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 288

found inactivated in most cases, despite pronounced oxidative, energetic, and
genotoxic stress (Tokarska-Schlattner et al. 2005 ; Gratia et al. 2012 ). This is
probably due to activation of PKB/Akt via DNA-damage signaling kinases that
induce the inhibitory cross talk via AMPK

1-Ser485 phosphorylation. In other
situations, also LKB1 may become inactivated (Dolinsky et al. 2009 ). Stress
resulting from many but not all forms of pressure overload also results in AMPK
activation, mainly increasing glucose uptake and glycolysis (Tian et al. 2001 ;Li
et al. 2007 ; Allard et al. 2007 ; Zhang et al. 2008 ), as well as changing the gene
expression profile (Hu et al. 2011 ).
Information about the cellular environment and whole-body energy and nutrient
state is connected to AMPK signaling via endocrine, paracrine, and autocrine
mechanisms. These include a diverse array of hormones and cytokines identified
in noncardiac cells that act via largely unknown cellular signaling cascades on
AMPK upstream kinases, including adiponectin (Shibata et al. 2004 ), leptin
(Minokoshi et al. 2004 ), resistin (Kang et al. 2011 ), ghrelin (Kola et al. 2005 ),
IL6 (Kelly et al. 2004 ), and CNTF (Watt et al. 2006 ). Regulation of AMPK by these
factors partially depends on the tissue. While in peripheral tissues leptin activates
and ghrelin inhibits AMPK in the regulation of fatty acid oxidation and glucose
uptake, their effects in hypothalamus are different, since they inhibit (leptin) or
stimulate (ghrelin) AMPK-controlled food intake [for reviews see (Kahn
et al. 2005 ; Steinberg and Kemp 2009 )]. In the heart, AMPK seems to be involved
in the positive effects of adiponectin for cardioprotection during ischemia and for
reduced cardiac hypertrophy (Shibata et al. 2004 , 2005 ). For example, AMPK
limits accumulation and densification of microtubules that occur in response to
hypertrophic stress (Fassett et al. 2013 ). Also leptin may modulate AMPK in the
heart, since impaired leptin signaling correlates with reduced AMPK activation and
metabolic defects or reduced postconditioning after ischemia (McGaffin et al. 2009 ;
Bouhidel et al. 2008 ). Proinflammatory cytokines like IL-6 rather reduce AMPK
protein and activation (Ko et al. 2009 ), although there may be opposite effects in
specific tissues like skeletal muscle due to a specific autocrine-paracrine effect
(Kelly et al. 2004 ). Other cytokines with functions in the heart include macrophage
migration inhibitory factor (MIF), which is involved in AMPK activation during
ischemia and hypoxia and its decrease with age in mice seems to reduce AMPK
activation during ischemia (Miller et al. 2008 ; Ma et al. 2010 ).

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11.5.4.5 Evolution of Cellular Homeostasis Signaling Circuits

From a phylogenetic perspective, it is interesting to note that AMPK homologues
evolved early with eukaryotic life. However, yeast homologues of AMPK lack the
direct allosteric AMP-activation, although they already possess the ADP-regulation
of the

-Thr172 phosphorylation state (Mayer et al. 2011 ). Since such lower
eukaryotes neither express a CK/PCr system, it can be concluded that they still
tolerate larger fluctuations in energy state. It seems that those more sophisticated
regulatory circuits evolved only with multicellular life. It will be interesting to

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