scholarly journals Matrix Revisited

2014 ◽  
Vol 114 (4) ◽  
pp. 717-729 ◽  
Author(s):  
Andrew N. Carley ◽  
Heinrich Taegtmeyer ◽  
E. Douglas Lewandowski
Keyword(s):  
Cellular Response ◽  
Contractile Function ◽  
Pressure Overload ◽  
Metabolic Phenotype ◽  
Metabolic Enzyme ◽  
Energetic Efficiency ◽  
Mitochondrial Matrix ◽  
Metabolic Intermediates ◽  
Signaling Mechanisms ◽  
Metabolic Reserve

Metabolic signaling mechanisms are increasingly recognized to mediate the cellular response to alterations in workload demand, as a consequence of physiological and pathophysiological challenges. Thus, an understanding of the metabolic mechanisms coordinating activity in the cytosol with the energy-providing pathways in the mitochondrial matrix becomes critical for deepening our insights into the pathogenic changes that occur in the stressed cardiomyocyte. Processes that exchange both metabolic intermediates and cations between the cytosol and mitochondria enable transduction of dynamic changes in contractile state to the mitochondrial compartment of the cell. Disruption of such metabolic transduction pathways has severe consequences for the energetic support of contractile function in the heart and is implicated in the pathogenesis of heart failure. Deficiencies in metabolic reserve and impaired metabolic transduction in the cardiomyocyte can result from inherent deficiencies in metabolic phenotype or maladaptive changes in metabolic enzyme expression and regulation in the response to pathogenic stress. This review examines both current and emerging concepts of the functional linkage between the cytosol and the mitochondrial matrix with a specific focus on metabolic reserve and energetic efficiency. These principles of exchange and transport mechanisms across the mitochondrial membrane are reviewed for the failing heart from the perspectives of chronic pressure overload and diabetes mellitus.

Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ludovic O Bénard ◽  
Daniel S Matasic ◽  
Mathilde Keck ◽  
Anne-Marie Lompré ◽  
Roger J Hajjar ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Aortic Banding ◽  
Cross Section Area ◽  
Abdominal Aortic ◽  
Section Area

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding. Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure. Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control. While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice. This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.

Investigations of Intercellular Mitochondrial Transfer in Neural Cells by Applied Single Molecule Genotyping

2021 ◽  
Author(s):  
◽  
Matthew Rowe
Keyword(s):  
Cell Line ◽  
Single Molecule ◽  
Cellular Response ◽  
Rolling Circle Amplification ◽  
Metabolic Phenotype ◽  
Neural Cells ◽  
Mitochondrial Transfer ◽  
Mitochondrial Ribosome

<p>Over the past decade and a half, evidence for transfer of whole mitochondria between mammalian cells has emerged in the literature. The notion that mitochondria are restricted to the cell of origin has been overturned by this curious phenomenon, yet the physiological relevance of these transfer events remains unclear.   This thesis investigates intercellular mitochondrial transfer in co-cultures of neural cells in vitro, to understand whether neural cells placed under stress demonstrate an enhanced rate of intercellular mitochondrial transfer. This would implicate the phenomenon as a cellular response to stress.   Reliable techniques for quantitative study of intercellular mitochondrial transfer are limited so far in this field. To address this, a novel quantitative approach was developed to detect intercellular mitochondrial transfer, based on single molecule genotyping by target-primed rolling circle amplification. This enabled imaging of individual mitochondrial DNA molecules in situ, to detect those molecules which had moved between cells. Through this strategy, intercellular mitochondrial transfer was detected in new in vitro co-culture models.   Primary murine pericytes derived from brain microvessels, were found to readily transfer mitochondria to a murine astrocyte cell line in vitro. Cisplatin, a DNA damaging agent; and chloramphenicol, a mitochondrial ribosome inhibitor, used to induce acute cellular injuries in the murine astrocyte cell line. These injuries were characterised and found to induce apoptosis, cause changes in growth characteristics, mitochondrial gene expression, and alter the metabolic phenotype of the cells. A derivative of the astrocyte cell line which completely lacks mitochondrial respiration, was found to model a chronic metabolic injury.  As pericytes are prevalent throughout the brain, the pericyte/astrocyte co-culture model was selected to evaluate how the rate of intercellular mitochondrial transfer was altered, when the astrocytes were injured prior to co-culture. Through in situ single molecule genotyping and high throughput confocal microscopy, quantitative data was produced on how the rate of intercellular mitochondrial transfer was altered by injury in these models. The rate of intercellular mitochondrial transfer remained unaltered by chloramphenicol, however both cisplatin and the chronic metabolic injury model demonstrated reduced numbers of pericyte mitochondrial DNAs transferred into the injured astrocytes.   These studies demonstrate successful application of a novel approach to study intercellular mitochondrial transfer and enable quantitative studies of this phenomenon.</p>

Contractile function in chronic gradually developing subcoronary aortic stenosis

1981 ◽  
Vol 240 (1) ◽  
pp. H80-H84
Author(s):  
B. A. Carabello ◽  
R. Mee ◽  
J. J. Collins ◽  
R. A. Kloner ◽  
D. Levin ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Cardiac Muscle ◽  
Animal Studies ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Stroke Work ◽  
Group A ◽  
Group B

Whether hypertrophied cardiac muscle functions normally or abnormally is a point of controversy in the literature. Most animal studies showing depressed performance of hypertrophied cardiac muscle have used experimental methods in which hypertrophy was produced by acutely imposing a pressure overload on the left or right ventricle, which may cause myocardial injury. To assess the possibility that chronic, slowly developing hypertrophy is associated with normal myocardial function, we developed an experimental model in which increased afterload is imposed gradually on the left ventricle in the dog. A snug band was placed around the aorta beneath the left coronary artery in puppies without producing a stenosis. As the puppies grew, relative aortic stenosis developed as increased cardiac output flowed across that fixed outflow area. One group (group A) of six puppies was banded early, whereas a second group (group B, five puppies) was banded late and served as controls. Left ventricular weight (g) to body weight (kg) ratio remained normal in group B animals (3.9 +/- 0.14), whereas this ratio was increased to 5.3 +/- 0.24 (P < 0.001) in group A animals indicating development of moderate cardiac hypertrophy. Ejection fraction, dP/dt, Vcf, and stroke work per gram of myocardium were virtually identical in both groups. We conclude that moderate, gradually developing cardiac hypertrophy as produced by this model is associated with normal myocardial contractile performance.

scholarly journals Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

Function ◽  
2020 ◽  
Vol 1 (2) ◽  
Author(s):  
Rachel Lopez ◽  
Bahador Marzban ◽  
Xin Gao ◽  
Ellen Lauinger ◽  
Françoise Van den Bergh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Free Energy ◽  
Inorganic Phosphate ◽  
Contractile Function ◽  
Adenine Nucleotides ◽  
Pressure Overload ◽  
Atp Synthesis ◽  
Whole Body ◽  
Metabolic Dysfunction ◽  
Mechanical Function

Abstract Cardiac mechanical function is supported by ATP hydrolysis, which provides the chemical-free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the capacity for ATP synthesis and associated free energy to drive cellular processes. Yet it remains unclear if and how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. We hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic constriction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to assess relationships between metrics of whole-organ pump function and myocardial energetic state. A multiscale computational model of cardiac mechanoenergetic coupling was used to identify and quantify the contribution of metabolic dysfunction to observed mechanical dysfunction. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates as well as a reduction in total levels of adenine nucleotides and creatine in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats are correlated with impaired mechanical function, consistent with the overall hypothesis. Furthermore, computational analysis of myocardial metabolism and contractile dynamics predicts that increased levels of inorganic phosphate in TAC compared to control animals kinetically impair the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.

P6276Impact of the cardiac specific deletion of AMPKalpha2 on the contractile and metabolic phenotype of the heart in male and female mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Grimbert ◽  
M N Sanz ◽  
C Rucker-Martin ◽  
M Novotova ◽  
M Gressette ◽  
...  
Keyword(s):  
Contractile Function ◽  
Left Ventricular ◽  
Metabolic Phenotype ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Male And Female ◽  
Female Mice ◽  
Sex Specificity ◽  
Specific Deletion

Abstract Introduction Mitochondrial dysfunction plays a major role in the Heart Failure (HF) pathophysiology.The AMP activated protein kinase (AMPK) is activated by a high AMP-ADP/ATP ratio and regulates a number of metabolic pathways. Many studies have highlighted a protective role of AMPK in HF, but its relevance to cardiac tissue, its metabolic part and its sex specificity are not well established. Purpose Then, the aim of this study is to determine the role of AMPK in the healthy and failing heart in male and female mice. Methods We developed and validated a mouse strain with an adult-inducible cardiac-specific deletion of AMPKα2, the major cardiac isoform, using the Cre-Lox system (40mg/kg tamoxifen injection on two consecutive days at adult age). At four months after the deletion, cardiac contractility, morphology and metabolism were studied in control and KO mice from both sexes. Results We observed only in male KO mice a decrease of left ventricular ejection fraction (−10%), an increase of the total fibrosis (+64%) and defects in mitochondrial structures. Male KO mice also showed a reduced (−28%) mitochondrial respiration via complex I associated with a different cardiolipin species distribution. Conclusion Our results reveal in adult healthy hearts, a sex-specificity in the effects of AMPKα2 deletion, leading to impaired contractile function related to metabolic and non-metabolic alterations only in male mice.

scholarly journals Cardiac contractile dysfunction and protein kinase C–mediated myofilament phosphorylation in disease and aging

2019 ◽  
Vol 151 (9) ◽  
pp. 1070-1080
Author(s):  
Vani S. Ravichandran ◽  
Himanshu J. Patel ◽  
Francis D. Pagani ◽  
Margaret V. Westfall
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Animal Models ◽  
Troponin I ◽  
Contractile Function ◽  
Pressure Overload ◽  
Human Myocardium ◽  
Brown Norway ◽  
Circulatory Support ◽  
Kinase C

Increases in protein kinase C (PKC) are associated with diminished cardiac function, but the contribution of downstream myofilament phosphorylation is debated in human and animal models of heart failure. The current experiments evaluated PKC isoform expression, downstream cardiac troponin I (cTnI) S44 phosphorylation (p-S44), and contractile function in failing (F) human myocardium, and in rat models of cardiac dysfunction caused by pressure overload and aging. In F human myocardium, elevated PKCα expression and cTnI p-S44 developed before ventricular assist device implantation. Circulatory support partially reduced PKCα expression and cTnI p-S44 levels and improved cellular contractile function. Gene transfer of dominant negative PKCα (PKCαDN) into F human myocytes also improved contractile function and reduced cTnI p-S44. Heightened cTnI phosphorylation of the analogous residue accompanied reduced myocyte contractile function in a rat model of pressure overload and in aged Fischer 344 × Brown Norway F1 rats (≥26 mo). Together, these results indicate PKC-targeted cTnI p-S44 accompanies cardiac cellular dysfunction in human and animal models. Interfering with PKCα activity reduces downstream cTnI p-S44 levels and partially restores function, suggesting cTnI p-S44 may be a useful target to improve contractile function in the future.

Cellular response to reperfused oxygen in the postischemic myocardium

1996 ◽  
Vol 271 (2) ◽  
pp. H687-H695 ◽  
Author(s):  
Y. Chung ◽  
T. Jue
Keyword(s):  
Cellular Response ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Formation Rate ◽  
Lactate Concentration ◽  
High Energy ◽  
O2 Consumption ◽  
1H Nuclear Magnetic Resonance ◽  
Lactate Formation ◽  
Postischemic Myocardium

Perfused rat heart experiments focused on determining the critical O2 level in postischemic myocardium. After a 20-min global ischemia, reperfusion began with O2-saturated saline buffer reflowing at different rates (0.5-12 ml/min). The 1H nuclear magnetic resonance (NMR) signal of the Val E11 myoglobin (Mb) gave an index of the intracellular oxygenation, whereas the 31P-NMR spectra reflected the high-energy phosphate and pH status. At the same time, physiological monitors recorded both contractile function and O2 consumption. Biochemical analysis determined the lactate concentration. Within 6-12 min of reperfusion, the O2 reached a new steady state, which depended directly on the flow rate. Below 12 ml/min reflow, the postischemic O2 level was consistently lower than the corresponding control values. Phosphocreatine, P(i), pH, myocardial O2 consumption, and lactate formation rate exhibited a similar linear relationship with MbO2 saturation in both the control and postischemic myocardium. It appears that neither the cellular energy production nor the steep intracellular O2 gradient has changed substantially in the postischemic myocardium.

High fat diet and pressure overload: Improved contractile function but reduced survival

2014 ◽  
Vol 62 (S 01) ◽  
Author(s):  
A. Schrepper ◽  
M. Schwarzer ◽  
S. Freiberger ◽  
P.A. Amorim ◽  
T. Doenst
Keyword(s):  
High Fat Diet ◽  
Contractile Function ◽  
Pressure Overload ◽  
High Fat
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