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Cardiac pathways of protein and energy metabolism in health and disease

English title Cardiac pathways of protein and energy metabolism in health and disease
Applicant Brink Marijke
Number 135559
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cardiovascular Research
Start/End 01.05.2011 - 31.10.2015
Approved amount 321'273.00
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All Disciplines (4)

Discipline
Cardiovascular Research
Biochemistry
Cellular Biology, Cytology
Molecular Biology

Keywords (6)

hypertrophy; growth factors; cardiac remodeling; heart failure; signal transduction; G-protein coupled receptors

Lay Summary (English)

Lead
Lay summary

Cardiac pathways of protein and energy metabolism in health and disease

The heart is a plastic organ, which gradually changes its geometry, cellular composition and function during the development of metabolic and cardiovascular disease, especially hypertension and ischemic heart disease, but also independently during obesity and diabetes. Specific cardiac changes are associated with disturbed neurohormonal balances and inflammatory responses and if pathological triggers are not controlled in a timely manner, heart failure may develop. Heart failure is a most pressing health problem and economic burden because it affects high numbers of elderly individuals in our Western society.

Relevant to the adaptive and maladaptive cardiac growth responses occurring in the above-mentioned pathologies, we have previously analyzed the pathways by which the inflammatory mediator tumor necrosis factor (TNF)-a  and the metabolic mediator insulin-like growth factor (IGF)-I regulate protein translation and degradation in  myocytes. We demonstrated that IGF-I stimulates protein translation via mammalian target of rapamycin (mTOR) and blocks TNF-a-induced expression of atrogin-1, an enzyme known to target sarcomere proteins for proteasomal degradation and to cause atrophy. mTOR occurs in two functionally and structurally distinct protein complexes, mTORC1 and mTORC2, of which the cardiac functions are not known. The present project aims to determine how mTOR regulates protein turnover and energy metabolism via mTORC1 and mTORC2 under baseline conditions and during adaptations of the heart to physiological or pathological stress. To this end, we have developed mouse models from which raptor and rictor, essential components of mTORC1 and mTORC2, respectively, are deleted in a temporally controlled and cardiomyocyte specific manner. Our data obtained to date show that mTORC1 inactivation causes dilated cardiomyopathy within six weeks and that the development of dysfunction is precipitated under conditions of increased cardiac work induced by exercize or by aortic constriction. We will use these in vivo models in combination with primary cardiomyocyte cultures to further dissect the signaling pathways and mechanisms that are involved.

The better understanding of cardiac growth regulatory pathways that we will obtain with our studies may contribute to a rationale for better prevention as well as to the identification of new therapeutic targets to treat cardiac disease at an early stage. Moreover, since mTOR inhibitors have strong potential as immunosuppressive and anti-cancer drugs, knowledge on the cardiac functions of mTORC1 and mTORC2 is important.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
mTOR, cardiomyocytes and inflammation in cardiac hypertrophy
Xu Lifen, Brink Marijke (2016), mTOR, cardiomyocytes and inflammation in cardiac hypertrophy, in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1863(7), 1894-1903.
Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes
Pentassuglia Laura, Heim Philippe, Lebboukh Sonia, Morandi Christian, Xu Lifen, Brink Marijke (2016), Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes, in American Journal of Physiology-Endocrinology and Metabolism, 310(9), E782-E794.
Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy
Shende Pankaj, Xu Lifen, Morandi Christian, Pentassuglia Laura, Heim Philippe, Lebboukh Sonia, Berthonneche Corinne, Pedrazzini Thierry, Kaufmann Beat A., Hall Michael N., Rüegg Markus A., Brink Marijke (2015), Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy, in Cardiovascular Research, 109, 103-114.
Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice.
Shende Pankaj, Plaisance Isabelle, Morandi Christian, Pellieux Corinne, Berthonneche Corinne, Zorzato Francesco, Krishnan Jaya, Lerch René, Hall Michael N, Rüegg Markus A, Pedrazzini Thierry, Brink Marijke (2011), Cardiac raptor ablation impairs adaptive hypertrophy, alters metabolic gene expression, and causes heart failure in mice., in Circulation, 123(10), 1073-82.
European Perspectives in Cardiology - Spotlight Marijke Brink
Brink Marijke and Nichols Marc (2011), European Perspectives in Cardiology - Spotlight Marijke Brink, Circulation, LWW (Wolters Kluwer), USA.

Collaboration

Group / person Country
Types of collaboration
Michael Hall / Biozentrum Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Duska Dragun / Charité Berlin Germany (Europe)
- Publication
- Exchange of personnel
René Lerch / Hopital Cantonal Genève Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Markus Rüegg / Biozentrum Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Thierry Pedrazzini / Department of Medicine Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
International Society of Heart Research 33rd Annual Meeting Poster Regulators and effectors of mTORC2 in the heart 30.06.2015 Bordeaux, France Brink Marijke;
8th Ascona Workshop on Cardiomyocyte Biology 2015 Talk given at a conference Regulators and effectors of mTORC2 in the heart 03.05.2015 Ascona Monte Verita, Switzerland Brink Marijke;
8th Ascona Workshop on Cardiomyocyte Biology 2015 Poster 3 poster presentations (Heim, Lebboukh, Xu) 03.05.2015 Ascona Monte Verita, Switzerland Lebboukh Sonia; Brink Marijke; Heim Philippe; Xu Lifen;
Cardiovascular and Metabolic Research Meeting 2015 Talk given at a conference 1 selected oral (Lebboukh) and 2 poster (Xu, Battilana) presentations 22.01.2015 Fribourg, Switzerland Xu Lifen; Brink Marijke; Lebboukh Sonia;
Cardiovascular and Metabolic Research Meeting 2015 Talk given at a conference Invited Keynote Lecture: "Inhibiting mTOR: helping or harming the heart?" 22.01.2015 Fribourg, Switzerland Brink Marijke;
Cardiovascular and Metabolic Research Meeting 2016 Talk given at a conference Neuregulin1β promotes glucose uptake in cardiomyocytes via Src/mTORC2 and IRS-1 14.01.2015 Fribourg, Switzerland Heim Philippe; Brink Marijke; Xu Lifen;
Targeting the Kinome 2014 Poster Nrg1β enhances glucose uptake in cardiomyocytes via mTOR, Src and Akt 26.09.2014 Basel, Switzerland Xu Lifen; Brink Marijke;
Frontiers in CardioVascular Biology 2014 Poster The effect of rapamycin in cardiac mTORC2-deficient mice under pressure overload conditions 04.07.2014 Barcelona, Italy Shende Pankaj S.; Xu Lifen; Brink Marijke;
Frontiers in Cardiovascular Biology 2014 Poster Nrg1beta enhances glucose uptake in cardiomyocytes via mTOR, Src and Akt 04.07.2014 Barcelona, Italy Xu Lifen; Lebboukh Sonia; Brink Marijke;
Gordon Research Conference "Cardiac Regulatory Mechanisms" 2014 Poster EFFECTS OF RAPAMYCIN IN CARDIAC MTORC2-DEFICIENT MICE 08.06.2014 New London, NH , United States of America Brink Marijke; Xu Lifen; Shende Pankaj S.;
ESC - Heart Failure Association Winter Research Meeting on Translational Research 2013 Poster Cardiac mTORC2 inac.va.on promotes apoptosis and accelerates the progression to dysfunc.on in pressure-­‐overload hypertrophy 23.01.2014 Les Diablerets, Switzerland Xu Lifen; Brink Marijke; Lebboukh Sonia; Shende Pankaj S.;
Cardiovascular and Metabolic Research Conference 2014 Poster 3 poster presentations (Xu / Lebboukh / Pentassuglia) 16.01.2014 Fribourg, Switzerland Brink Marijke; Lebboukh Sonia; Xu Lifen;
Annual Meeting of the Swiss Society of Cardiology 2013 Talk given at a conference Cardiac mTORC2 inactivation promotes apoptosis and autophagy and accelerates the progression to dysfunction in pressure overload hypertrophy 12.06.2013 Lugano, Switzerland Xu Lifen; Shende Pankaj S.; Brink Marijke;
AGLA and Cardiovascular and Cardiovascular Biology Meeting 2013 Talk given at a conference 1 selected oral (Heim) and 2 poster (Pentassuglia, Xu) presentations 16.01.2013 Fribourg, Switzerland Heim Philippe; Brink Marijke; Xu Lifen;
European Society of Cardiology - Annual Meeting 2012 Talk given at a conference Invited talk: mTORC1 - A link between altered cardiac metabolism and heart failure 26.08.2012 München, Germany Brink Marijke;
Annual Meeting of the Swiss Society of Cardiology 2012 Poster Rictor is involved in the adaptive response of the heart to pressure overload 12.06.2012 Lausanne, Switzerland Xu Lifen; Brink Marijke; Shende Pankaj S.;
Swiss Cardiovascular Research and Clinical Implications Meeting 2011 Talk given at a conference 2 selected oral (Pentassuglia / Xu) and 1 poster presentation (Shende) 07.10.2011 Muntelier / Murten, Switzerland Brink Marijke; Xu Lifen; Shende Pankaj S.;
TOR, PI3K and Akt - 20 years on (2011) Poster Rictor/mTORC2 regulates cardiac function under conditions of pressure overload but not during postnatal cardiac growth 11.09.2011 Basel, Switzerland Shende Pankaj S.; Brink Marijke;


Self-organised

Title Date Place
7th Ascona International Workshop on Cardiomyocyte Biology 2012 28.04.2012 Ascona Monte Verita, Switzerland

Awards

Title Year
Young Investigator Award of the European Society of Cardiology 2011

Associated projects

Number Title Start Funding scheme
116483 Regulation of protein turnover in cardiac muscle by the ubiquitin proteasome pathway 01.05.2007 Project funding (Div. I-III)
169996 Gender-specific mechanisms of cardiac dysfunction in obesity 01.10.2016 Project funding (Div. I-III)
204537 Neuregulin-induced cardioprotection in doxorubicin-treated xenograft models 01.10.2021 Project funding (Div. I-III)
67176 Mechanisms of cardiac cachexia: role of angiotensin II, insulin- like growth factor-I, TNF-alpha, and corticosterone 01.07.2002 Project funding (Div. I-III)
61896 Catabolic actions of angiotensin II in skeletal muscle and their dependency on the autocrine insulin-like growth factor-I system, glucocorticoids and TNF-alpha 01.12.2000 Project funding (Div. I-III)

Abstract

The heart is a plastic organ which gradually changes its geometry, cellular composition and function during the development of metabolic and cardiovascular disease, especially hypertension and ischemic heart disease but also independently during obesity and diabetes. Specific cardiac changes are associated with disturbed neurohormonal balances and inflammatory responses and if pathological triggers are not controlled in a timely manner, heart failure may develop. Heart failure is a most pressing health problem and economic burden because it affects high numbers of elderly individuals in our Western society.Relevant to adaptive and maladaptive cardiac growth responses occurring in the above-mentioned pathologies, my laboratory has previously established pathways by which the inflammatory mediator tumor necrosis factor (TNF)-a and the metabolic mediator insulin-like growth factor (IGF)-I regulate protein translation and degradation in myocytes. We demonstrated that IGF-I stimulates protein translation via mammalian target of rapamycin (mTOR) and blocks TNF-a-induced expression of atrogin-1, an enzyme known to target sarcomere proteins for proteasomal degradation and cause atrophy. mTOR occurs in two functionally and structurally distinct protein complexes, mTORC1 and mTORC2, of which the functions in health and during cardiac remodeling are not known. The research proposed here aims to place these two branches of mTOR signaling into heart-specific pathways of atrophy and hypertrophy induced by stimuli such as insulin, IGF-I, TNF-a and phenylephrine. Thus, we will use our recent mechanistic insights to assess how mTOR coordinates protein turnover and energy metabolism via mTORC1 and mTORC2 under baseline conditions and during adaptations of the heart to physiological or pathological stress. To this end, we have developed mouse models from which raptor and rictor, essential components of mTORC1 and mTORC2, are deleted in a temporally-controlled and cardiomyocyte specific manner. Data obtained to date show that cardiac mTORC1 inactivition causes dilated cardiomyopathy within six weeks and that the development of dysfuncion is precipitated under conditions of increased cardiac preload or afterload. We will use these in vivo models in combination with primary cardiomyocyte cultures to analyze the distinct mTOR-mediated cellular mechanisms that affect cardiac function. Our specific aims are:1: to dissect the molecular and cellular pathways in which mTORC1 and mTORC2 are implicated in the heart under baseline conditions.2: to test if mTORC2 inactivation leads to reduced cardiac function via changed metabolism under conditions of cardiac stress.3: to identify compensatory pathways of muscle protein synthesis in sedentary and exercising mice.The better understanding of cardiac growth regulatory pathways that we will obtain with our studies may contribute to a rationale for better prevention as well as to the identification of new therapeutic targets to treat cardiac disease at an early stage. Moreover, since mTOR inhibitors have strong potential as immunosuppressive and anti-cancer drugs, knowledge on the cardiac functions of mTORC1 and mTORC2 is important.
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