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 254

Abstract Integrated mechanisms of regulation of energy metabolism at cellular,
tissue, and organ levels are analyzed from a systems biology perspective. These
integrated mechanisms comprise the coordinated function of three cycles of mass
and energy transfer and conversion: (1) the Randle cycle of substrate supply, (2) the
Krebs cycle coupled with energy transformation in mitochondrial oxidative phos-
phorylation, and (3) the kinase cycles of intracellular energy transfer and signal
transduction for regulation of energy fluxes. These cycles are extended and partially
governed by information transfer systems like those linked to protein kinase
signaling. In the heart, these cycles are closely related to the Ca 2+ cycle during
excitation-contraction coupling. According to the view of integrated metabolic
cycles, the phosphocreatine/creatine kinase system represents a most important
subsystem determining the efficiency of regulation of metabolic and energy fluxes
in heart, brain, and oxidative skeletal muscles. It carries about 80 % of the energy
flux between mitochondria and cytoplasm in heart. The substrate uptake, respiration
rate, and energy fluxes are regulated in response to workload via phosphotransfer
pathways and Ca 2+ cycling. We propose integrated network mechanisms to explain
the linear relationship between myocardial oxygen consumption and heart work
output under conditions of metabolic stability (metabolic aspect of
Frank-Starling's law of the heart). The efficiency of energy transfer, force of
contraction, and metabolic regulation of respiration and energy fluxes depend
upon the intracellular concentration of total creatine, which is decreased in heart
failure. The role of creatine, creatine kinase, and adenylate kinase phosphotransfer
and AMP-activated protein kinase (AMPK) signaling systems and their interrela-
tionship with substrate supply and Ca 2+ cycles are analyzed. Finally, an introduc-
tion to the AMPK signaling network is provided with a particular emphasis on the
heart in health and disease.

11.1 Introduction

In this chapter, we describe from a systems biology perspective the integration and
regulation of substrate and energy supply in living organisms and the role of the
creatine/creatine kinase (Cr/CK) system. Systems biology focuses on the
mechanisms of interactions between system components at molecular, cellular,

T. Kaambre
Laboratory of Bioenergetics, National Institute of Chemical Physics and Biophysics, Tallinn,
Estonia
R. Guzun ( * )
Laboratory of Fundamental and Applied Bioenergetics, Univ. Grenoble Alpes, Grenoble,
France
INSERM, U1055 Grenoble, France
EFCR and Sleep Laboratory, Univ. Hospital of Grenoble (CHU), Grenoble, France
e-mail: [e-mail]