Modular regulation analysis of heart contraction: application to in situ demonstration of a direct mitochondrial activation by calcium in beating heart

Diolez, Philippe; Deschodt-Arsac, Véronique; Raffard, Gérard; Simon, Cécile; Santos, Pierre Dos; Thiaudière, Eric; Arsac, Laurent M.; Franconi, Jean‐Michel

doi:10.1152/ajpregu.00189.2006

Cited by 26 publications

(99 citation statements)

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“…The principles of MoCA have been extensively described elsewhere (17), and only a short description will be found here. In MoCA, complex systems may be simplified by grouping reactions and reactants into large modules connected by a small number of explicit intermediates (6).…”

Section: Methodsmentioning

confidence: 99%

“…These modifications of ATP/phosphocreatine (PCr) production and consumption processes are concomitant with the alteration of the phosphorylated metabolite content of the heart during CH, mainly a PCr decrease (23,30,31), indicative of heart energetics failure (19). Calcium ion (Ca 2ϩ ) plays a crucial role in excitation-contraction coupling, and in vitro studies (2)(3)(4) as well as our more recent in situ study (17) have evidenced that Ca 2ϩ also directly activates mitochondrial oxidative phosphorylation. In CH, an alteration of calcium homeostasis associated with a decrease in calcium transients and resulting heart contractility has been reported (9,34).…”

mentioning

confidence: 98%

“…41 for review). The cardiovascular and muscular biochemical network has an intuitively modular structure (41); therefore, by associating noninvasive 31 P-magnetic resonance spectroscopy (MRS) with the analytic tools of metabolic control analysis (5, 8), we have developed an experimental integrative approach to in situ cardiac (16,17) and skeletal (1) muscle energetics. In situ MoCA gives quantitative information on the internal control and regulation of integrated organ function and represents a powerful way to investigate pathological or drug effects.…”

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confidence: 99%

“…In the present study we applied our new modular control analysis (MoCA), an integrative approach to intact beating heart energetics (16,17), to better understand the overall effect as well as the relative importance of these various modifications induced by CH on the regulation of energetics in hearts from mice submitted to hypobaric hypoxic conditions. Indeed, an appealing aspect of modular network analysis is the feature of "emergence," in which unexpected new properties arise from the cooperative interactions (integration) between biological processes (see Ref.…”

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confidence: 99%

“…Determined in the intact beating heart, the elasticity coefficients toward the global intermediate PCr quantify the sensitivity of each module to the energetic intermediates and can therefore be used to detect any significant modification in the enzymatic processes of the module. MoCA has been used recently to demonstrate the parallel activation of both ATP/PCr producer and consumer by Ca 2ϩ acting as an external effector (17) and during activation of perfused heart contraction by epinephrine (27). The application of MoCA on isolated, perfused hearts from mice subjected to a chronic hypoxic environment was carried out in order to highlight which of the above changes induced by CH really affect the very mechanisms of contractile function.…”

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Modular control analysis of effects of chronic hypoxia on mouse heart

Calmettes

Deschodt-Arsac²,

Thiaudière³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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R13-R19, 2007) was applied here on perfused hearts to describe the modifications of the regulation of heart energetics induced in mice exposed to 3-wk chronic hypoxia. MoCA combines 31 P-NMR spectroscopy and modular (top down) control analysis to describe the integrative regulation of energy metabolism in the intact beating heart, on the basis of two modules [ATP/phosphocreatine (PCr) production and ATP/PCr consumption] connected by the energetic intermediates. In contrast with previous results in rat heart, in which all control of contraction was on ATP demand, mouse heart energetics presented a shared control of contraction between ATP/PCr-producing and -consuming modules. In chronic hypoxic mice, the decrease in heart contractile activity and PCr-to-ATP ratio was surprisingly associated with an important and significant higher response of ATP/PCr production (elasticity) to PCr changes compared with control hearts (Ϫ10.4 vs. Ϫ2.46). By contrast, no changes were observed in ATP/PCr consumption since comparable elasticities were observed. Since elasticities determine the regulation of energetics of heart contraction, the present results show that this new parameter may be used to uncover the origin of the observed dysfunctions under chronic hypoxia conditions. Considering the decrease in mitochondrial content reported after exposure to chronic hypoxia, it appears that the improvement of ATP/PCr production response to ATP demand may be viewed as a positive adaptative mechanism. It now appears crucial to understand the very processes responsible for ATP/PCr producer elasticity toward the energetic intermediates, as well as their regulation. perfused mouse heart; systems biology; 31 P-labeled magnetic resonance spectroscopy CHRONIC HYPOXIA (CH) induces numerous adaptative changes in heart physiology, including remodeling. Indeed, in addition to the effect of lowered oxygen availability on oxidative cardiac metabolism, the heart is submitted to an increased workload as a result of the hypoxia-induced pulmonary hypertension (21,22). This pathological situation induces complex structural, hormonal, and biochemical modifications that affect both energy-producing and energy-consuming processes in heart cells (see Refs. 20,33). Concerning energy-producing modifications, an important reduction in the mitochondrial mass has been observed, associated with the reduction of the activities of respiratory chain complexes (29). In parallel, several studies reported a metabolic switch from fatty acid to carbohydrate utilization after CH (13,25,28,36,37). In regard to energyconsuming processes, one of the early mechanisms observed in isolated mammalian cardiomyocytes submitted to acute hypoxia is a downregulation of protein and RNA synthesis (9, 34). Moreover, biochemical investigations under CH also revealed a modification of the contractile apparatus itself, characterized by an increase in ␤-myosin heavy chain expression in both ventricles (35). These modifications of ATP/phosphocreatine (PCr) production and consumption proces...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Modular control analysis of effects of chronic hypoxia on mouse heart

Calmettes

Deschodt-Arsac²,

Thiaudière³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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A fast black‐blood sequence for four‐dimensional cardiac manganese‐enhanced MRI in mouse

et al. 2010

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The increasing number of mouse models of cardiac diseases requires improvements in the current MRI tools. Anatomic and functional cardiac phenotyping by MRI calls for both time and space resolution in three dimensions. Black-blood contrast is often needed for the accurate delineation of myocardium and chambers, and is consistent with manganese contrast enhancement. In this article, we propose a fast, three-dimensional, time-resolved (four-dimensional), black-blood MRI sequence that allows mouse heart imaging at 10 periods of the cardiac cycle within 30 min at an isotropic resolution of 200 µm. Two-dimensional imaging was possible within 80 s. Blood cancellation was achieved by employing bipolar gradients without the use of a double inversion recovery preparation scheme. Saturation slices were added in two-dimensional experiments for better blood nulling. The rapidity of the two-dimensional acquisition protocol allowed the measurement of the time course of contrast enhancement on manganese infusion. Owing to the very high contrast-to-noise ratio, manganese-enhanced MRI in four dimensions made possible the accurate assessment of regional cardiac volumes in healthy animals. In experimentally infarcted mice, the size of the ischemic zone could be measured easily with this method. The technique might be valuable in evaluating mouse heart diseases and their follow-up in longitudinal studies.

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Mitochondrial network energetics in the heart

Aon

Cortassa

2012

WIREs Mechanisms of Disease

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At the core of eukaryotic aerobic life, mitochondria function like “hubs” in the web of energetic and redox processes in cells. In the heart, these networks - extending beyond the complex connectivity of biochemical circuit diagrams and apparent morphology - exhibit collective dynamics spanning several spatio-temporal levels of organization, from the cell, to the tissue, and the organ. The network function of mitochondria, i.e. mitochondrial network energetics, represents an advantageous behaviour. Its coordinated action, under normal physiology, provides robustness despite failure in a few nodes, and improves energy supply toward a swiftly changing demand. Extensive diffuse loops, encompassing mitochondrialcytoplasmic reaction/transport networks, control and regulate energy supply and demand in the heart. Under severe energy crises, the network behaviour of mitochondria and associated glycolytic and other metabolic networks collapse, thereby triggering fatal arrhythmias.

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Modular regulation analysis of heart contraction: application to in situ demonstration of a direct mitochondrial activation by calcium in beating heart

Abstract: Diolez P, Deschodt-Arsac V, Raffard G, Simon C, Dos Santos P, Thiaudière E, Arsac L, Franconi J-M. Modular regulation analysis of heart contraction: application to in situ demonstration of a direct mitochondrial activation by calcium in beating heart.

Cited by 26 publications

References 35 publications

Modular control analysis of effects of chronic hypoxia on mouse heart

Modular control analysis of effects of chronic hypoxia on mouse heart

A fast black‐blood sequence for four‐dimensional cardiac manganese‐enhanced MRI in mouse

Mitochondrial network energetics in the heart

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