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 277

a number of reviews (Ingwall and Weiss 2004 ; Ingwall 2006 ; Ventura-Clapier
et al. 2002 , 2004 ). Most recently, two younger Chinese patients with acute
myocardial infarction and presenting with muscle MM-CK deficiency have been
diagnosed with somatic mutations in the M-CK gene. These mutants at amino acid
E79 prevent correct folding and dimerization of M-CK. In parallel, correct targeting
of the enzyme to subcellular structures is hampered and enzymatic CK activity
dramatically lowered (Wu et al. 2013 ). These data with human cardiac infarction
patients have shown that active dimeric MM-CK together with its substrates Cr and
PCr are important for normal heart function.
Thus, the current opinion, supported by a host of data derived from different
experimental approaches and provided by a number of different independent
laboratories, is that Cr and PCr together with microcompartmentalized CK isoforms
are physiologically essential for normal body function, specifically for optimal
performance of skeletal and heart muscle, brain, neuronal cells, skin, retina and
auditory cell, spermatozoa, and other cells of intermittant high-energy requirements
(Wallimann et al. 1992 , 2011 ). This fundamental hypothesis is strongly supported
by the more or less severe phenotypes observed in double and single CK isoenzyme
knockout mice, respectively (Steeghs et al. 1997 ; Streijger et al. 2005 ; Heerschap
et al. 2007 ), as well as by the phenotypes of AGAT and GAMT knockout mice,
presenting with disturbed energy metabolism body weight control, hampered fer-
tility, muscular dystrophy, and cognitive and behavioral impairment, etc. (Nabuurs
et al. 2013 ; Schmidt et al. 2004 ; ten Hove et al. 2005 ; Torremans et al. 2005 ).
In a most recent, provocative publication, entitled “Life without creatine”,
Lygate and colleagues purport that the phenotype of the GAMT knockout mouse
was basically “normal”. Specifically, they do not find a skeletal or cardiac muscle
phenotype (Lygate et al. 2013 ). This contradicts the phenotype of the same trans-
genic mouse described earlier (Schmidt et al. 2004 ; ten Hove et al. 2005 ; Kan
et al. 2005 ). Most importantly it is in contrast to the AGAT knockout creatine
deficiency mouse (Nabuurs et al. 2013 ). This latter AGAT knockout mouse, in
contrast to the GAMT knockout mouse, does not synthesize guanidine acetate
(GAA), which in the GAMT knockout skeletal muscle was shown to be
phosphorylated by CK to form an alternative energy-rich phosphagen, phospho-
GAA, which still can be utilized as high-energy phosphagen, albeit at lower
efficiency (Heerschap et al. 2007 ). Thus, it will be most important to reevaluate
cardiac energy metabolism and heart phenotype in the GAMT knockout mouse to
completely rule out any compensatory effects of the high concentrations of
phospho-GAA accumulated in these knockout mice and to rule out a still possible
contribution of phospho-GAA as an still alternative energy source. Corresponding
experiments with the pure creatine deficiency AGAT knockout, presenting with a
rather severe phenotype that is reversible by simple creatine supplementation
(Nabuurs et al. 2013 ), are warranted and should provide some answers to these
pending questions. To get a physiologically more meaningful answer to the true
function of CK in heart it will be paramount to stress the heart to maximal
performance and work output, where one would expect to see the true effects of
creatine deficiency also in this organ.