mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4

Park, Yeonwoo; Reyna-Neyra, Andrea; Philippe, Lucas; Thoreen, Carson C.

doi:10.1016/j.celrep.2017.04.042

Cited by 215 publications

(228 citation statements)

References 28 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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“…Given the prominent role of mTOR in regulating mRNA translation, modulation of mTOR signaling by various stimuli could be a major conduit used to influence the synthesis and thus the activity of a specific transcription factor. However, this mechanism has been observed for only two factors, namely in ATF4‐mediated regulation of purine synthesis and cellular amino acid supply , and in HIF‐1α‐dependent neoangiogenesis and glycolysis . A more prominent mechanism is mTOR signaling‐dependent cellular localization of transcription factors, a process sometimes linked with direct phosphorylation of the factor by mTOR.…”

Section: Modulation Of Transcription Factor Activity By Mtor Signalingmentioning

confidence: 99%

“…It is now well documented that manipulating mTOR signaling, whether by genetic or pharmacological means, influences the expression of sizable gene networks involved in cell growth and proliferation, most particularly metabolic genes . Gene regulation by mTOR signaling could be occurring via two major mechanisms: either indirectly by modulating the epigenome as well as the activity of transcription factors, including the three RNA polymerases, or directly by nmTOR acting as a transcription factor or cofactor on chromatin.…”

Section: Introductionmentioning

confidence: 99%

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

Giguère

2018

The FEBS Journal

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Mechanistic (or mammalian) target of rapamycin (mTOR) is a kinase that regulates almost all functions related to cell growth and metabolism in response to extra-and intracellular stimuli, such as availability of nutrients, the presence of growth factors, or the energy status of the cell. As part of two distinct protein complexes, mTORC1 and mTORC2, the kinase has been shown to influence cell growth and proliferation by controlling ribosome biogenesis, mRNA translation, carbohydrate and lipid metabolism, protein degradation, autophagy as well as microtubule and actin dynamics. In addition to these well-characterized functions, mTOR can also influence gene transcription. While most studies focused on investigating how canonical mTOR signaling regulates the activity of transcription factors outside the nucleus, recent findings point to a more direct role for mTOR as a transcription factor operating on chromatin in the nucleus. In particular, recent genome-wide identification of mTOR targets on chromatin reveals that its activities in the nucleus and cytoplasm are functionally and biologically linked, thus uncovering a novel paradigm in mTOR function.

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“…mTORC1 activation and subsequent enhanced protein synthesis exacerbate ER stress, which is partially regulated by mTORC1. mTORC1 controls the activating transcription factor 4 (ATF4), a key effector of the integrated stress response …”

Section: Lysosomes In Pancreatic β‐Cells: From Physiology To Diabetesmentioning

confidence: 99%

“…mTORC1 controls the activating transcription factor 4 (ATF4), a key effector of the integrated stress response. 80 While the mTORC1-dependent increase of β-cell mass is beneficial in short-term, prolonged constitutive mTORC1 activation in pancreatic β-cells appears to be deleterious. In fact, mice selectively lacking TSC2 in pancreatic β-cells (which resulted in a chronic activation of mTORC1) develop T2D in an age-dependent manner.…”

Section: Mtorc1 Signalling In β-Cellsmentioning

confidence: 99%

Lysosomes in nutrient signalling: A focus on pancreatic β‐cells

Mészáros

Pasquier

Vivot

et al. 2018

Diabetes Obesity Metabolism

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Regulated insulin secretion from pancreatic β-cells is a major process maintaining glucose homeostasis in mammals. Enhancing insulin release in response to chronic nutrient overload and obesity-related insulin resistance (pre-diabetes) requires several adaptive cellular mechanisms maintaining β-cell health under such stresses. Once these mechanisms are overwhelmed, β-cell failure occurs leading to full-blown Type 2 Diabetes (T2D). Nutrient-dependent macroautophagy represents one such adaptive mechanism in β-cells. While macroautophagy levels are high and protective in β-cells in pre-diabetes, they decrease at later stages contributing to β-cell failure. However, mechanisms compromising macroautophagy in β-cells remain poorly understood. In this review, we discuss how recently discovered signalling cascades that emanate from the limiting membrane of lysosomes contribute to changes in macroautophagy flux in physiology and disease. In particular, these mechanisms are put into context with β-cell function highlighting most recently described links between nutrient-dependent lysosomal signalling pathways and insulin secretion. Understanding these mechanisms in response to metabolic stress might pave the way for development of more tailored treatment strategies aimed at preserving β-cell health.

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mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4

Cited by 215 publications

References 28 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

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

Lysosomes in nutrient signalling: A focus on pancreatic β‐cells

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