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 265

and Braissant 2010 ). In this way, creatine participates in the regulation of metabo-
lism at the organ level. An increase in total Cr and PCr in cells also increases the
PCr/ATP ratio and thus energy charge (Wallimann et al. 2011 ). Mutations in either
of the genes coding for AGAT, GAMT (endogenous creatine synthesis), or CRT
(creatine transport) in humans lead to the so-called creatine deficiency syndrome
with a severe neuromuscular and neurological phenotype including developmental
delay of expressive language and cognitive speech, mental retardation, autistic-like
behavior, epilepsy, and brain atrophy (for review, see (Stockler et al. 2007 )).
11.4.2 Direct Measurement of Energy Fluxes: Principal Role
of the Phosphocreatine Pathway in Energy Transfer
in the Heart
While Cr has been known for 175 years after its discovery by Michel Chevreul, the
hypothesis of the PCr pathway was formulated by Samuel Bessman (Bessman and
Carpenter 1985 ; Bessman and Fonyo 1966 ; Bessman and Geiger 1981 ) and inde-
pendently by Martin Klingenberg ( 1970 , 1976 , 2008 ; Wallimann 1975 ; Turner
et al. 1973 ; Saks et al. 1978 ) about 50 years ago. An important factual basis of
this hypothesis is given by the observation made by Belitzer and Tsybakova ( 1939 ),
who showed that Cr addition stimulated respiration in skeletal muscle
homogenates, resulting in PCr production (Belitzer and Tsybakova 1939 ). A fun-
damental contribution to the existence of a PCr pathway of energy transfer in heart,
muscle, brain, and other tissues was been made by Theo Wallimann's group. They
showed that different CK isoenzymes belong to different compartments, with
MtCK in mitochondria and cytosol and MM-CK in myofibrils and the membrane
of sarcoplasmic reticulum. They also resolved the atomic structure of CKs and
characterized interaction mechanisms with neighboring structures (Wallimann
et al. 1992 , 2007 ; Schlattner et al. 1998 , 2006a , b ; Schlattner and Wallimann
2004 ; Eder et al. 1999 , 2000 ; Fritz-Wolf et al. 1996 ). MM-CK was also shown to
localize in the sarcolemmal membrane (Saks et al. 1977 ). Such in vivo compart-
mentation of CK and ATP in muscle cells represents the cellular basis of the CK
cycle, one of the phosphotransfer pathways of energy transport (Wallimann
et al. 1992 , 2007 ; Schlattner et al. 2006a , b ; Schlattner and Wallimann 2004 ;
Saks 2007 , 2008 , 2009 ; Aliev et al. 2012 ; Saks et al. 2007b ). Detailed functional
studies combining the use of mathematical modeling with experimental data have
shown that within myofibrils, and in the subsarcolemmal area, the diffusion coeffi-
cient for ATP is decreased by factor of 10 5 as compared to water solution (Abraham
et al. 2002 ; Alekseev et al. 2012 ; Selivanov et al. 2004 ). Diffusion limitations result
in ATP compartmentation in cells, where the local ATP and ADP pools are
connected by the phosphotransfer pathways. An equally important and fundamental
contribution was been made by Dzeja and Terzic groups who measured quantita-
tively, using an isotope tracer method, energy fluxes between different cellular