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 256

N
U
T
R
I
T
I
O

Glucose

W
O
R
K

Randle
cycle

ATP
synthase

Kinases'
cycles

Krebs
cycle

ATP ase

AcCoA

N Fay Acids

Ca 2+ cycle E-C coupling ,

Length-dependent
sarcomere
acvaon

Fig. 11.2 General representation of regulation of energy fluxes via metabolic cycles at the cellular
level. The regulatory action that energy transfer cycles, such as the creatine kinase (CK) and
adenylate kinase systems (AK), exert on fuel supply is realized through the Randle cycle and
energy transforming Krebs cycle, coupled to oxidative phosphorylation. Any decrease in the use of
intracellular energy diminishes Krebs cycle activity and tends to favor the accumulation of
substrates

et al. 1978 , 2007a , 2010 , 2012 ; Saks 2007 ; Dzeja and Terzic 2003 , 2009 ). In the
heart, contraction is initiated by excitation-contraction coupling that includes
processes linked to intracellular Ca 2+ cycling (Bers 2002 ; Bers and Despa 2006 ).
Under physiological conditions, contractile force and cardiac work are regulated by
ventricular filling and sarcomere length-dependent mechanism (Frank-Starling's
law) at constant amplitude of Ca 2+ transients. A main regulatory motif of cardiac
energy fluxes is represented by metabolic feedback regulation through local
changes in Pi, ADP, AMP, Cr, and phosphocreatine (PCr) ratios (Saks
et al. 2006a , 2010 , 2012 ; Bose et al. 2003 ; Dos Santos et al. 2000 ; Aliev
et al. 2012 ). Under conditions of adrenergic stimulation, cardiac Ca 2+ cycling in
the cytoplasm and mitochondria becomes most important for energy flux regulation
(Balaban 2002 ; Griffiths and Rutter 2009 ; Tarasov et al. 2012 ; Glancy and Balaban
2012 ). Control and regulation of mitochondrial respiration by both adenine
nucleotides and Ca 2+ have been analyzed in an integrated model of cardiomyocyte
function (Cortassa et al. 2009 ).
In this work, we aim to analyze regulatory interactions involved in the modula-
tion of energy supply and demand in the network comprised by Randle and Krebs
cycles and phosphotransfer pathways in the heart. Contribution of calcium cycling
to the regulation of energy supply-demand in the heart has been extensively
reviewed elsewhere (Balaban 2002 , 2009a , b , 2012 ; Tarasov et al. 2012 ; Glancy
and Balaban 2012 ). The synchronization of the mitochondrial network in cardiac
cells is treated by Cortassa and Aon in Chap. 5 .