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 291

III deacetylase SIRT1, which deacetylates and thus activates FOXO1/3 and
PGC-1 α (Canto et al. 2009 ).

11.5.5.2 Protein Metabolism, Cell Growth, and Proliferation

AMPK also acts via cross talk with other major cellular signaling hubs. The most
important may be the mammalian target of rapamycin complex 1 (mTORC1) which
is inhibited by activated AMPK via multiple mechanisms, including phosphoryla-
tion of tuberous sclerosis complex protein-2 (TSC2) (Inoki et al. 2003 ) upstream of
mTORC1, or direct phosphorylating the mTORC1 subunit Raptor (Gwinn
et al. 2008 ). This reduces the multiple TORC1 functions in stimulation of protein
biosynthesis and cell cycle (Kwiatkowski and Manning 2005 ) and inhibition of
autophagy (Meijer and Codogno 2007 ). Autophagy is also directly stimulated by
AMPK-induced phosphorylation of the protein kinase ULK1 (Kim et al. 2011b ;
Egan et al. 2011 ). AMPK further reduces protein synthesis more indirectly by
inhibiting eukaryotic elongation factor 2 kinase (eEF2K) (Browne et al. 2004 )
and downregulating ribosomal RNA (Hoppe et al. 2009 ) and several cyclins
(Wang et al. 2002 ). Phosphorylation of the tumor suppressor p53 and the cyclin-
dependent kinase inhibitor p27 KIP1 will both contribute to cell cycle arrest and
eventual autophagy (Imamura et al. 2001 ; Jones et al. 2005 ; Liang et al. 2007 ).
AMPK also stimulates protein-ubiquitination and proteasome-dependent degrada-
tion (Viana et al. 2008 ; Solaz-Fuster et al. 2008 ).

11.5.5.3 Cell Contractility, Dynamics, and Shape

AMPK phosphorylates cardiac troponin I (cTnI) during ischemia and thus increases
its calcium sensitivity, suggesting that AMPK activation improves myocyte con-
traction (Oliveira et al. 2012a ). Cellular models also suggest that AMPK controls
microtubule dynamics through phosphorylation of the microtubule plus end protein
CLIP-170 (Nakano et al. 2010 ) and dynamics of cells and in particular of the
mitotic spindle via different indirect mechanisms that increase phosphorylation of
the non-muscle myosin regulatory light chain (MRLC) (Lee et al. 2007 ; Banko
et al. 2011 ).

11.5.5.4 Cellular Ion Homeostasis

The maintenance of ion gradients across cell membranes and intracellular ion
homeostasis are further highly energy-demanding processes. Thus it is little
surprising that AMPK, like CK, might also regulate these processes. Indeed,
different ion transporters are inhibited by AMPK, directly or indirectly, including
cystic fibrosis transmembrane conductance regulator Cl-channel (CFTR) (Hallows
et al. 2003 ) and ATP-sensitive potassium (KATP) channel (Kir6.2) (Chang