Application of the Principles of Systems Biology and Wiener's Cybernetics for Analysis of Regulation of Energy Fluxes in Muscle Cells in Vivo

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.

Modular organization of cardiac energy metabolism: energy conversion, transfer and feedback regulation

“…). Thus, Cr is an efficient feedback regulator of respiration in permeabilized cardiomyocytes, as well as in skeletal oxidative m. soleus and mixed human m. vastus lateralis (Guzun & Saks ). Low apparent affinity of MtCK for Cr in these muscles (the apparent K m Cr is about 1.0–1.5 m m ) shows that low concentrations of Cr are capable to significantly increase respiration rates up to the maximal rate of ADP‐stimulated respiration (Guzun et al .…”

Adaptive Control Model Reveals Systematic Feedback and Key Molecules in Metabolic Pathway Regulation

“…To understand biological complexity, for example, in cybernetics it is long posited that behavioral robustness is the result of structural complexity (Wiener, 1965). Recent examples include metabolic networks in Escherichia coli, human hepatocytes, and erythrocytes (Behre et al, 2008), and in adult rat cardiomyocytes and human skeletal muscle (Guzun and Saks, 2010) that have been studied using this bottom-up approach. To influence biological performance, for example, it is shown that sliding mode control can be applied in a generalized bioreactor based on nonlinear model dynamics to specify appropriate nutrient flow rates, in order to achieve and maintain a desired amount of cells (Fossas et al, 2001).…”

Systems Level Regulation of Cardiac Energy Fluxes Via Metabolic Cycles: Role of Creatine, Phosphotransfer Pathways, and AMPK Signaling

“…Assuming that ATP, ADP, PCr, and Cr are related through equilibrium relationships, the observation of metabolic stability was interpreted to exclude any other explanation of workload dependence of cardiac oxygen consumption than a mechanism involving the control of mitochondrial respiration by ADP or Pi only. The popular assumption of CK equilibrium, as in a mixed bag of enzymes (Wiseman and Kushmerick 1995), however, is in contradiction with the experimental evidence (Saks 2008;Guzun and Saks 2010). This includes recent high-resolution 31 P NMR experiments showing that the major part of adenine nucleotides, notably ATP in muscle cells, exists associated with macromolecules and that free ADP may be only transiently present in the cytoplasm (Nabuurs et al 2010(Nabuurs et al , 2013.…”