scholarly journals Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mehrshad Sadria ◽  
Anita T. Layton
Keyword(s):  
Energy Balance ◽  
Computational Model ◽  
Metabolic Stress ◽  
Cellular Aging ◽  
Signalling Pathways ◽  
Environmental Signals ◽  
Metabolic Signalling ◽  
The Face ◽  
Cell Energy ◽  
Salvage Pathways

Abstract Background Cells adapt their metabolism and activities in response to signals from their surroundings, and this ability is essential for their survival in the face of perturbations. In tissues a deficit of these mechanisms is commonly associated with cellular aging and diseases, such as cardiovascular disease, cancer, immune system decline, and neurological pathologies. Several proteins have been identified as being able to respond directly to energy, nutrient, and growth factor levels and stress stimuli in order to mediate adaptations in the cell. In particular, mTOR, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and energy balance in mammals. Methods To understand the complex interactions of these signalling pathways and environmental signals, and how those interactions may impact lifespan and health-span, we have developed a computational model of metabolic signalling pathways. Specifically, the model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and the amino acid sensors such as sestrin, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+ -consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α. Results The model simulates the interactions among key regulators such as AKT, mTORC1, AMPK, NAD+ , and SIRT, and predicts their dynamics. Key findings include the clinically important role of PRAS40 and diet in mTORC1 inhibition, and a potential link between SIRT1-activating compounds and premature autophagy. Moreover, the model captures the exquisite interactions of leucine, sestrin2, and arginine, and the resulting signal to the mTORC1 pathway. These results can be leveraged in the development of novel treatment of cancers and other diseases. Conclusions This study presents a state-of-the-art computational model for investigating the interactions among signaling pathways and environmental stimuli in growth, ageing, metabolism, and diseases. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and assess their functional implications on longevity and ageing‐related diseases.

scholarly journals Interactions Among mTORC, AMPK and SIRT A Computational Model for Cell Energy Balance and Metabolism

2020 ◽  
Author(s):  
Mehrshad Sadria ◽  
Anita T. Layton
Keyword(s):  
Energy Balance ◽  
Computational Model ◽  
Metabolic Stress ◽  
Cellular Aging ◽  
Signalling Pathways ◽  
Environmental Signals ◽  
Metabolic Signalling ◽  
The Face ◽  
Cell Energy ◽  
Salvage Pathways

Abstract BackgroundCells adapt their metabolism and activities in response to signals from their surroundings, and this ability is essential for their survival in the face of perturbations. In tissues a deficit of these mechanisms is commonly associated with cellular aging and diseases, such as cardiovascular disease, cancer, immune system decline, and neurological pathologies. Several proteins have been identified as being able to respond directly to energy, nutrient, and growth factor levels and stress stimuli in order to mediate adaptations in the cell. In particular, mTOR, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and energy balance in mammals.MethodsTo understand the complex interactions of these signalling pathways and environmental signals, and how those interactions may impact lifespan and health-span, we have developed a computational model of metabolic signalling pathways. Specifically, the model includes the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and the amino acid sensors such as sestrin, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+-consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α.ResultsThe model simulates the interactions among key regulators such as Akt, mTORC1, AMPK, NAD+, and SIRT, and predicts their dynamics. Key findings include the clinically important role of PRAS40 and diet in mTORC1 inhibition, and a potential link between SIRT1-activating compounds and premature autophagy. Moreover, the model captures the exquisite interactions of leucine, sestrin2, and arginine, and the resulting signal to the mTORC1 pathway. These results can be leveraged in the development of novel treatment of cancers and other diseases.ConclusionsThis study presents a state-of-the-art computational model for investigating the interactions among signaling pathways and environmental stimuli in growth, ageing, metabolism, and diseases. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and assess their functional implications on longevity and ageing‐related diseases.

scholarly journals Interactions among mTORC, AMPK, and SIRT: A Computational Model for Cell Energy Balance and Metabolism

2020 ◽  
Author(s):  
Mehrshad Sadria ◽  
Anita T. Layton
Keyword(s):  
Computational Model ◽  
Chronic Stress ◽  
Metabolic Stress ◽  
Signalling Pathways ◽  
Degenerative Diseases ◽  
Health Span ◽  
Environmental Signals ◽  
Complex Interactions ◽  
Cellular Ageing

AbstractKey proteins such as mTORC, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and ageing mechanisms. An impairment in these mechanisms is commonly associated with cellular ageing and degenerative diseases. To understand the complex interactions of ageing□related signalling pathways and environmental signals, and the impacts on lifespan and health-span, we developed a computational model of ageing signalling pathways. The model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and amino acid sensors, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+-consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α. Key findings include the clinically important role of PRAS40, sestrin2, and diet in the treatment of cancers and other diseases, and a potential link between SIRT1-activating compounds and premature autophagy. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and to assess their functional implications on longevity and ageing□related diseases.Author SummaryIn cellular ageing, mitochondrial function declines over time, which affects normal mechanisms of cells and organisms and leads to myriad of degenerative diseases and other health problems. To investigate the mechanisms that affect the ageing process, we focus on pathways that play a key role in the management of metabolic stress: the mTORC, AMPK, and sirtuins pathways. Our goal is to understand the complex interactions of ageing and metabolism related signalling pathways and environmental signals, and the impacts on lifespan and health-span. To accomplish that goal, we developed a computational model of signalling pathways related to ageing and metabolism. By conducting model simulations, we have unraveled the clinically important role of PRAS40, sestrin2, and diet in the treatment of cancers and other diseases, and a double-edged sword effect of SIRT1-activating compounds in their use as a health remedy. We view this model as an essential step towards a tool for studying metabolism, longevity, and ageing-related diseases. By extending the present model as appropriate, we can simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress,.

scholarly journals Glycomacropeptide, a low-phenylalanine protein isolated from cheese whey, supports growth and attenuates metabolic stress in the murine model of phenylketonuria

2012 ◽  
Vol 302 (7) ◽  
pp. E885-E895 ◽  
Author(s):  
Patrick Solverson ◽  
Sangita G. Murali ◽  
Adam S. Brinkman ◽  
David W. Nelson ◽  
Murray K. Clayton ◽  
...  
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Lean Mass ◽  
Metabolic Stress ◽  
Casein Diet ◽  
Wild Type ◽  
Total Fat ◽  
Spleen Mass ◽  
Main Effects

Phenylketonuria (PKU) is caused by a mutation in the phenylalanine (phe) hydroxylase gene and requires a low-phe diet plus amino acid (AA) formula to prevent cognitive impairment. Glycomacropeptide (GMP) contains minimal phe and provides a palatable alternative to AA formula. Our objective was to compare growth, body composition, and energy balance in Pahenu2 (PKU) and wild-type mice fed low-phe GMP, low-phe AA, or high-phe casein diets from 3–23 wk of age. The 2 × 2 × 3 design included main effects of genotype, sex, and diet. Fat and lean mass were assessed by dual-energy X-ray absorptiometry, and acute energy balance was assessed by indirect calorimetry. PKU mice showed growth and lean mass similar to wild-type littermates fed the GMP or AA diets; however, they exhibited a 3–15% increase in energy expenditure, as reflected in oxygen consumption, and a 3–30% increase in food intake. The GMP diet significantly reduced energy expenditure, food intake, and plasma phe concentration in PKU mice compared with the casein diet. The high-phe casein diet or the low-phe AA diet induced metabolic stress in PKU mice, as reflected in increased energy expenditure and intake of food and water, increased renal and spleen mass, and elevated plasma cytokine concentrations consistent with systemic inflammation. The low-phe GMP diet significantly attenuated these adverse effects. Moreover, total fat mass, %body fat, and the respiratory exchange ratio (CO2 produced/O2 consumed) were significantly lower in PKU mice fed GMP compared with AA diets. In summary, GMP provides a physiological source of low-phe dietary protein that promotes growth and attenuates the metabolic stress induced by a high-phe casein or low-phe AA diet in PKU mice.

scholarly journals Evolution of Stress Response in the Face of Unreliable Environmental Signals

2012 ◽  
Vol 8 (8) ◽  
pp. e1002627 ◽  
Author(s):  
Markus Arnoldini ◽  
Rafal Mostowy ◽  
Sebastian Bonhoeffer ◽  
Martin Ackermann
Keyword(s):  
Stress Response ◽  
Environmental Signals ◽  
The Face

scholarly journals Protein Phosphatases in G1 Regulation

2020 ◽  
Vol 21 (2) ◽  
pp. 395 ◽  
Author(s):  
Ruth Martín ◽  
Vilte Stonyte ◽  
Sandra Lopez-Aviles
Keyword(s):  
Cell Cycle ◽  
Protein Phosphatases ◽  
Eukaryotic Cells ◽  
Signalling Pathways ◽  
Cyclin Dependent Kinase ◽  
Restriction Point ◽  
Environmental Signals ◽  
Substrate Phosphorylation ◽  
Cell Cycle Machinery

Eukaryotic cells make the decision to proliferate, to differentiate or to cease dividing during G1, before passage through the restriction point or Start. Keeping cyclin-dependent kinase (CDK) activity low during this period restricts commitment to a new cell cycle and is essential to provide the adequate timeframe for the sensing of environmental signals. Here, we review the role of protein phosphatases in the modulation of CDK activity and as the counteracting force for CDK-dependent substrate phosphorylation, in budding and fission yeast. Moreover, we discuss recent findings that place protein phosphatases in the interface between nutritional signalling pathways and the cell cycle machinery.

scholarly journals Priority directions of development “Uzbekneftegas” jsc in the conditions of globalization of the world economy

2019 ◽  
Vol 139 ◽  
pp. 01008
Author(s):  
G.Zh. Allaeva
Keyword(s):  
Economic Development ◽  
Energy Balance ◽  
Natural Gas ◽  
World Economy ◽  
Economic Globalization ◽  
Hydrocarbon Production ◽  
The World ◽  
The Face ◽  
The Republic

The article considers the role of “Uzbekneftegas” JSC in the economic development of the fuel and energy complex of the Republic in the face of increasing global economic globalization. The structure of the company, the priority areas for the development of JSC activities are shown. The perspective directions in hydrocarbon production are considered. The data on the production, use and distribution of natural gas by sectors of the economy of Uzbekistan are presented, and the structure of the energy balance of the Republic of Uzbekistan is shown.

scholarly journals Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

2020 ◽  
Vol 21 (14) ◽  
pp. 5165 ◽  
Author(s):  
Mara Bonelli ◽  
Rita Terenziani ◽  
Silvia Zoppi ◽  
Claudia Fumarola ◽  
Silvia La Monica ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Glucose Uptake ◽  
Asbestos Exposure ◽  
Metabolic Stress ◽  
Mtor Inhibitors ◽  
Mtor Signaling ◽  
Metabolic Effects ◽  
Hypoxic Conditions ◽  
Cell Energy ◽  
Dual Blockade

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

Genetics of food intake, live weight, condition score and energy balance

1999 ◽  
Vol 24 ◽  
pp. 63-73 ◽  
Author(s):  
R. F. Veerkamp ◽  
E. P. C. Koenen
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Weight Change ◽  
Genetic Selection ◽  
Metabolic Stress ◽  
Live Weight ◽  
Food Utilization ◽  
Score Change ◽  
Condition Score ◽  
Selection For

AbstractThe objectives of this study were to investigate genetic variation for traits that are part of the food utilization complex and to investigate the scope for future genetic improvement of traits possibly linked to metabolic stress: live weight (change), condition score (change) and energy balance. Many aspects of the food utilization complex appear to be heritable and are affected by genetic selection for yield. In general, genetic selection for yield increases intake and body tissue mobilization and energy balance is expected to decrease. However, unfavourable effects of genetic selection can be compensated for by measuring additional traits to be included in breeding programmes. Food intake, live weight (change) and condition score (change) are all potential options. Which traits should be measured, at what lactation stages and in which (nutritional) environment will merely depend on the coheritability with health and fertility, the genetic correlation with milk yield and the cost of measuring the trait effectively in a breeding programme.

scholarly journals AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Nicolas Aznar ◽  
Arjun Patel ◽  
Cristina C Rohena ◽  
Ying Dunkel ◽  
Linda P Joosen ◽  
...  
Keyword(s):  
Tight Junctions ◽  
Metabolic Stress ◽  
Cell Junctions ◽  
Epithelial Polarity ◽  
Energetic Stress ◽  
The Face ◽  
Epithelial Tight Junctions ◽  
And Function ◽  
Necessary And Sufficient ◽  
Suppressive Action

Loss of epithelial polarity impacts organ development and function; it is also oncogenic. AMPK, a key sensor of metabolic stress stabilizes cell-cell junctions and maintains epithelial polarity; its activation by Metformin protects the epithelial barrier against stress and suppresses tumorigenesis. How AMPK protects the epithelium remains unknown. Here, we identify GIV/Girdin as a novel effector of AMPK, whose phosphorylation at a single site is both necessary and sufficient for strengthening mammalian epithelial tight junctions and preserving cell polarity and barrier function in the face of energetic stress. Expression of an oncogenic mutant of GIV (cataloged in TCGA) that cannot be phosphorylated by AMPK increased anchorage-independent growth of tumor cells and helped these cells to evade the tumor-suppressive action of Metformin. This work defines a fundamental homeostatic mechanism by which the AMPK-GIV axis reinforces cell junctions against stress-induced collapse and also provides mechanistic insight into the tumor-suppressive action of Metformin.

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