P404Impaired response to calcium transients is compensated by improved inherent energetic homeostasis in chronic hypoxic hearts

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Cardiac diseases are essentially multifactorial problems affecting numerous interactions and kinetic properties in highly organized cell, tissue and organ structures. Therefore, an exhaustive investigation of the effects of cardiac drugs and adaptations needs integrative approaches. Based on rigorously founded theory, metabolic control analysis (MCA) has the capacity to quantify kinetic responses of main energetic parts of the contractile system. In spite of impairments in contractile activity, mitochondrial content, cell energy status and calcium transients, we recently demonstrated an improved energy homeostasis in chronic hypoxic hearts explained by higher mitochondrial sensitivity to ATP/PCr changes, based on combined 31P-NMR spectroscopy and the analytical framework of metabolic control analysis (MoCA).

In the present study, MoCA describes co-variations in cell energy status (PCr, ATP) and cardiac work (RPP), induced by calcium, adrenaline and ruthenium red, in perfused hearts of control rats vs. rats adapted for three weeks to a simulated altitude of 5500 m in a barochamber.

In basal conditions, lower cardiac work and PCr concentration confirmed energetic impairments in chronic hypoxic hearts. At high calcium concentration in the perfusate, cardiac work increased by 40% in control as well as in hypoxic hearts but PCr drop less in hypoxic hearts thus indicating the improved energy homeostasis thanks to better mitochondrial sensitivity to PCr. Adrenaline, typically stimulating calcium transients and thereby parallel activation of supply and demand components, increased cardiac work twice as much in control hearts (RPP +100%) without any significant PCr variations. Ruthenium red, an inhibitor of MCU has the capacity to uncover the mitochondrial contribution in parallel activation by calcium transients. While ruthenium red added to adrenaline inhibited effects of calcium transients in control hearts (RPP -60%), the effect was absent in hypoxic hearts.

We conclude that although chronic hypoxic hearts failed to use calcium transients to optimize their inotropic response to a specific adrenergic stimulation, they present specific adaptation of the energetic homeostasis based on improved energy supply sensitivity in the case of stimulation by calcium. Interestingly this better regulation of the energetic system is not explained by a direct effect on mitochondria by calcium but rather by an optimal metabolic feedback. We concluded that quantitative MCA applications have likely the potential to shape combined drugs therapy.

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