Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy

Davogustto, Giovannis E; Salazar, Rebecca; Vásquez, Hernán; Karlstaedt, Anja; Dillon, William P.; Guthrie, Paul D.; Martin, Joseph R.; Vitrac, Heidi; Guardia, Gina De La; Vela, Deborah; Ribas‐Latre, Aleix; Baumgartner, Corrine; Eckel‐Mahan, Kristin; Taegtmeyer, Heinrich

doi:10.1016/j.yjmcc.2021.05.016

Cited by 23 publications

(20 citation statements)

References 56 publications

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“…These results are in line with similar findings in the myocardium in male C57BL/6J mice [ 71 ]. In addition, our findings regarding mTOR expression and cardiac remodeling in the 5.5CG coincided, to some extent, with recent data indicating that mTORC1 activation via inducible cardiac-specific TSC2 knockdown results in hypertrophy without contractile dysfunction [ 75 ].…”

Section: Discussionsupporting

confidence: 88%

Effects of caloric overload before caloric restriction in the murine heart

Maldonado

Chen

Duan

et al. 2022

Aging

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The beneficial effects of caloric restriction (CR) against cardiac aging and for prevention of cardiovascular diseases are numerous. However, to our knowledge, there is no scientific evidence about how a high-calorie diet (HCD) background influences the mechanisms underlying CR in whole heart tissue (WHT) in experimental murine models. In the current study, CR-treated mice with different alimentary backgrounds were subjected to transthoracic echocardiographic measurements. WHT was then analyzed to determine cardiac energetics, telomerase activity, the expression of energy-sensing networks, tissue-specific adiponectin, and cardiac precursor/cardiac stem cell markers. Animals with a balanced diet consumption before CR presented marked cardiac remodeling with improved ejection fraction (EF) and fractional shortening (FS), enhanced OXPHOS complex I, III, and IV, and CKMT2 enzymatic activity. Mice fed an HCD before CR presented moderate changes in cardiac geometry with diminished EF and FS values, but improved OXPHOS complex IV and CKMT2 activity. Differences in cardiac remodeling, left ventricular systolic/diastolic performance, and mitochondrial energetics, found in the CR-treated mice with contrasting alimentary backgrounds, were corroborated by inconsistencies in the expression of mitochondrial-biogenesis-related markers and associated regulatory networks. In particular, disruption of eNOS and AMPK -PGC-1α-mTOR-related axes. The impact of a past habit of caloric overload on the effects of CR in the WHT is a scarcely explored subject that requires deeper study in combination with analyses of other tissues and organs at higher levels of organization within the organ system. Such research will eventually lead to the development of preventative and therapeutic strategies to promote health and longevity.

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Section: Discussionsupporting

confidence: 88%

Effects of caloric overload before caloric restriction in the murine heart

Maldonado

Chen

Duan

et al. 2022

Aging

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“…In spite of the presence of metabolic and structural signatures typical of proliferating cells, enhanced cell cycle activity, and DNA replication in the heart, none of these markers represent a direct surrogate for new myocytes formation, and even increased detection of AURKB is not always indicative of successful cytokinesis [ 11 , 18 ]. Unlike during the embryonic and neonatal stages, energetic reliance on glycolysis and activation of proliferation pathways including the ERK1/2, PI3K/AKT and mTOR pathways in the postnatally stressed heart are usually associated with hypertrophic rather than hyperplasic growth [ 9 , 25 , 31 ]. This results in increased polyploidization and multinucleation of myocytes in the injured myocardial tissue, two nuclear events which are paradoxically known to contribute to the loss of proliferative capacity of those cells [ 16 , 28 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Prolonged cardiac NR4A2 activation causes dilated cardiomyopathy in mice

2022

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Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, and death within 40 days. Chronic NR4A2 induction also precipitated cardiac decompensation during transverse aortic constriction (TAC)-induced pressure overload. Mechanistically, NR4A2 caused adult cardiac myocytes to return to a fetal-like phenotype, with a switch to glycolytic metabolism and disassembly of sarcomeric structures. NR4A2 also re-activated cell cycle progression and stimulated DNA replication and karyokinesis but failed to induce cytokinesis, thereby promoting multinucleation of cardiac myocytes. Activation of cell cycle checkpoints led to induction of an apoptotic response which ultimately resulted in excessive loss of cardiac myocytes and impaired left ventricular contractile function. In summary, myocyte-specific overexpression of NR4A2 in the postnatal mammalian heart results in increased cell cycle re-entry and DNA replication but does not result in cardiac myocyte division. Our findings expose a novel function for the nuclear receptor as a critical regulator in the self-renewal of the cardiac myocyte and heart regeneration.

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“…Similar, metabolite extractions using organic solvents (e.g., methanol:water, 80:20 w/w) quench metabolic profiles and help to reduce enzymatic activities. Measuring more instable metabolites such as NADPH or AMP, a mixture of acetonitrile:methanol:water (40:40:20, w/w) with 0.1 M formic acid can effectively capture and preserve readouts ( 86 , 91 ). Additionally, adding internal standards during sample extraction can help tracking sample loss and allows correction between batches ( 87 ).…”

Section: Stable-isotope Tracer Methods For Measuring Cardiac Metabolism In Vivo and Ex Vivomentioning

confidence: 99%

Stable Isotopes for Tracing Cardiac Metabolism in Diseases

Karlstaedt

2021

Front. Cardiovasc. Med.

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Although metabolic remodeling during cardiovascular diseases has been well-recognized for decades, the recent development of analytical platforms and mathematical tools has driven the emergence of assessing cardiac metabolism using tracers. Metabolism is a critical component of cellular functions and adaptation to stress. The pathogenesis of cardiovascular disease involves metabolic adaptation to maintain cardiac contractile function even in advanced disease stages. Stable-isotope tracer measurements are a powerful tool for measuring flux distributions at the whole organism level and assessing metabolic changes at a systems level in vivo. The goal of this review is to summarize techniques and concepts for in vivo or ex vivo stable isotope labeling in cardiovascular research, to highlight mathematical concepts and their limitations, to describe analytical methods at the tissue and single-cell level, and to discuss opportunities to leverage metabolic models to address important mechanistic questions relevant to all patients with cardiovascular disease.

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Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy

Cited by 23 publications

References 56 publications

Effects of caloric overload before caloric restriction in the murine heart

Effects of caloric overload before caloric restriction in the murine heart

Prolonged cardiac NR4A2 activation causes dilated cardiomyopathy in mice

Stable Isotopes for Tracing Cardiac Metabolism in Diseases

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