Modular control analysis of effects of chronic hypoxia on mouse heart

Abstract

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...

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

“…Despite the severe mitochondrial alteration after CH reported previously in the entire heart [6], MoCA evidenced an increased elasticity of the energy-producing processes (mainly mitochondria) in CH hearts leading to an improved response to an increase in energy demand [8]. The beneficial consequence of this surprising modification of mitochondrial regulation for integrative cardiac energetics is an unexpected decrease in the control exerted by energy-production on contraction which represents a clear positive adaptation of oxidative phosphorylation system to CH [8]. However, while this result strengthens the idea that mitochondrial energetics plays a crucial role in heart protection against chronic hypoxia, the direct relationship with CH-induced cardioprotection remains to be investigated.…”

“…In parallel, a perturbation of calcium handling has been observed [7], leading to the decrease in calcium transients and therefore alteration of contractility [7]. Those modifications are concomitant with a decrease in phosphorylated metabolites concentrations in CH hearts, mainly phosphocreatine (PCr) [8], [9]. Altogether, these results evidence the development of a global heart failure in CH hearts [1], [10], [11].…”

“…Since recent evidence indicates that defects in communication between ATP-producing and ATP-consuming cellular sites are a major factor contributing to energetic deficiency in heart failure [23], tools such as MoCA, allowing study of the integrated cardiovascular function, are of particular interest [24]. Recently, we applied MoCA to study the effects of a 3-week CH on the energetics of contraction of intact perfused mouse hearts [8]. Despite the severe mitochondrial alteration after CH reported previously in the entire heart [6], MoCA evidenced an increased elasticity of the energy-producing processes (mainly mitochondria) in CH hearts leading to an improved response to an increase in energy demand [8].…”

“…Recently, we applied MoCA to study the effects of a 3-week CH on the energetics of contraction of intact perfused mouse hearts [8]. Despite the severe mitochondrial alteration after CH reported previously in the entire heart [6], MoCA evidenced an increased elasticity of the energy-producing processes (mainly mitochondria) in CH hearts leading to an improved response to an increase in energy demand [8]. The beneficial consequence of this surprising modification of mitochondrial regulation for integrative cardiac energetics is an unexpected decrease in the control exerted by energy-production on contraction which represents a clear positive adaptation of oxidative phosphorylation system to CH [8].…”

System analysis of the effect of various drugs on cardiac contraction energetics

“…supply, demand and metabolite changes, by which the effect(s) of a drug/hormone [3,4] or a pathology [5,6] are transmitted. In particular, the study of inotropic drugs/action permits the qualitative and quantitative description of the activation of heart contraction.…”