**2. Metabolism in the adult healthy heart**

The main substrates for ATP production are carbohydrates and free fatty acids [98]. In particular, long-chained FFA, glucose, glycogen, lactate, pyruvate, ketone bodies (acetoacetate, beta-hydroxybutyrate), and amino acids (leucine, valine, and isoleucine). These compounds are metabolized to intermediates, which enter the Krebs cycle as an acetyl-coenzyme A (ACoA) or other metabolic equivalents. During substrate utilization, the proton is generated. This proton produces an energetic gradient between mitochondrial membranes, which stimulates the oxidative chain to produce chemical energy and phosphorylate ADP to ATP [60, 61, 171, 184].

Such diversity of substrates for common energy source production predispose to several concepts: (1) myocardial metabolism is very adaptive to organism condition and substrate environment and can vary between main energy resources; unfortunately, in heart failure this flexibility is mostly lost; (2) myocardial metabolism is a self-regulated mechanism; all the intermediates of the tricarboxylic acid cycle are mediators, controlling the main metabolic path and intensity of energy production (Randle cycle); (3) metabolites can be used as components for cell structure resynthesis, and, at the same time, cellular structures could be used as an energetic substrate; (4) metabolic dysfunction and accumulation of metabolites can damage cellular proteins and change the form and function of contractile filaments; (5) myocardial metabolism is not "intracellular chemistry"; this is a functional system, which is presented with specific structure and mediator mechanisms, assessing adaptation of cardiomyocytes to environmental variations [76, 171].

Myocardial metabolism efficiency is highly dependent on pathway and substratesutilized for ATP production. There is a Kyoto Encyclopedia of Genes and Genomes (KEGG) scheme—a collectively designed map of known molecular interactions and feedback systems of energetic metabolism in the myocardium. This map made helps to understand possible ways of energy production in the myocardium and limit its activity [30, 69]. However, we should observe common features of myocardial metabolism.

In aerobic conditions, mitochondrial oxidative phosphorylation is the main source of ATP (about 90%); the rest of macroergic compounds are produced by anaerobic utilization. Mitochondrial oxidative phosphorylation produces energy due to FADH and NADH dehydration, collected from FFA beta-oxidation and, in lesser amounts, other sources. The schematic structure of metabolic interactions designed by Stanley et al. shows the main features of energy production cycles (**Figure 1**) [140].

Transport of FFA in the cardiomyocyte is presented in two ways: passive diffusion and by specific protein transporters. Long-chained FFA are diffused in the cell, metabolized in acyl-CoA, and transported to the special proteins on the mitochondrial membrane to interact with acetyl-CoA synthase. While active transport, induced by muscle contraction or insulin (Ins) action, is sustained by FATP1, FATP6,

**61**

*Myocardial Metabolism*

assosiated translocators [102].

**Figure 1.**

lation in the cardiomyocytes [46].

resynthesis in oxidative phosphorylation.

*DOI: http://dx.doi.org/10.5772/intechopen.80870*

and CD36 [78]. These proteins translocate FFA through the membrane, and then couple it with CoA, which is transported to lipid beta-oxidation cycle by carnitine-

*Coupled metabolic reactions in the cell and mitochondria in cardiomyocyte [161]. GLUT—glucose transporter, G-6-P—glucose 6-phosphate, MCT—monocarboxylate transporter, PDH—pyruvate dehydrogenase, FAT fatty acid membrane transporter, TG—triglyceride, and CPT-1—carnitine palmitoyltransferase 1.*

Further, cytosolic carnitine palmitoyltransferase-1 (CPT-1) connects acyl-CoA with carnitine, forming long-chained acylcarnitine. This compound is transported with acylcarnitine translocase through the inner mitochondrial membrane and utilized in FFA beta-oxidation cycles with acetyl-CoA production. Then acetyl-CoA is metabolized in the Krebs cycle to ATP, H2O, and CO2. For example, in the tricarboxylic acid cycle, palmitate is oxidized with 23 moles of O2 to produce 105 moles of ATP [63]. Nevertheless, in comparison with glucose, FFA are not effective energy sources due to their high demand for oxygen. The part of transported FFA is esterified and collected in the cytoplasm as lipid droplets (triacylglycerol-TAG) [68, 100, 101, 181]. TAGproduced ATP is about 10% of all gained ATP in physiological conditions [117]. Also, TAG is an important part of FFA oxidation, in cases when TAG-hydrolase blockade lipid beta-oxidation is severely reduced, which leads to massive lipid droplet accumu-

The next step is activation of the Krebs cycle. This rotor starts with acetyl-CoA, collected from FFA beta-oxidation or pyruvate decarboxylation. Produced NADH and FADH2 transports are equivalent to electron chain, which stimulates ATP

Metabolic pathways of energy production are ruled by directing components (enzymes) and feedback connection (substrate-final product). The mitochondria can bear high-energy demand states, increasing oxygen consumption almost on 85% from the basal level. This ability is very important due to the fact that most of the time it consumes only 25% of the oxidative capacity [111]. Therefore, activation/ inhibition of enzymatic systems can control ATP synthesis, and, due to feedback, can correct energetic substrates, in cases of increased metabolites collection or regulation disorders. This kind of metabolic flexibility is very useful in myocardial diseases, associated or modulated by energy resources depletion and absence [31, 32].

In addition, in normal conditions myocardium utilizes lactate, which metabolizes to pyruvate by lactate dehydrogenase and gets involved in the Krebs cycle. In cases of metabolic disorders, the myocardium starts to excrete lactate in the bloodstream. This way appears when there is oxygen deficiency and the energy has to be produced by anaerobic glycolysis (ischemia, terminal stages of cardiomyopathies)

#### **Figure 1.**

*Veterinary Anatomy and Physiology*

**2. Metabolism in the adult healthy heart**

cardiomyocytes to environmental variations [76, 171].

of myocardial metabolism.

(**Figure 1**) [140].

of pathological interactions between components of neurohumoral regulation systems [203]. Decompensation is a condition, which is always connected with reduced energy production and suppressed myocardial metabolism. For example, systolic dysfunction leads to sympathoadrenal system hyperactivation, which is associated with increased heart rate. Catecholamines activate beta-adrenergic receptors, which increase myocardial oxygen consumption due to raised FFA utilization to produce enough energy. This situation leads to increased ADP volume and negative inotropic effect, which is badly tolerated during heart failure and geometrically progress during chronic sympathetic tonus [36, 96, 115, 122, 164].

The main substrates for ATP production are carbohydrates and free fatty acids [98]. In particular, long-chained FFA, glucose, glycogen, lactate, pyruvate, ketone bodies (acetoacetate, beta-hydroxybutyrate), and amino acids (leucine, valine, and isoleucine). These compounds are metabolized to intermediates, which enter the Krebs cycle as an acetyl-coenzyme A (ACoA) or other metabolic equivalents. During substrate utilization, the proton is generated. This proton produces an energetic gradient between mitochondrial membranes, which stimulates the oxidative chain to produce chemical energy and phosphorylate ADP to ATP [60, 61, 171, 184].

Such diversity of substrates for common energy source production predispose to several concepts: (1) myocardial metabolism is very adaptive to organism condition and substrate environment and can vary between main energy resources; unfortunately, in heart failure this flexibility is mostly lost; (2) myocardial metabolism is a self-regulated mechanism; all the intermediates of the tricarboxylic acid cycle are mediators, controlling the main metabolic path and intensity of energy production (Randle cycle); (3) metabolites can be used as components for cell structure resynthesis, and, at the same time, cellular structures could be used as an energetic substrate; (4) metabolic dysfunction and accumulation of metabolites can damage cellular proteins and change the form and function of contractile filaments; (5) myocardial metabolism is not "intracellular chemistry"; this is a functional system, which is presented with specific structure and mediator mechanisms, assessing adaptation of

Myocardial metabolism efficiency is highly dependent on pathway and substratesutilized for ATP production. There is a Kyoto Encyclopedia of Genes and Genomes (KEGG) scheme—a collectively designed map of known molecular interactions and feedback systems of energetic metabolism in the myocardium. This map made helps to understand possible ways of energy production in the myocardium and limit its activity [30, 69]. However, we should observe common features

In aerobic conditions, mitochondrial oxidative phosphorylation is the main source of ATP (about 90%); the rest of macroergic compounds are produced by anaerobic utilization. Mitochondrial oxidative phosphorylation produces energy due to FADH and NADH dehydration, collected from FFA beta-oxidation and, in lesser amounts, other sources. The schematic structure of metabolic interactions designed by Stanley et al. shows the main features of energy production cycles

Transport of FFA in the cardiomyocyte is presented in two ways: passive diffusion and by specific protein transporters. Long-chained FFA are diffused in the cell, metabolized in acyl-CoA, and transported to the special proteins on the mitochondrial membrane to interact with acetyl-CoA synthase. While active transport, induced by muscle contraction or insulin (Ins) action, is sustained by FATP1, FATP6,

**60**

*Coupled metabolic reactions in the cell and mitochondria in cardiomyocyte [161]. GLUT—glucose transporter, G-6-P—glucose 6-phosphate, MCT—monocarboxylate transporter, PDH—pyruvate dehydrogenase, FAT fatty acid membrane transporter, TG—triglyceride, and CPT-1—carnitine palmitoyltransferase 1.*

and CD36 [78]. These proteins translocate FFA through the membrane, and then couple it with CoA, which is transported to lipid beta-oxidation cycle by carnitineassosiated translocators [102].

Further, cytosolic carnitine palmitoyltransferase-1 (CPT-1) connects acyl-CoA with carnitine, forming long-chained acylcarnitine. This compound is transported with acylcarnitine translocase through the inner mitochondrial membrane and utilized in FFA beta-oxidation cycles with acetyl-CoA production. Then acetyl-CoA is metabolized in the Krebs cycle to ATP, H2O, and CO2. For example, in the tricarboxylic acid cycle, palmitate is oxidized with 23 moles of O2 to produce 105 moles of ATP [63]. Nevertheless, in comparison with glucose, FFA are not effective energy sources due to their high demand for oxygen. The part of transported FFA is esterified and collected in the cytoplasm as lipid droplets (triacylglycerol-TAG) [68, 100, 101, 181]. TAGproduced ATP is about 10% of all gained ATP in physiological conditions [117]. Also, TAG is an important part of FFA oxidation, in cases when TAG-hydrolase blockade lipid beta-oxidation is severely reduced, which leads to massive lipid droplet accumulation in the cardiomyocytes [46].

The next step is activation of the Krebs cycle. This rotor starts with acetyl-CoA, collected from FFA beta-oxidation or pyruvate decarboxylation. Produced NADH and FADH2 transports are equivalent to electron chain, which stimulates ATP resynthesis in oxidative phosphorylation.

Metabolic pathways of energy production are ruled by directing components (enzymes) and feedback connection (substrate-final product). The mitochondria can bear high-energy demand states, increasing oxygen consumption almost on 85% from the basal level. This ability is very important due to the fact that most of the time it consumes only 25% of the oxidative capacity [111]. Therefore, activation/ inhibition of enzymatic systems can control ATP synthesis, and, due to feedback, can correct energetic substrates, in cases of increased metabolites collection or regulation disorders. This kind of metabolic flexibility is very useful in myocardial diseases, associated or modulated by energy resources depletion and absence [31, 32].

In addition, in normal conditions myocardium utilizes lactate, which metabolizes to pyruvate by lactate dehydrogenase and gets involved in the Krebs cycle. In cases of metabolic disorders, the myocardium starts to excrete lactate in the bloodstream. This way appears when there is oxygen deficiency and the energy has to be produced by anaerobic glycolysis (ischemia, terminal stages of cardiomyopathies)

[6, 47, 104, 162]. The main transporter controlling excretion and consumption of lactate is the monocarboxylate transporter (MCT). This family consists of four subclasses, in the myocardium only 1 form of MCT-1 is presented. Also, they take a part in ketone body transport [40, 50, 64].

Glycolysis is another coexisting pathway for energy production. The first step of glycolysis starts with glucose transport through the cell membrane by the specific transporter (GLUT). In the cytoplasm glucose is metabolized to pyruvate, which is transported to the mitochondrial matrix by pyruvate dehydrogenase (PDH). Pyruvate is transformed to acetyl-CoA and gets involved to the Krebs cycle [61, 162].

The GLUT family includes 12 classes; the most important for myocardial metabolism are GLUT 1 and GLUT 4, which supplies glucose in the cardiomyocytes. GLUT 4 is insulin dependent and plays a significant role in insulin resistance formation; GLUT 1 is weakly insulin dependent; it is the source of basal glucose transport for myocytes; in addition, it could be additively recruited from cytosol in stress conditions [167]. GLUT 1 is mostly located on the sarcolemma, while GLUT 4 also attenuated to T-tubules, which is useful for "deep" glucose transport during raised energy demand and exercises. In normal conditions GLUT 1 protein expression is higher due to persisting glucose demand as an energy source. GLUT 4 concentration in the myocardium and muscle is almost equal, which means that developing insulin resistance of different etiologies leads to decreased glucose flux both in the skeletal muscle and in the myocardium. GLUT 4 is the main glucose transporter to the muscle cell, but in experiments with GLUT 4 knockout, animals show that glucose can be translocated to the myocyte by different mechanisms [34, 196].

After transport into the cell, glucose was converted to glucose-6-phosphate (G6P) by cytosolic hexokinase 2 (HX2), and then it was utilized in glycolytic reactions or stored as glycogen. Phosphofructokinases—glycolytic enzymes—which irreversibly convert G6P to fructose-6-phosphate, forming fructose-1 and 6-bisphosphate and dephosphorylating ATP to ADP. These kinases are limiting threshold for glycolytic activity and depending on ATP, AMP, citrate concentrations, and pH [131].

After glucose is converted to pyruvate, its metabolism trifurcates to lactate conversion, decarboxylation to acetyl-CoA, and carboxylation to malate or oxaloacetate. Decarboxylation is an irreversible process, catalyzed by pyruvate dehydrogenase (PDH). PDH activation is closely connected with cytosolic Ca+2 and Mg+2 concentrations, sympathetic tonus, while inhibition depends on FFA concentration in the environment. PDH is a multienzyme complex, consisting of two main parts: pyruvate dehydrogenase itself and pyruvate dehydrogenase kinase assessing pyruvate utilization. Pyruvate consumption increases in cases of decreased FAA utilization or artificial inhibition of lipid beta-oxidation. FFA and glucose turnovers in the mitochondria are controlled by the Randle cycle, and by its ways, we could admit that PDH activity is determined depending on the substrate environment (**Figure 2**) [106, 107, 137, 138].

The lactate-lactate dehydrogenase-pyruvate system is made for additive pyruvate production in cases of high demand or its discharge to lactate when the FFA wing is activated in Randle's cycle. In heart failure, FAA consumption is increased due to adrenergic hyperactivation and compensatory mechanisms; this leads to PDH inhibition, and glucose metabolites are converted to lactate, instead of pyruvate, and eliminated to the bloodstream. This causes lactate and pyruvate depletion in the cytosol; the relative lactate/pyruvate ration raises and negatively influences energy supplementation for submembrane structures, which control ion recirculation [20, 98, 121, 136, 153].

The final step of glucose utilization is an oxidation of acetyl-CoA to CO2 in the Krebs cycle and formation of 31 ATP molecules. Due to produced ATP amounts, oxidative glycolysis is the most effective energy source.

**63**

*Myocardial Metabolism*

**Figure 2.**

*DOI: http://dx.doi.org/10.5772/intechopen.80870*

*Pyruvate metabolism in normal myocardium (Stanley et al., 2002).*

nocorticism, etc. [98, 128, 201].

cyte outer membranes [68, 100, 101, 181].

It should be noted that such intermediates as G6P and lactate can also be metabolized in alternative ways. G6P can be utilized in the pentose phosphate pathway (PPP), producing NADH in association with O2 or a pentose (substrate for nucleotides) in a hypoxic environment. In addition, G6P can be converted to sorbitol, uridine diphosphate-N-acetylglucosamine, which can provide O-associated glycosylation of contractile filaments and Ca+2 ion pumps of the sarcoplasmic reticulum (SR). In cases of massive protein glycosylation, the cell can undergo apoptosis [6, 56, 80, 141]. The intensity of FFA utilization by a healthy myocardium depends on the concentration of non-esterified FFA in the blood, the activity of metabolism

modulation mediators (catecholamine, thyroxin, triiodothyronine, insulin, cortisol, adropin) can be increased four times during the day. FFA are transported to cardiomyocytes in non-esterified form, bound with albumin or as chylomicrons, lipoproteins, and then they translocated in the cytoplasm and oxidized. FFA releases are depended on catecholamine-induced activation of hormone-dependent lipase [195]. Therefore, FFA plasma level significantly increased in cases of adrenergic activation, insulin depletion, insulin resistance, hypothyroid condition, hyperadre-

In addition, FFA myocardial metabolism is also influenced by secondary messenger, AMP-activated protein kinase (AMPK), which activity is closely connected with the AMP/ATP ratio in the cytosol. This molecule has several actions: (1) AMPK inhibits malonyl-CoA production, switching off acetyl-CoA-synthase, leading to decreased FFA cytosol accumulation; (2) ongoing decrease of malonyl-CoA inhibits bounding of CPT-1 and stimulates transport of acetyl-CoA to the mitochondria for oxidation; and (3) AMPK stimulates expression of FATP and CD36 on cardiomyo-

It should be mentioned that peroxisome proliferator-activated receptor-alpha (PPAR-a) is also a regulator of FFA oxidation. This receptor is a part of ligandactivated family of nuclear receptors. Ligands of the FFA receptor, in active form PPAR-a, activate the synthesis of lipid beta-oxidation enzymes [59]. In experiments, it was observed that this receptor deactivation leads to decreasing FFA oxidation capacity in cardiomyocytes, due to significant depletion of lipid oxidation enzymes. During ischemia and insulin resistance in diabetic mice, induced by streptozotocin, PPAR-a knockout animals were more stable in the ischemia–reperfusion protocol, than the control group mice. This can be explained by the fact that the inhibition

#### **Figure 2.**

*Veterinary Anatomy and Physiology*

part in ketone body transport [40, 50, 64].

[6, 47, 104, 162]. The main transporter controlling excretion and consumption of lactate is the monocarboxylate transporter (MCT). This family consists of four subclasses, in the myocardium only 1 form of MCT-1 is presented. Also, they take a

can be translocated to the myocyte by different mechanisms [34, 196].

activity and depending on ATP, AMP, citrate concentrations, and pH [131]. After glucose is converted to pyruvate, its metabolism trifurcates to lactate conversion, decarboxylation to acetyl-CoA, and carboxylation to malate or oxaloacetate. Decarboxylation is an irreversible process, catalyzed by pyruvate dehydrogenase (PDH). PDH activation is closely connected with cytosolic Ca+2 and Mg+2 concentrations, sympathetic tonus, while inhibition depends on FFA concentration in the environment. PDH is a multienzyme complex, consisting of two main parts: pyruvate dehydrogenase itself and pyruvate dehydrogenase kinase assessing pyruvate utilization. Pyruvate consumption increases in cases of decreased FAA utilization or artificial inhibition of lipid beta-oxidation. FFA and glucose turnovers in the mitochondria are controlled by the Randle cycle, and by its ways, we could admit that PDH activity is determined depending on the substrate environment

After transport into the cell, glucose was converted to glucose-6-phosphate (G6P) by cytosolic hexokinase 2 (HX2), and then it was utilized in glycolytic reactions or stored as glycogen. Phosphofructokinases—glycolytic enzymes—which irreversibly convert G6P to fructose-6-phosphate, forming fructose-1 and 6-bisphosphate and dephosphorylating ATP to ADP. These kinases are limiting threshold for glycolytic

The lactate-lactate dehydrogenase-pyruvate system is made for additive pyruvate production in cases of high demand or its discharge to lactate when the FFA wing is activated in Randle's cycle. In heart failure, FAA consumption is increased due to adrenergic hyperactivation and compensatory mechanisms; this leads to PDH inhibition, and glucose metabolites are converted to lactate, instead of pyruvate, and eliminated to the bloodstream. This causes lactate and pyruvate depletion in the cytosol; the relative lactate/pyruvate ration raises and negatively influences energy supplementation for submembrane structures, which control ion recircula-

The final step of glucose utilization is an oxidation of acetyl-CoA to CO2 in the Krebs cycle and formation of 31 ATP molecules. Due to produced ATP amounts,

Glycolysis is another coexisting pathway for energy production. The first step of glycolysis starts with glucose transport through the cell membrane by the specific transporter (GLUT). In the cytoplasm glucose is metabolized to pyruvate, which is transported to the mitochondrial matrix by pyruvate dehydrogenase (PDH). Pyruvate is transformed to acetyl-CoA and gets involved to the Krebs cycle [61, 162]. The GLUT family includes 12 classes; the most important for myocardial metabolism are GLUT 1 and GLUT 4, which supplies glucose in the cardiomyocytes. GLUT 4 is insulin dependent and plays a significant role in insulin resistance formation; GLUT 1 is weakly insulin dependent; it is the source of basal glucose transport for myocytes; in addition, it could be additively recruited from cytosol in stress conditions [167]. GLUT 1 is mostly located on the sarcolemma, while GLUT 4 also attenuated to T-tubules, which is useful for "deep" glucose transport during raised energy demand and exercises. In normal conditions GLUT 1 protein expression is higher due to persisting glucose demand as an energy source. GLUT 4 concentration in the myocardium and muscle is almost equal, which means that developing insulin resistance of different etiologies leads to decreased glucose flux both in the skeletal muscle and in the myocardium. GLUT 4 is the main glucose transporter to the muscle cell, but in experiments with GLUT 4 knockout, animals show that glucose

**62**

(**Figure 2**) [106, 107, 137, 138].

tion [20, 98, 121, 136, 153].

oxidative glycolysis is the most effective energy source.

*Pyruvate metabolism in normal myocardium (Stanley et al., 2002).*

It should be noted that such intermediates as G6P and lactate can also be metabolized in alternative ways. G6P can be utilized in the pentose phosphate pathway (PPP), producing NADH in association with O2 or a pentose (substrate for nucleotides) in a hypoxic environment. In addition, G6P can be converted to sorbitol, uridine diphosphate-N-acetylglucosamine, which can provide O-associated glycosylation of contractile filaments and Ca+2 ion pumps of the sarcoplasmic reticulum (SR). In cases of massive protein glycosylation, the cell can undergo apoptosis [6, 56, 80, 141].

The intensity of FFA utilization by a healthy myocardium depends on the concentration of non-esterified FFA in the blood, the activity of metabolism modulation mediators (catecholamine, thyroxin, triiodothyronine, insulin, cortisol, adropin) can be increased four times during the day. FFA are transported to cardiomyocytes in non-esterified form, bound with albumin or as chylomicrons, lipoproteins, and then they translocated in the cytoplasm and oxidized. FFA releases are depended on catecholamine-induced activation of hormone-dependent lipase [195]. Therefore, FFA plasma level significantly increased in cases of adrenergic activation, insulin depletion, insulin resistance, hypothyroid condition, hyperadrenocorticism, etc. [98, 128, 201].

In addition, FFA myocardial metabolism is also influenced by secondary messenger, AMP-activated protein kinase (AMPK), which activity is closely connected with the AMP/ATP ratio in the cytosol. This molecule has several actions: (1) AMPK inhibits malonyl-CoA production, switching off acetyl-CoA-synthase, leading to decreased FFA cytosol accumulation; (2) ongoing decrease of malonyl-CoA inhibits bounding of CPT-1 and stimulates transport of acetyl-CoA to the mitochondria for oxidation; and (3) AMPK stimulates expression of FATP and CD36 on cardiomyocyte outer membranes [68, 100, 101, 181].

It should be mentioned that peroxisome proliferator-activated receptor-alpha (PPAR-a) is also a regulator of FFA oxidation. This receptor is a part of ligandactivated family of nuclear receptors. Ligands of the FFA receptor, in active form PPAR-a, activate the synthesis of lipid beta-oxidation enzymes [59]. In experiments, it was observed that this receptor deactivation leads to decreasing FFA oxidation capacity in cardiomyocytes, due to significant depletion of lipid oxidation enzymes. During ischemia and insulin resistance in diabetic mice, induced by streptozotocin, PPAR-a knockout animals were more stable in the ischemia–reperfusion protocol, than the control group mice. This can be explained by the fact that the inhibition

of FFA oxidative utilization promotes glycolysis. Inactivated PPAR-a allows to perform increased oxidative glycolysis (decreased FFA oxidation in the Randle cycle), improve GLUT 4 translocation and PDH activation, and improve the severity of insulin resistance. In cases of hypoxic ischemia, this will give a chance for cardiomyocytes' survival due to glycolysis and energy production. In addition, increased PPAR-a expression promotes GLUT 4 genes suppression, leading to insulin resistance and, indirectly, stimulates FFA oxidation metabolites accumulation, this inhibits glycolysis wing of the Randle cycle, decreases GLUT 4 trafficking activity, and suppresses insulin receptor sensitivity due to PI-3-kinase inhibition [33, 127].

However, in cases of active oxidation in tricarboxylic acid cycle with high production of malonyl-CoA, normal transport of FFA to the mitochondrial inner membrane is stopped. Also, membrane translocation of lipids is inhibited by insulin [28, 72].

Utilization of amino acids (predominately leucine, valine, and isoleucine) in energy metabolism is less effective than glycolysis and FFA beta-oxidation. Active amino acid utilization leads to metabolite accumulation; this state is associated with cardiomyopathies and respiratory chain damage in the mitochondria. Metabolism of this substrate is associated with ketoacid formation; part of them could be converted to acetyl-CoA and used in the Krebs cycle [145].

Another substrate are ketone bodies (beta-hydroxybutyrate and acetoacetate). These compounds are produced by the liver during FFA oxidation, and under normal conditions, their level in the plasma is very low, and so they do not actively utilize in myocardial energy metabolism. However, lipomobilization and insulin depletion (diabetes mellitus) could be exceptions for this situation; this condition leads to decreased glycolysis and lactate consumption by cardiomyocytes. In addition, ketone body utilization inhibits FFA oxidation, altering the process of dissociation of acetyl- CoA to free CoA. This complex promotes secondary to heart failure often noted in patients with diabetes mellitus [49, 95, 160].

In experimental models, it was noted that ketone utilization inhibits lactate oxidation for 30–60% and palmitate for 22%. Later, in vivo experiments admitted that parallel administration of FFA and hydroxybutyrate markedly inhibits FFA oxidation in pigs. It has to be noted that the levels of malonyl-CoA and acetyl-CoA were unchanged. In a similar experiment, it was shown that high concentration of ketone bodies promotes the Krebs cycle blockade and downregulates contractility of cardiomyocytes. So, ketones could be energy substrate to the myocardium, but it blocks other more useful ways of energy production, due to significant demand for oxygen [160, 173].

Some intercellular conditions can influence on metabolism intensity and oxidative potential. The significant parameter of the functional condition of the cell is redox potential. Pyridine compounds (NAD, NADH, NADP, NADPH) play the most important role in this state. One of the simplest estimations of redox potential in a cell is cytoplasmic and mitochondrial NAD/NADH ratio. It is considered that NAD depletion and NADH raise characterize inhibition of oxidation in the mitochondria and slowing of Krebs cycle. This was also noted during hypoxia, enzyme defects, and lack of energy substrates [93].

There are complexes of cytoplasmic oxidoreductase enzymes dependent on NAD concentration. The most active one is lactate dehydrogenase (LDH). LDH, depending on the intracellular environment, can produce NAD and lactate from pyruvate, or reverse this reaction to produce pyruvate and NADH. There are many malate dehydrogenases (MDH) in the mitochondria, which is the part of the malate–aspartate shuttle. In particular, MDH catalyzes the metabolism of oxaloacetate and NADH to malate and NAD, and then malate is transported to the mitochondria, while the NAD/NADH ratio increased in the cytoplasm. In addition,

**65**

[70, 136, 165].

metabolism modulation.

*Myocardial Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.80870*

predominant in the myocardium [55, 118].

**3. Regulation of carbohydrates and FFA oxidation**

the Krebs cycle intensity [163, 189].

from aspartate [12, 67, 85, 146].

MDH takes part in nitrogen metabolism, rarely can be activated to produce energy

High NAD/NADH ratio promotes normal substrate oxidation and saves redox potential to sustain electron transport in oxidative metabolism. As already been said, LDH and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) both use NAD/NADH as a cofactor. GAPDH produces NADH, which is oxidized to NAD by LDH. In anaerobic conditions, both of these enzymes produce NAD, which is utilized in glycolysis. In the aerobic state, NADH reoxidation is connected with its utilization in the mitochondrial respiratory chain. Due to impermeability of mitochondrial membranes to NAD and NADH, there are several shuttles for NADH transport and NAD resynthesis. Discussed above, the malate–aspartate shuttle is

Increased ATP consumption promotes oxidative phosphorylation and increases NAD/NADH ratio. This condition activates several NAD-dependent enzymes: isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and MDH which increase

The main regulator of carbohydrates oxidation is FFA utilization. Increased FFA

consumption leads to its intermediate accumulation, which blocks PDH. At the same time, decreased FFA consumption promotes glycolysis and lactate oxidation, due to citrate, NADH, and acetyl-CoA deficiency in the mitochondrial matrix. The

last part is often noted in cardiomyopathies and during ischemia [54, 161]. Modern researches showed an impressive role of small molecule proteins energy homeostasis regulators. Of course, there are many molecules and factors that control energy metabolism, one stimulates appetite (ghrelin, galanin, neuropeptide Y) and another is an anorexigenic (leptin, nesfatin-1) [71, 155]. The first found molecule, which regulates energetic homeostasis, was insulin (Ins); its action was first noted as neurogenic appetite suppression. Later leptin was found—hormone, produced by adipose tissue—and elucidates general adipose tissue state [199]. Then ghrelin and nesfatin-1 were found, with antagonist action to leptin effects on adipose tissue [77, 120]. On the next decades, there was intensive research in the field of lipid homeostasis and appetite-controlling peptides. Many molecules

were found; the most important are preptin, irisin, and adropin.

Insulin (Ins) is a hormone with a huge specter of physiological influence, but in this papers, we discuss only three effects: on heart pump function, on Ca+2 ion circulation, and as a mediator between cell communication. Ins-induced transport of glucose is the main mechanism of energy production of membrane-associated ATPases and ion pumps. Controlling pump function, Ins indirectly influences cytoplasmic concentration and equilibration of Ca+2; it mediates cascades of reactions to stimulate Ca consumption or excretion. Ins is involved in endothelial function, regulating NO production and tissue perfusion (including coronary vessels). And, of course, it influences on the contractile ability of cardiomyocytes due to energy

As an indirect effect, abilities of Ins to control the availability of energy substrates (effects on liver and adipose tissue) and tissue perfusion should be noted. Ins inhibits TG hydrolysis in adipose tissue (depressing lipomobilizating hormones), decreasing the level of circulating FFA. In addition, reactive Ins secretion increases tissue perfusion due to blood vessels smooth muscle relaxation. This effect plays a significant role during exercise, hypertension, and acute and chronic heart failure

#### *Myocardial Metabolism DOI: http://dx.doi.org/10.5772/intechopen.80870*

*Veterinary Anatomy and Physiology*

[28, 72].

of FFA oxidative utilization promotes glycolysis. Inactivated PPAR-a allows to perform increased oxidative glycolysis (decreased FFA oxidation in the Randle cycle), improve GLUT 4 translocation and PDH activation, and improve the severity of insulin resistance. In cases of hypoxic ischemia, this will give a chance for cardiomyocytes' survival due to glycolysis and energy production. In addition, increased PPAR-a expression promotes GLUT 4 genes suppression, leading to insulin resistance and, indirectly, stimulates FFA oxidation metabolites accumulation, this inhibits glycolysis wing of the Randle cycle, decreases GLUT 4 trafficking activity, and suppresses insulin receptor sensitivity due to PI-3-kinase inhibition [33, 127]. However, in cases of active oxidation in tricarboxylic acid cycle with high production of malonyl-CoA, normal transport of FFA to the mitochondrial inner membrane is stopped. Also, membrane translocation of lipids is inhibited by insulin

Utilization of amino acids (predominately leucine, valine, and isoleucine) in energy metabolism is less effective than glycolysis and FFA beta-oxidation. Active amino acid utilization leads to metabolite accumulation; this state is associated with cardiomyopathies and respiratory chain damage in the mitochondria. Metabolism of this substrate is associated with ketoacid formation; part of them could be

Another substrate are ketone bodies (beta-hydroxybutyrate and acetoacetate).

These compounds are produced by the liver during FFA oxidation, and under normal conditions, their level in the plasma is very low, and so they do not actively utilize in myocardial energy metabolism. However, lipomobilization and insulin depletion (diabetes mellitus) could be exceptions for this situation; this condition leads to decreased glycolysis and lactate consumption by cardiomyocytes. In addition, ketone body utilization inhibits FFA oxidation, altering the process of dissociation of acetyl- CoA to free CoA. This complex promotes secondary to heart

In experimental models, it was noted that ketone utilization inhibits lactate oxidation for 30–60% and palmitate for 22%. Later, in vivo experiments admitted that parallel administration of FFA and hydroxybutyrate markedly inhibits FFA oxidation in pigs. It has to be noted that the levels of malonyl-CoA and acetyl-CoA were unchanged. In a similar experiment, it was shown that high concentration of ketone bodies promotes the Krebs cycle blockade and downregulates contractility of cardiomyocytes. So, ketones could be energy substrate to the myocardium, but it blocks other more useful ways of energy production, due to significant demand for

Some intercellular conditions can influence on metabolism intensity and oxidative potential. The significant parameter of the functional condition of the cell is redox potential. Pyridine compounds (NAD, NADH, NADP, NADPH) play the most important role in this state. One of the simplest estimations of redox potential in a cell is cytoplasmic and mitochondrial NAD/NADH ratio. It is considered that NAD depletion and NADH raise characterize inhibition of oxidation in the mitochondria and slowing of Krebs cycle. This was also noted during hypoxia, enzyme defects,

There are complexes of cytoplasmic oxidoreductase enzymes dependent on NAD concentration. The most active one is lactate dehydrogenase (LDH). LDH, depending on the intracellular environment, can produce NAD and lactate from pyruvate, or reverse this reaction to produce pyruvate and NADH. There are many malate dehydrogenases (MDH) in the mitochondria, which is the part of the malate–aspartate shuttle. In particular, MDH catalyzes the metabolism of oxaloacetate and NADH to malate and NAD, and then malate is transported to the mitochondria, while the NAD/NADH ratio increased in the cytoplasm. In addition,

converted to acetyl-CoA and used in the Krebs cycle [145].

failure often noted in patients with diabetes mellitus [49, 95, 160].

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oxygen [160, 173].

and lack of energy substrates [93].

MDH takes part in nitrogen metabolism, rarely can be activated to produce energy from aspartate [12, 67, 85, 146].

High NAD/NADH ratio promotes normal substrate oxidation and saves redox potential to sustain electron transport in oxidative metabolism. As already been said, LDH and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) both use NAD/NADH as a cofactor. GAPDH produces NADH, which is oxidized to NAD by LDH. In anaerobic conditions, both of these enzymes produce NAD, which is utilized in glycolysis. In the aerobic state, NADH reoxidation is connected with its utilization in the mitochondrial respiratory chain. Due to impermeability of mitochondrial membranes to NAD and NADH, there are several shuttles for NADH transport and NAD resynthesis. Discussed above, the malate–aspartate shuttle is predominant in the myocardium [55, 118].

Increased ATP consumption promotes oxidative phosphorylation and increases NAD/NADH ratio. This condition activates several NAD-dependent enzymes: isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, and MDH which increase the Krebs cycle intensity [163, 189].
