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Martínez et al. Cardiomyocyte energetic changes in ischemia and arrythmogenesis

cardiomyocyte’s metabolic demand, which results Carbohydrate metabolism in cardiomyocytes
in an increase in intracellular concentrations of Carbohydrates are also a valuable source of energy
adenosine monophosphate (AMP) and reactive in the myocardium, with glucose providing roughly a
oxygen species [31] . In turn, this upregulates AMP- quarter of the total energy produced in a well-irrigated
activated protein kinase (AMPK), a key metabolic heart. Of this total ATP, approximately 10%-40%
regulator. AMPK is a serine/threonine kinase which derives from the oxidation of glucose-lactate within
acts as a metabolic sensor in cardiomyocytes. It is the TCA, and only 2% derives from glycolysis [43] .
activated during high energy requirement states,
enhancing FA availability, uptake and oxidation Glucose enters the cardiomyocyte through glucose
in these cells by promoting the expression and transporter proteins (GLUT). Fourteen different
activation of lipoprotein lipase and CD36, also known GLUTs have been described in humans, all of which
as fatty acid translocase [31] . This favors the entry appear to be able to transport hexoses or polyols,
of long-chain FA into the cell, preserving stable although it is suspected that many other GLUT
levels of ATP in the face of increased metabolic substrates remain undiscovered [44] . GLUT 1-5 are
demand [32] . Nevertheless, excessive expression of the most studied to date, and they are well-known
CD36 has been associated with impaired cardiac to be glucose and/or fructose transporters in various
insulin sensitivity, reduced uptake of glucose, and tissues and cell types [45] . In cardiomyocytes, GLUT4 is
excessive uptake of FA, subsequently causing the main transporter, translocating to the membrane
cardiomyocyte lipotoxicity and retention of GLUT4 in response to signaling by insulin, increased work
in their cytoplasm [33] . Recent in vitro studies in demand, or ischemia, with GLUT1 playing an
cardiomyocytes have shown that use of CD36 accessory role [14] .
blockers or deletion of its coding gene ameliorates
contractile dysfunction mediated by lipotoxicity, and The products of glycolysis are utilized in both the TCA
reduced lipid-induced damage [34,35] . AMPK can also cycle and the respiratory chain in order to generate
inhibit acetyl-CoA carboxylase, which enhances ATP through oxidative phosphorylation [46] . Although
mitochondrial FA uptake. In addition, in energy only 2% the heart’s ATP is produced in glycolysis, it
depletion states, AMPK increases GLUT4 expression becomes very important under anaerobic or ischemic
and inhibits its internalization and also enhances conditions. Indeed, in heart failure and hypertrophy,
glycolysis by phosphorylation of phosphofructokinase there is a metabolic switch towards favoring
2. It may also facilitate glycogen storage in adequate carbohydrate over FA metabolism in the heart, with a
ATP supply states [36] . notable change being the acceleration of glycolysis [47] .
This increase in the glycolytic flux appears to be due
In addition to their plasma concentration, an important to a functional upregulation in the pathway’s enzyme,
long-term regulator of FA β-oxidation is the modulation rather than a clear increase in the expression of
by peroxisome proliferator-activated receptor (PPAR) [37] . glycolytic enzymes [48] .
Numerous coactivator proteins, such as PPAR-γ co-
activator 1-α can powerfully induce the transcription This shift towards utilization of glucose in the
of PPAR target genes, including those involved in hypertrophic myocardium had traditionally been
FA storage (such as diacylglycerol acyltransferase, considered a maladaptive change. Nevertheless,
promoted by PPARα), FA oxidation (such as medium- recent studies in bioengineering-modified mice have
chain acyl-CoA dehydrogenase, promoted by PPARα/ demonstrated glucose-dependence not to be harmful
β/δ/γ), and glucose metabolism (such as pyruvate in adult hearts, and a decrease in the utilization of
dehydrogenase kinase 4, promoted by PPARα) [38,39] . glucose appears to be deleterious in failure and
hypertrophy [49] . For example, mice with GLUT1
PPAR also plays an important role in the regulation overexpression - and thus, increased glycolysis -
of oxidative stress in the cardiovascular system, with appear to be protected against heart failure and left
several isoforms implicated in various transcriptional ventricular dilatation, even when subjected to pressure
mechanisms for antioxidant genes [40,41] . For example, overload [50,51] . On the other hand, those with deletion
PPARα and PPARγ promote the transcription and of GLUT4 and insulin receptors in the heart failure,
activation of Cu/Zn-superoxide dismutase (SOD1), and showed worse responses to cardiac hypertrophy-
Mn-superoxide dismutase (SOD2) and catalase in promoting stimuli [52] .
cardiac tissue. Furthermore, PPARα augments IGF-
1 transcription, subsequently activating the IGF-1/ The phosphocreatine-creatine kinase system
PI3K pathway, inhibiting apoptosis and protecting incardiomyocytes
cardiomyocytes under ischemic stress [42] . Because both the systole and diastole are active,

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