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 276

Fig. 11.12 The role of
Creatine in the regulation of
contraction in frog heart .
After 8 h of perfusion
without creatine, frog heart
strips assume a hypodynamic
state with decreased
contractile force (FC) and
lowered Cr and PCr levels.
Addition of 20 mM Cr to the
perfusate restored to normal
the values of all these
variables. Reproduced with
permission from (Saks
et al. 1978 )

6.0

1 Cr

3.0
1.0

3 ATP

2 PCr

0.5

4 FC

0 4h 8h +10min +15min

time of p e rfusion

no creatine

with
creatine

no
creatine

spectroscopy showed a near-complete absence of Cr and PCr in resting hind limb
muscle of AGAT / mice. Compared to wild type, the inorganic phosphate/ -ATP

ratio was increased fourfold, while ATP levels were reduced to nearly half and
overall mitochondrial content was increased. The Cr-deficient AGAT / mice
presented with significantly reduced grip strength and suffered from severe muscle
atrophy. Oral Cr administration led to rapid accumulation in skeletal muscle (faster
than in brain) and reversed all muscle abnormalities revealing that the condition of
the AGAT / mice can be switched between Cr-deficient and normal simply by
dietary manipulation. The consequences of AGAT deficiency were more pro-
nounced than those of muscle-specific CK deficiency (Nabuurs et al. 2013 ),
which suggests a multifaceted involvement of Cr in addition to its role in the
PCr-CK system and in muscle energy homeostasis, as, e.g., by direct effects on
biomembranes (Tokarska-Schlattner et al. 2012 ). It was also shown by the group of
Stefan Neubauer in Oxford that a moderate elevation of total Cr levels in the heart
by approximately 50 % in transgenic mice overexpressing the Cr transporter (CRT)
conveyed significant protection and improved recovery of the hearts upon experi-
mental induction of ischemia/reperfusion (Lygate et al. 2012 ). In one of their most
important work the Neubauer's group has shown that a decrease of PCr content in
the heart of patients with dilated cardiomyopathy is accompanied with significantly
increased mortality rates (Neubauer 2007 ).
The role of altered phosphotransfer pathways in heart pathology of animal
models, as well as human patients, is well documented and has been described in

β