Improved Energy Supply Regulation in Chronic Hypoxic Mouse Counteracts Hypoxia-Induced Altered Cardiac Energetics

Abstract

BackgroundHypoxic 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 FindingsSwiss 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 31P-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/SignificanceAs 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.

Ouabain—The Key to Cardioprotection?

“…55 Increased NKA activity contributes to cardiac protection produced by hypoxia-induced preconditioning. 61 These results are in line with Rein's observation that ouabain does not resolve oxygen deficiency as such but due to changes of metabolism rather allows a subsistence despite persistent oxygen deficiency and eliminates myocardial insufficiency. 57 NKA is a major component in the cell's energy balance.…”

Mitochondrial network energetics in the heart

“…The magnitude of the elasticity coefficient for phosphocreatine increased with chronic hypoxia leading to a decrease in the control coefficients for energy supply in contrast to controls in which reduced oxygen availability revealed large control coefficients for energy supply. These results may be interpreted as chronic hypoxia resulting in increased oxidative phosphorylation enabling improved performance under high energy demand (100). …”

“…These results may be interpreted as chronic hypoxia resulting in increased oxidative phosphorylation enabling improved performance under high energy demand. 100 The quantitative work performed with permeabilized cells or muscle preparations provided in situ or in vivo information, respectively, concerning the control of oxidative phosphorylation under conditions that preserve spatial organization. In both cases, under fully integrated functional conditions, new mechanisms and concepts could be unveiled.…”

Acute and chronic effects of bupivacaine on muscle energetics during contraction in vivo: a modular metabolic control analysis

“…Quantitative answers can yet be obtained from regulation analysis concepts of partial response coefficients (regulatory strengths [14]), an approach apparent from the early days of control analysis [15,16], but to which serious attention has been paid only in application to integrated metabolic systems [17][18][19][20]. Our group has developed MoCA (modular control analysis) of the energetics of contraction in the beating heart [21] and has applied it to skeletal muscle [13], by combining tools of metabolic control analysis with noninvasive 31 P-MRS. By using PCr as a surrogate of energetic intermediates because of a high signal-to-noise ratio for PCr in MRS, the ATP/PCr supply and demand system that is conceptually defined greatly simplifies the experiments that are required and the regulation patterns that are obtained thanks to a systemic approach [22][23][24][25][26][27]. The main principles of MoCA are that the responses of the steady-state flux of ATP/PCr supply and ATP/PCr demand pathways to changes in concentration of their linking intermediate (PCr) are experimentally measured under conditions where other parameters and variables are constant.…”