Abstract
The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener’s cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener’s cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures – intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations of cytosolic ADP, Pi and Cr/PCr ensures metabolic stability necessary for normal function of cardiac cells.
Highlights
Cellular life depends on the availability of energy to maintain intracellular ionic homeostasis, biosynthesis and to perform the biological work, such as muscular contraction
Quantitative modeling is a powerful method of Systems Biology and very useful for research of integrated cellular metabolism in Molecular System Bioenergetics
Careful analysis shows that simple theories of reaction equilibrium in homogenous medium do not allow describing adequately the mechanisms of regulation of cellular integrated metabolism, in particular the role of creatine kinase system in muscle cell energetics and mechanisms of regulation of respiration in vivo
Summary
Cellular life depends on the availability of energy to maintain intracellular ionic homeostasis, biosynthesis and to perform the biological work, such as muscular contraction. The aim of this review article is to analyze this new data and the theoretical approaches in quantitative modeling of energy fluxes in vivo, with a main focus on the regulation of mitochondrial respiration in cardiac and skeletal muscle cells under normal physiological conditions when heart function is governed by the Frank-Starling law [8]. Under these conditions heart functioning is characterized by metabolic stability or homeostasis, when large-scale changes in the workload and respiration rates are observed at practically unchanged intracellular levels of ATP and phosphocreatine [19,20].
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