BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis. mTORC2 phosphorylates serum/glucocorticoid regulated kinase 1 (SGK1), Akt, Ras‐related C3 botulinum toxin substrate 1 (Rac1), and protein kinase Cα (PKCα) to regulate cell survival, glycolytic enzymes, pentose phosphate pathway enzymes, glutaminase, and cytoskeletal organization . Due to feedback between mTORC1 and mTORC2, crosstalk with other pathways leading to the compensatory activation of extracellular signal‐regulated kinase (ERK)/mitogen‐activated protein kinase pathway (MAPK), and a higher risk of side effects, the therapeutic efficacy of FDA‐approved mTORC1 inhibitors such as everolimus is limited …”

Section: Introductionmentioning

confidence: 99%

“…3 In particular, mTOR signaling pathway is a pivotal regulator of cellular growth, differentiation, survival, metabolism, and stress response. [4][5][6][7] mTOR complex 1 (mTORC1) phosphorylates ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-BP1 to modulate translation, autophagy, lipid biosynthesis, mitochondrial biogenesis, and ribosome biogenesis. mTORC2 phosphorylates serum/glucocorticoid regulated kinase 1 (SGK1), Akt, Ras-related C3 botulinum toxin substrate 1 (Rac1), and protein kinase Cα (PKCα) to regulate cell survival, glycolytic enzymes, pentose phosphate pathway enzymes, glutaminase, and cytoskeletal organization.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel therapeutic roles of MC‐4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways

et al. 2018

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Current clinical trials of new anticancer therapies against metastatic renal cell carcinoma (RCC), including molecular‐targeted therapies, have not shown promise. The purpose of this study was to preclinically assess the antitumor effects of MC‐4, a partially purified material of Artemisia annua L., as a monotherapy or in combination with the known mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, everolimus, against Caki‐1 (Von Hippel‐Lindau (VHL)+/+) and 786‐O (VHL−/−) human RCC cells. MC‐4 monotherapy significantly increased tumor growth inhibition and autophagic cell death in RCC cells in vitro and in vivo. Everolimus led to compensatory Akt activation by inhibiting only mTORC1 signaling pathway. In contrast to everolimus, MC‐4 enhanced phosphatase and tensin homolog expression and reduced its downstream effector, Akt/pyruvate kinase muscle isozyme M2 (PKM2), leading to decreased expression of glucose transporter 1, which is associated with cancer cell metabolism. The synergistic antitumor and anti‐metastatic effects induced by co‐administration of MC‐4 and everolimus involve cell growth inhibition and autophagic cell death via dual targeting of phosphatidylinositol 3‐kinase (PI3K)/Akt/PKM2 and mTORC1. These findings suggest that MC‐4 is a novel Akt/PKM2 inhibitor that can overcome the limitation of existing mTOR inhibitors and can be considered a novel strategy to treat patients with rapidly progressing advanced RCC.

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AMPK activation suppresses mTOR/S6K1 phosphorylation and induces leucine resistance in rats with sepsis

Shi

Zhang

et al. 2020

Cell Biology International

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Although it has been known that protein synthesis is suppressed in sepsis, which cannot be corrected by leucine supplement (also known as leucine resistance), the molecular signaling mechanism remains unclear. This study aimed to investigate the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway in sepsis-induced leucine resistance and its upstream signals, and to seek a way to correct leucine resistance in sepsis. Sepsis was produced by cecal ligation and puncture (CLP) model in rat. Both septic rats and sham operation rat received total parenteral nutrition (TPN) with or without leucine for 24 h, and then protein synthesis and AMPK/mTOR and protein kinase B (PKB) were tested. In vitro C2C12 cells were treated with or without leucine, and we tested the AMPK/mTOR pathway and protein synthesis. We blocked AMPK by compound C and stimulated it by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) individually. The results showed that AMPK was highly phosphorylated and suppressed mTOR/S6K1 activation in CLP rats. In vitro when AMPK was activated by AICAR, protein synthesis was suppressed and leucine resistance was observed. High phosphorylation of AMPK was accompanied by PKB inactivation in CLP rats. When PKB was blocked, both AMPK activation and leucine resistance were observed. In CLP rats, nutrition support with intensive insulin therapy reversed leucine resistance by activating PKB and suppressing AMPK phosphorylation. These findings suggest that high phosphorylation of AMPK induced by PKB inactivation in sepsis suppresses mTOR, S6K1 phosphorylation, and protein synthesis and leads to leucine resistance. Intensive insulin treatment can reverse leucine resistance by suppressing AMPK activation through activation of PKB.

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Canonical signaling and nuclear activity of mTOR—a teamwork effort to regulate metabolism and cell growth

Cited by 57 publications

References 124 publications

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

Novel therapeutic roles of MC‐4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways

AMPK activation suppresses mTOR/S6K1 phosphorylation and induces leucine resistance in rats with sepsis

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