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Improved energy supply regulation in chronic hypoxic mouse counteracts hypoxia-induced altered cardiac energetics.

Calmettes G, Deschodt-Arsac V, Gouspillou G, Miraux S, Muller B, Franconi JM, Thiaudiere E, Diolez P - PLoS ONE (2010)

Bottom Line: Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged.This higher elasticity induces an improved response of energy supply to cellular energy demand.The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Résonance Magnétique des Systèmes Biologiques, UMR 5536 CNRS Université Bordeaux 2, Bordeaux, France. guillaume.calmettes@rmsb.u-bordeaux2.fr

ABSTRACT

Background: Hypoxic states of the cardiovacular system are undoubtedly associated with the most frequent diseases of modern time. Therefore, understanding hypoxic resistance encountered after physiological adaptation such as chronic hypoxia, is crucial to better deal with hypoxic insult. In this study, we examine the role of energetic modifications induced by chronic hypoxia (CH) in the higher tolerance to oxygen deprivation.

Methodology/principal findings: Swiss mice were exposed to a simulated altitude of 5500 m in a barochamber for 21 days. Isolated perfused hearts were used to study the effects of a decreased oxygen concentration in the perfusate on contractile performance (RPP) and phosphocreatine (PCr) concentration (assessed by (31)P-NMR), and to describe the integrated changes in cardiac energetics regulation by using Modular Control Analysis (MoCA). Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged. MoCA demonstrated that this adaptation to hypoxia is the direct consequence of the higher responsiveness (elasticity) of ATP production of CH hearts compared with Controls (-1.88+/-0.38 vs -0.89+/-0.41, p<0.01) measured under low oxygen perfusion. This higher elasticity induces an improved response of energy supply to cellular energy demand. The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.

Conclusions/significance: As suggested by the present study, the mechanisms responsible for this increase in elasticity and the consequent improved ability of CH heart metabolism to respond to oxygen deprivation could participate to limit the damages induced by hypoxia.

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Related in: MedlinePlus

Elasticities plot of the adaptation of CH hearts to hypoxia.Open square: elasticities of Control hearts under high oxygen condition (energy supply: −2.46±0.73, energy demand: 1.98±1.15, values obtained from [8]). Solid square: elasticities of Control hearts in low oxygen condition (energy supply: −0.89±0.41, energy demand: 2.09±0.66). Solid circles: elasticities of CH hearts in low oxygen condition (energy supply: −1.88±0.38, energy demand: 1.73±0.62). Shadowed zone indicates normal control pattern (normal distribution of the control between energy supply and demand) in mouse heart energetics, as described in [8].
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pone-0009306-g003: Elasticities plot of the adaptation of CH hearts to hypoxia.Open square: elasticities of Control hearts under high oxygen condition (energy supply: −2.46±0.73, energy demand: 1.98±1.15, values obtained from [8]). Solid square: elasticities of Control hearts in low oxygen condition (energy supply: −0.89±0.41, energy demand: 2.09±0.66). Solid circles: elasticities of CH hearts in low oxygen condition (energy supply: −1.88±0.38, energy demand: 1.73±0.62). Shadowed zone indicates normal control pattern (normal distribution of the control between energy supply and demand) in mouse heart energetics, as described in [8].

Mentions: Values of elasticities and control coefficients of a metabolic system are subject to a number of constraints and inter-relationships [20]. This relation, illustrated in figure 3, provides the keys to understand how the elasticities of energy supply and demand affect the distribution of control coefficients on contraction. If we plot the value of the elasticity of a module against that of the other module, the line passing through this point and the origin describes the combinations of elasticities that give the same control pattern (figure 3). The effects of decreasing oxygen availability as well as CH adaptation on “normal” mouse heart energetics [8] could then be easily understood with this figure. Indeed, as illustrated, the decrease in energy supply elasticity induced by acute hypoxia on Control hearts, without any change in energy demand elasticity, move the system in a situation where control of energy supply on contraction becomes predominant (figure 3, acute hypoxia arrow). This situation is detrimental for cardiac bioenergetics and could be interpreted as energy deficiency, a situation encountered during heart failure [11], [31]. However, because of the higher elasticity of energy-supply developed in heart during chronic hypoxia, the effect of acute hypoxia is compensated (figure 3, chronic hypoxia arrow) and bioenergetics of CH heart keeps the same control distribution among energy supply and demand under low oxygen availability than healthy hearts under normal oxygen conditions. An important consequence is the absence of effect of decreased oxygen availability on energy-supply in CH hearts evidenced by Modular Regulation Analysis (figure 2).


Improved energy supply regulation in chronic hypoxic mouse counteracts hypoxia-induced altered cardiac energetics.

Calmettes G, Deschodt-Arsac V, Gouspillou G, Miraux S, Muller B, Franconi JM, Thiaudiere E, Diolez P - PLoS ONE (2010)

Elasticities plot of the adaptation of CH hearts to hypoxia.Open square: elasticities of Control hearts under high oxygen condition (energy supply: −2.46±0.73, energy demand: 1.98±1.15, values obtained from [8]). Solid square: elasticities of Control hearts in low oxygen condition (energy supply: −0.89±0.41, energy demand: 2.09±0.66). Solid circles: elasticities of CH hearts in low oxygen condition (energy supply: −1.88±0.38, energy demand: 1.73±0.62). Shadowed zone indicates normal control pattern (normal distribution of the control between energy supply and demand) in mouse heart energetics, as described in [8].
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2823784&req=5

pone-0009306-g003: Elasticities plot of the adaptation of CH hearts to hypoxia.Open square: elasticities of Control hearts under high oxygen condition (energy supply: −2.46±0.73, energy demand: 1.98±1.15, values obtained from [8]). Solid square: elasticities of Control hearts in low oxygen condition (energy supply: −0.89±0.41, energy demand: 2.09±0.66). Solid circles: elasticities of CH hearts in low oxygen condition (energy supply: −1.88±0.38, energy demand: 1.73±0.62). Shadowed zone indicates normal control pattern (normal distribution of the control between energy supply and demand) in mouse heart energetics, as described in [8].
Mentions: Values of elasticities and control coefficients of a metabolic system are subject to a number of constraints and inter-relationships [20]. This relation, illustrated in figure 3, provides the keys to understand how the elasticities of energy supply and demand affect the distribution of control coefficients on contraction. If we plot the value of the elasticity of a module against that of the other module, the line passing through this point and the origin describes the combinations of elasticities that give the same control pattern (figure 3). The effects of decreasing oxygen availability as well as CH adaptation on “normal” mouse heart energetics [8] could then be easily understood with this figure. Indeed, as illustrated, the decrease in energy supply elasticity induced by acute hypoxia on Control hearts, without any change in energy demand elasticity, move the system in a situation where control of energy supply on contraction becomes predominant (figure 3, acute hypoxia arrow). This situation is detrimental for cardiac bioenergetics and could be interpreted as energy deficiency, a situation encountered during heart failure [11], [31]. However, because of the higher elasticity of energy-supply developed in heart during chronic hypoxia, the effect of acute hypoxia is compensated (figure 3, chronic hypoxia arrow) and bioenergetics of CH heart keeps the same control distribution among energy supply and demand under low oxygen availability than healthy hearts under normal oxygen conditions. An important consequence is the absence of effect of decreased oxygen availability on energy-supply in CH hearts evidenced by Modular Regulation Analysis (figure 2).

Bottom Line: Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged.This higher elasticity induces an improved response of energy supply to cellular energy demand.The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Résonance Magnétique des Systèmes Biologiques, UMR 5536 CNRS Université Bordeaux 2, Bordeaux, France. guillaume.calmettes@rmsb.u-bordeaux2.fr

ABSTRACT

Background: Hypoxic states of the cardiovacular system are undoubtedly associated with the most frequent diseases of modern time. Therefore, understanding hypoxic resistance encountered after physiological adaptation such as chronic hypoxia, is crucial to better deal with hypoxic insult. In this study, we examine the role of energetic modifications induced by chronic hypoxia (CH) in the higher tolerance to oxygen deprivation.

Methodology/principal findings: Swiss mice were exposed to a simulated altitude of 5500 m in a barochamber for 21 days. Isolated perfused hearts were used to study the effects of a decreased oxygen concentration in the perfusate on contractile performance (RPP) and phosphocreatine (PCr) concentration (assessed by (31)P-NMR), and to describe the integrated changes in cardiac energetics regulation by using Modular Control Analysis (MoCA). Oxygen reduction induced a concomitant decrease in RPP (-46%) and in [PCr] (-23%) in Control hearts while CH hearts energetics was unchanged. MoCA demonstrated that this adaptation to hypoxia is the direct consequence of the higher responsiveness (elasticity) of ATP production of CH hearts compared with Controls (-1.88+/-0.38 vs -0.89+/-0.41, p<0.01) measured under low oxygen perfusion. This higher elasticity induces an improved response of energy supply to cellular energy demand. The result is the conservation of a healthy control pattern of contraction in CH hearts, whereas Control hearts are severely controlled by energy supply.

Conclusions/significance: As suggested by the present study, the mechanisms responsible for this increase in elasticity and the consequent improved ability of CH heart metabolism to respond to oxygen deprivation could participate to limit the damages induced by hypoxia.

Show MeSH
Related in: MedlinePlus