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 278

In conclusion, until the enigma of the results provided by (Lygate et al. 2013 )
(see above) is solved, all available data still indicate that the CK system together
with PCr and Cr is central to the regulatory mechanisms of metabolic and energy
fluxes in those cells under intermitantly fluctuating high-energy requirements,
including the heart (Taegtmeyer and Ingwall 2013 ).
11.5 The Signaling Network of AMP-Activated Protein
Kinase (AMPK) in the Heart
11.5.1 Protein Kinase Signaling Networks in Metabolic
Control of Cardiac Function
Metabolic cycles as described before provide immediate metabolic feedback for
changes in energy input (nutrient supply) and energy output (workload). They are
particularly important in the heart, an organ that maintains a high degree of
metabolic stability and a particularly well-controlled energy homeostasis. An
additional layer of regulation, which ascertains this metabolic stability, is achieved
by information transfer via protein kinase signaling. All major protein kinase
pathways were shown to play important roles in the heart, controlling contraction
force, contractility, and heart rate in particular during cardiac development, under
prolonged strong stimulation, and under emerging pathological conditions.
The possibly best studied example is the cyclic adenosine nucleotide (cAMP)-
dependent protein kinase A (PKA) (Taylor et al. 2008 ), together with its homolo-
gous cGMP-dependent protein kinase G (PKG) (Takimoto 2012 ). Their control of
cardiac contraction strength, ion fluxes, and hypertrophy relies on a precise spatio-
temporal regulation of substrate phosphorylation. In case of PKA, A-kinase anchor-
ing proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) play a
major role in this spatiotemporal organization and the occurrence of cAMP
microdomains (Edwards et al. 2012 ; Mika et al. 2012 ; Diviani et al. 2013 ). This
emphasizes the importance of cellular localization and organization for protein
kinase-mediated information fluxes, as already outlined above for cardiac CK
isoenzymes.
Also some other protein kinase signaling pathways have to be considered as
relevant for cardiac metabolism. Protein kinase B (PKB or Akt) is an essential
component of the growth response of an organism to nutritional input. In the heart,
it participates in the regulation of myocyte growth under physiological conditions
(Walsh 2006 ; Hers et al. 2011 ). PKC isoforms regulate cardiac contraction and
hypertrophic responses, as well as other signaling pathways in more pathological
situations such as ischemia and reperfusion injuries (Steinberg 2012 ). While
calcium-regulated PKD is a more recent addition to the kinome, less well studied
in respect to the cardiovascular system (Avkiran et al. 2008 ), members of the