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 287

far. Glutathionylation at Cys299 and Cys304 in the -subunit activates the kinase

under oxidative conditions in cellular models and is favored by binding to certain
GST isoforms (Klaus et al. 2013 ; Zmijewski et al. 2010 ). This latter mechanism
may be part of a more general redox regulation of the kinase (Han et al. 2010 ; Jeon
et al. 2012 ). ROS and RNS activate AMPK, but it is unclear whether this happens
via increases in [ADP] and [AMP], or whether noncanonical mechanisms at the
level of AMPK (like glutathionylation) or upstream kinases play a role. Vice versa,
AMPK regulates NADPH homeostasis and an entire battery of ROS-detoxifying
enzymes. Another non-covalent allosteric regulator is glycogen as well as other
synthetic branched oligosaccharides that inhibit AMPK activity by binding to the
β

α

-GBD domain (McBride et al. 2009 ).

11.5.4.4 Upstream Regulation in Cardiac (Patho) Physiology

In the heart, AMPK activity is increased by a wide array of signals acting via
upstream kinases and modulation of adenylate levels under both pathological and
physiological stress and involving various hormones and cytokines (Zaha and
Young 2012 ). Classical physiological stimuli of AMPK are exercise or hypoxia.
Both also occur in the heart (Coven et al. 2003 ; Musi et al. 2005 ; Frederich
et al. 2005 ) and promote the metabolism of glucose and fatty acids via different
downstream targets (see below). However, it is unclear whether this activation is
due to altered energy state as in skeletal muscle or rather relies on alternative
upstream signaling. AMPK is also involved in the adaptive response of the heart to
caloric restriction (Chen et al. 2013b ), but nutrient effects in the heart may be more
complex (Clark et al. 2004 ). Possibly, within the physiological range, the role of
cardiomyocyte AMPK is different from other cell types, because of the remarkable
metabolic stability of this organ maintained by multiple other mechanisms, including
the metabolic cycles outlined before.
As pathological stimulus, ischemia is the best studied in form of both no-flow
and partial ischemia in isolated perfused animal hearts, as well as regional ischemia
due to coronary ligation in vivo (Russell et al. 2004 ; Kudo et al. 1996 ; Wang
et al. 2009 ; Paiva et al. 2011 ; Kim et al. 2011a ), for a review, see (Young 2008 ).
They both lead to rapid and lasting AMPK activation. As already mentioned,
besides energetic stress, oxidative stress may be a determinant of such activation,
acting through different forms of ROS (Sartoretto et al. 2011 ; Zou et al. 2002 ). In
endothelial cells, it is rather peroxynitrite formation that affects AMPK via the
protein kinase C

-LKB1 axis (Zou et al. 2004 ; Xie et al. 2006b ), while in other
non-excitable cells it may be rather a ROS-induced Ca 2+ release that triggers the
CamKK

ζ

axis (Mungai et al. 2011 ). ROS-facilitated glutathionylation of AMPK
(see above) as observed in cellular systems represents yet another direct activation
mechanism, but still has to be verified in cardiomyocytes (Klaus et al. 2013 ;
Zmijewski et al. 2010 ). However, the signaling function of ROS may be lost at
more intense oxidative stress that simply inactivates AMPK. In models of
cardiotoxicity induced by the anticancer drug doxorubicine, AMPK has been

β