Both skeletal muscle and cardiac muscle have the special ability to maintain energetic homeostasis in response to drastic elevations in energy expenditure. To meet this tremendous increase in the demand for ATP, mitochondrial oxidative phosphorylation has to increase in coordination. Mechanisms for such coordination are as yet poorly understood. The canonical feedback regulation by ADP and Pi was proposed some time ago, and is supported by some studies under specific conditions. However, for typical exercising muscle in vivo, most intracellular metabolites, including ADP and Pi, have only minor changes, insufficient for inducing enough ATP production to satisfy energy requirements. Moreover, a metabolic network such as mitochondria requires coordinated changes in fluxes, which means that various enzymes have to be activated simultaneously with similar scales. This phenomenon has led to the in parallel activation hypothesis. By defining specific activation factors for enzymes, this hypothesis has been successfully applied in various theoretical studies. Although this approach helps to quantitatively evaluate the role of activated enzymes in exercising muscle, the exact mechanisms still remain unclear. In parallel activation requires special modulators for coordinated regulation of multiple types of enzymes, or multistep control. Metabolic enzymes are associated with regulation at different levels, e.g., phosphorylation. Among all the possible factors, calcium (Ca2+) is, perhaps, the most important. Ca2+ not only is needed for muscle contraction, but also directly regulates various key enzymes in the mitochondria. Recently, Glancy et al. evaluated the effect of Ca2+ on mitochondrial respiration in situ. Their study provided new evidence that inter-mitochondrial Ca2+ alone can stimulate the entire energetic pathway simultaneously with similar magnitudes (represented by close conductance values for energetic metabolism pathways in mitochondria). It should be noticed that less evidence supports a role for Ca2+ activation of the enzymes in the electron transfer chain, except for ATP synthase. However, other mechanisms may exist to induce the activities of these enzymes in vivo, for example, Ca2+ induced mitochondrial tethering or more directly. In this study, we propose a simple specific hypothesis for the manner in which Ca2+ modulates mitochondrial energetic metabolism. We assume that the metabolic enzymes have two forms: a basal form or an active form in the absence or presence of Ca2+. Ca2+ can activate reactions by inducing the conversion from the basal form to active form. This hypothesis was incorporated into a published mathematical model of mitochondrial metabolism. This new model was validated to fit the steady-state Ca2+ -dependent responses of muscle mitochondrial respiration in State 4 or State 3. Model simulations were further performed and compared with experimental results from the creatine kinase clamp protocol (CK clamp).
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