Medical Biochemistry and Molecular Biology department Cardiac Fuels [Sources of energy for the Cardiac muscle] Intended learning outcomes of the lecture: By the end of this lecture you would be able to:- 1. Identify the major sources of energy (Glucose, lactate, FFA and ketone bodies) for the cardiac muscle under different physiological conditions. 2. Describe the energy pool of the heart. 3. Explain How fuels selection is controlled in cardiac muscle 4. Elaborate on the Inter-regulation of fatty acid and carbohydrate oxidation:(randle cycle) 5. Recognize the metabolic profile changes in in cardiac diseases 6. Explain How does the metabolic agent modulate metabolism and improve cardiac energetic. ATP production in the cardiac muscle: The heart is one of the most active tissues in the body. Myocardial function depends on a fine equilibrium between the work the heart has to perform to meet the requirements of the body & the energy in the form of ATP to sustain excitation-contraction coupling. Impaired substrate metabolism contributes to contractile dysfunction in heart failure. Heart muscle metabolism is designed to generate large amount of ATP by oxidative phosphorylation to support high rate of cardiac power. Under non-ischemic conditions almost all (>95%) of ATP formation in the heart comes from oxidative phosphorylation in the mitochondria, with the remainder derived from glycolysis and GTP formation in the citric acid cycle (substrate level phosphorylation). The heart uses 60% to 70% of generated ATP to fuel contraction and the remaining 30% to 40% for various ion pumps, especially the Ca 2+ -ATPase in the sarcoplasmic reticulum. Cardiac energy metabolism under normal aerobic conditions 1
The energy pool of the heart: 1- ATP ( 5 μmol/g wet weight) The heart has a relatively low ATP content and high rate of ATP hydrolysis, thus there is complete turnover of the myocardial ATP pool approximately every 10 s under normal conditions. 2- Phosphocreatine (PCr ; 8 μmol/g wet weight), serving as an ATP transport. In the mitochondria, the high-energy phosphate bond in ATP can be transferred to creatine by mitochondrial creatine kinase to form PCr. PCr can easily diffuse through the mitochondrial membrane into the cytosol because of its smaller molecular weight than ATP. Here, it can be used to generate ATP from ADP through reactions catalyzed by the cytosolic creatine kinase. Cardiac fuels in different conditions: Cardiac muscle can utilize 4 substrates for oxidative generation of ATP: fatty acids, glucose, lactate and ketone bodies. The contribution of these substrates to oxidative generation of ATP in the heart is influenced by hormonal control, work load and oxygen supply to the heart Fatty acid oxidation represents the major source of energy for myocardium, up to 80%. Glucose metabolism provides for the remaining quantity of energy. At rest, the heart operates at 15 25% of its maximal oxidative capacity. However, at maximal cardiac work the metabolic machinery consumes oxygen at 80 90% of the mitochondrial capacity for electron transport chain flux and oxygen consumption. There is a net increase in cardiac uptake of glucose from blood and lactate generated from skeletal muscle during low to moderate intensity exercise, without change in free fatty acid metabolism. Glucose utilization drops during high intensity exercise compared to lower intensity exercise. When the myocardium is stressed beyond the limits of its metabolic reserve, an aerobic limit is reached. As a consequence, anaerobic metabolism begins and ventricular performance declines. 2
Carbohydrates as an energy source for cardiac muscles: Carbohydrate substrates are glucose, glycogen, and lactate. Cardiac Glycogen is very small (~30 mmol/g wt compared with skeletal muscles, ~150 mmol/g wt). Glucose is transported from blood into cardiomyocyte through GLUT-4 (lesser extent GLUT-1). Insulin stimulation, increased work demand, or ischemia increase rate of glucose transport and uptake. Glycolysis produces 2 pyruvates + 2 NADH+ H, + 2 ATP for one glucose. In the mitochondria, pyruvate is dexarboxylated and oxidized into acetyl CoA by pyruvate dehydrogenase (PDH) or carboxylated into oxalacetate by pyruvate carboxylase. In the cytoplasm pyruvate can be reduced to lactate by lactate dehydrogenase (nonoxidative glycolysis). Citric acid cycle (CAC) in mitochondria will be fueled by both acetyl CoA and oxalacetate for complete oxidation of glucose. So, when glycolysis is coupled to oxidation ~ 36-38 ATP will be produced from one glucose The control of PDH activity by substrates availability and covalent modification is an essential part of overall control of glucose oxidation. Lactate is extracted from the blood (mostly coming from skeletal muscles), and converted to pyruvate in the cytosol, then further oxidized to acetyl-coa in the mitochondrial matrix. In the normal healthy human heart, pyruvate is derived in approximately equal proportions from glycolysis and lactate uptake Fatty acids as an energy source for cardiac muscles: The rate of fatty acid uptake by the heart is primarily determined by the concentration of free fatty acids in the plasma, coming from the breakdown of triglyceride in fat cells, which increases under conditions of metabolic stress, such as physical exercise, fasting, or myocardial ischemia. FFAs enter the cardiomyocyte by Passive diffusion or protein-mediated transport across sarcolema then activated to acyl CoA. Long chain fatty acyl-coa can be either: esterified to triglyceride (intracardiac pool, 10-30% of FA) or converted to acyl carnitine by (CATI) to cross mitochondrial membrane then regenerates to acyl CoA by (CATII). CAT-I can be strongly inhibited by malonyl CoA (precursor for FA synthesis). Mitochondrial acylcoa undergoes β-oxidation generating NADH and FADH2 and Acetyl-CoA which generates more NADH in citric acid cycle (CAC). 3
Moreover, the heart can use ketone bodies as a source of fuel in cases of starvation and uncontrolled DM. In these conditions liver mitochondria converts acetyl CoA derived from FA oxidation into ketone bodies (ketogenesis). The two functional water soluble KB are; Acetoacetate and 3-hydroxybutyrate are transported in the blood to the heart. In the heart they are reconverted to acetyl CoA, which can be oxidized by the TCA cycle to produce energy. This utilization process of ketone bodies as fuels is called ketolysis. Inter-regulation of fatty acid and carbohydrate oxidation: (Randle cycle) (glucose /fatty acid cycle) 1. Substrate selection and use in the heart are modulated by allosteric and hormonal regulation ( insulin, epinephrine) 2. FA and glucose use is tightly linked and co-regulated. Use of one substrate may directly inhibit the use of the other. 3. The primary physiological regulator of flux through PDH and the rate of glucose oxidation in the heart is fatty acid oxidation. 4. PDH activity is inhibited by high rate of FA oxidation via an increase in mitochondrial acetyl-coa/free CoA and NADH/NAD+ which activates PDH kinase. 5. Inhibition of FA oxidation increases uptake and oxidation of glucose and lactate by: lowering acetyl CoA and/or NADH levels in the mitochondria. This improves cardiac efficiency. 4
Alteration in energy metabolism in cardiovascular disease: Mitochondrial oxidative metabolism is critically dependent on oxygen supply to the heart, and any decrease in oxygen supply to the myocardium results in a decrease in the production of mitochondrial ATP. An initial adaptive response is to increase glycolysis, because glycolysis can produce ATP in the absence of oxygen. This stressful condition increase catecholamines which stimulate lipolysis. So, the heart is exposed to high concentrations of fatty acids. Alterations in the subcellular control of fatty acid oxidation result in fatty acid oxidation becoming the main residual source of mitochondrial oxidative metabolism. This results in low rates of glucose oxidation during ischemia. The high glycolysis coupled to low glucose oxidation results in the production of lactate and protons, leading to myocardial tissue acidosis. Accumulation of lactate can lead to accumulation of sodium and calcium requiring more ATP to maintain ion homeostasis. This redirection of ATP from contractile function to ion homeostasis decrease cardiac efficiency. 5
FA can decrease cardiac efficiency through other futile cycles: - The cycling of fatty acids between long chain acyl CoA and triacylglycerol uses ATP. - Efficiency of ATP production can also potentially be reduced by uncoupling the mitochondrial proton gradient due to increased uncoupling protein (UCP) activity. - High fatty acids activate sarcolemal calcium channels, so more ATP is used to maintain homeostasis. At the end stages of Heart Failure, the myocardium has low ATP content due to a decreased ability to generate ATP by oxidative metabolism, and thus is unable to effectively transfer the chemical energy from the metabolism of carbon fuels to contractile work. The metabolic changes are similar to those occur in ischemic heart disease. Optimization of cardiac energetic for treatment of heart disease: Metabolic agents are effective when added to standard therapies, because they act through optimization of cardiac substrate metabolism. Metabolic agents can partly inhibit fatty acid oxidation and stimulate glucose and lactate oxidation which can improve cardiac efficiency and cardiac function in the ischemic heart and heart failure e.g. Trimetazidine in angina pectoris. Assigned Task: 1. Elaborate on the metabolic fuels supplying energy to the heart under normal conditions and ischemic cardiac stress. 2. Discuss that although Fatty acid oxidation is an important source of cardiac energy; its inhibition could results in clinical benefit for patients with heart failure. Further readings: W.C. Stanley, F.A. Recchia, G.D. Lopaschuk: Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85:1093-1129, 2005. 6