Systems Level Regulation of Cardiac Energy Fluxes Via Metabolic Cycles: Role of Creatine, Phosphotransfer Pathways, and AMPK Signaling - Systems Biology of Metabolic and Signaling Networks - page 275

by the scheme depicted in Fig. 11.10d . This scheme shows feedback regulation of
respiration in vivo according to Norbert Wiener's cybernetic principles (Saks
et al. 2012 ; Guzun and Saks 2010 ): the usage of ATP (or release of free energy of
ATP hydrolysis,

Δ G ATP , to perform work, marked as output) and ATP regeneration

Δ

(or extraction of G ATP from substrates by oxidative phosphorylation, denoted as

input) are interconnected via the feedback signaling through oscillations of cyto-
plasmic concentrations of ADP, AMP, Pi, and Cr/PCr amplified within MI. In this
framework, the role of II tubulin in association with MOM in cardiomyocytes

would be to induce the linear response of mitochondrial respiration to workload-
dependent metabolic signals. This elegant feedback mechanism of regulation of
respiration on a beat-to-beat basis ensures metabolic stability necessary for normal
heart function and explains well the metabolic aspect of the Frank-Starling's law of
the heart (Saks 2007 ; Saks et al. 2006a , 2012 ). Importantly, recycling of adenine
nucleotides within MI when coupled to PCr production significantly decreases ROS
levels ensuring maximal efficiency of free energy transduction in mitochondria
while inhibiting permeability transition pore opening, thus protecting the heart
under stress conditions (Schlattner et al. 2006b ; Meyer et al. 2006 ).
While the mechanisms described above represent local signaling within ICEUs,
important mechanisms of synchronization of mitochondrial activity between
ICEUs and their integration into structurally and functionally organized cellular
systems are described by Cortassa and Aon in Chap. 5 . The role of Ca 2+ cycle in
maintaining high respiratory activity of mitochondria within ICEUs has been
described by Balaban's group and studied by mathematical modeling by
Cortassaet al. ( 2009 ).

β

11.4.4 Intracellular Creatine Concentration as a Regulatory

Factor in Heart Energetics

Many experimental and clinical studies have shown that intracellular Cr concentra-
tion is an important factor, determining the efficiency of intracellular energy
transfer in heart cells (Saks et al. 1978 , 2012 ; Wyss and Kaddurah-Daouk 2000 ;
Nascimben et al. 1996 ). The results of an earlier work of ours published more than
30 years ago are reproduced in Fig. 11.12 . This experiment shows that removal of
Cr from the frog heart cells results in decreased PCr content and diminished
contractile force; all parameters return to their initial value after restoration of Cr
content (Saks et al. 1978 ). Similar results were recently reported by (Nabuurs
et al. 2013 ) by assessing morphological, metabolic, and functional consequences
of systemic Cr depletion in skeletal muscle. These data were obtained in a mouse
model deficient in L- arginine:glycine amidino transferase (AGAT / ) which
catalyzes the first step of Cr biosynthesis. In this work, systemic Cr depletion
resulted in mitochondrial dysfunction and intracellular energy deficiency, as well
as structural and physiological abnormalities.

In vivo magnetic resonance