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Am J Physiol Regul Integr Comp Physiol (June 1, 2006). doi:10.1152/ajpregu.00189.2006
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Submitted on March 16, 2006
Accepted on May 22, 2006

Modular Regulation Analysis of Heart Contraction: Application to In situ Demonstration of a Direct Mitochondrial Activation by Calcium in beating heart

Philippe Diolez1*, Veronique Deschodt-Arsac1, Gerard Raffard1, Cecile Simon1, Pierre Dos Santos2, Eric Thiaudiere1, Laurent Arsac1, and Jean-Michel Franconi1

1 UMR5536 CNRS / Universite Bordeaux2, Laboratoire de Resonance Magnetique, Bordeaux, France
2 Atherosclerose, INSERM U441, Pessac, France

* To whom correspondence should be addressed. E-mail: philippe.diolez{at}rmsb.u-bordeaux2.fr.

Heart contraction is characterized by the absence of changes in energetic intermediates in response to large increase of activity. Little is known about the very mechanisms responsible for this almost exact adequation between energy production by mitochondria and utilization by myofilament contraction. Calcium ion (Ca2+) plays a crucial role in the excitation-contraction coupling and in vitro studies have evidenced that Ca2+ may also directly activate mitochondrial oxidative phosphorylation. However, until now no experimental approach could address this question in vivo on intact beating heart. We applied our new in situ Modular Control and Regulation Analyses (MoCA) on isolated beating rat heart perfused under two different calcium concentrations (2.0 and 3.5 mM) with pyruvate or glucose as substrate. Modular Control Analysis demonstrated experimentally that even though control by energy production was slightly higher under glucose conditions as compared to pyruvate, most of the control of heart contraction resides on energy utilization (between 78.8 % and 96.0 % with glucose and pyruvate, respectively). This behavior is the direct consequence of the high sensitivity (elasticity) of the energy Producer processes to ATP utilization. Interestingly, the increase in heart metabolic rate by Ca2+ did not significantly change the pattern of control distribution. The Regulation Analysis performed under the two calcium conditions demonstrated a balanced activation of myofibrils ATPases and mitochondrial ATP synthesis by Ca2+ increase. Due to glycolysis, activation of ATP production is however lower under glucose conditions as compared to pyruvate. This first study demonstrates in situ the hypothesis that the energetic adequation in heart contraction is mediated by a parallel activation of both processes of energy production and utilization by Ca2+. The results presented here show that Modular Control and Regulation Analyses allow in situ study of internal regulations in intact beating heart energetics and function, and may now be applied to heart dysfunctions and therapeutic effects.




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