Normal And Abnormal Cardiac Muscle Metabolism CVS/BIOCHEMISTRY DR.
Normal And Abnormal Cardiac Muscle Metabolism CVS/BIOCHEMISTRY DR. NABIL BASHIR SECOND SEMESTER, 2018 Metabolism In Healthy Myocardium Cardiac function is maintained by matching the synthesis and breakdown of ATP I. ATP is constantly synthesized in the mitochondria by oxidative phosphorylation II. ATP breakdown by myosin ATPase for systolic work & Ca2+ATPase for diastole Figure 1. Cardiac energy metabolism under normal
aerobic conditions Fatty acids are the primary source of energy for the heart, supplying 6090% of the energy for ATP synthesis. The balance (1040%) comes from the oxidation of pyruvate formed from glycolysis and lactate oxidation. Almost all of the ATP formation comes from oxidative phosphorylation in
the mitochondria; only a trivial amount of ATP (<2% of the total) is synthesized by glycolysis. To Move the Acyl-CoA into the Mitochondrion, the CoA is Swapped with a Molecule of Carnitine Four Steps in Fatty Acid Oxidation Sources of fatty acids plasma concentration of fatty acids is due to the hormonal control of hormone-sensitive lipase by insulin and noradrenaline (norepinephrine) in this tissue.
Insulin suppresses fatty acid levels( after meal) noradrenaline increases fatty acid release from fat cells (physical exercise, fasting, or myocardial ischaemia). Diabetic patients (both types 1 and 2) have high fatty acid levels because of low insulin levels and/or resistance to the normal insulin-induced suppression of fatty acid release from fat cells. Figure. 2: Mitochondrial energy metabolism. (NADH) and FADH2 transfer electrons from fatty acids, glucose and lactate to the electron transport chain. The process of oxidative phosphorylation is driven by the electron transport chain, which takes the energy from the oxidation of fatty acids, glucose and lactate, primarily via NADH.
Pyruvate Dehydrogenase Mitochondrial Enzyme Very large multimeric complex Three subunits - E1, E2, E3 Pyruvate An im als + NAD NADH + CO2 E1 Subunit of Pyruvate Dehydrogenase
Acetyl-CoA Figure 3 Regulation of pyruvate oxidation under normal aerobic conditions Pyruvate is formed in the cytosol from glycolysis and
lactate oxidation, and is converted to acetyl-coenzyme A (CoA) in the mitochondria by pyruvate dehydrogenase (PDH). The acetyl-CoA and reduced nicotinamide adenine dinucleotide (NADH) generated by fatty acid oxidation inhibit flux through PDH. Pharmacological inhibition of the rate of fatty acid oxidation removes inhibition of flux through PDH by NADH and acetyl-CoA, and results in more
pyruvate oxidation and thus more glucose and lactate uptake. Be careful not to confuse PD with the PD Phosphatase or the PD Kinase These ions Activate )Favor Dephosphorylation( PD = Pyruvate Dehydrogenase Phosphorylation Inactivates Dephosphorylation Activates
PD Kinase Puts Phosphate on hosphatase Takes Phosphate off Energy metabolism during ischemia 1. Accelerated glycolysis, lactate production and a fall in PH The primary result of ischemia is mitochondrial metabolic dysfunction decrease in ATP formation by oxidative phosphorylation stimulates glycolysis, increase in myocardial glucose uptake and glycogen breakdown occurs high rate of conversion of
pyruvate to lactate rise in tissue lactate content accumulation of lactate and H+, fall in intracellular pH, reduction in contractile work and Ca++ homeostasis . Figure 4 Cardiac energy metabolism during ischemia of moderate severity (approximately 40% of normal blood flow). ischemia results in an increase in glycolysis without an increase in the rate of pyruvate oxidation, thus causing lactate to
accumulate in the cell. Despite accelerated glycolysis and lactate production, the relatively high rate of residual oxygen consumption is fueled primarily by the oxidation of fatty acids. Fatty acids are the main fuel for the mitochondria during partial ischemia During ischemia High rates of fatty acid oxidation inhibit
pyruvate oxidation during ischemia The impaired pyruvate oxidation during ischemia of moderate severity is due to the rise in mitochondrial NADH secondary to the fall in oxygen consumption and to the high rates of fatty acid oxidation. Figure 5 Pyruvate oxidation during ischemia
There is accelerated glycolysis and lactate production in the cytosol. In the mitochondria there is a rise in the ratio of (NADH) to oxidized (NAD+) due to a decrease in oxygen consumption and continued fatty acid oxidation. Pharmacologically inhibiting fatty acid oxidation (e.g. with the 3-ketoacyl thiolase inhibitor trimetazidine) during
ischaemia removes inhibition of pyruvate dehydrogenase (PDH) by NADH and acetylcoenzyme A (CoA), and results in more pyruvate oxidation and reduced symptoms of angina. outlines
Plasma fatty acids come from the breakdown of triglyceride in fat cells Fatty acids supply approximately 6090% of the energy used to synthesize ATP The rate of fatty acid uptake by the heart is primarily determined by the concentration of fatty acids in the plasma, which varies widely between 01 and approximately 15 mmol/l . The rate of fatty acid beta oxidation is primarily regulated by the
concentration of free fatty acids in the plasma, the activity of the carnitine transferase/translocase system on the mitochondrial membranes, and the activity of a series of enzymes that catalyze the multiple steps of fatty acid beta-oxidation Glucose and lactate supply between approximately 10% and 40% of the energy requirement of the heart Glucose is taken up by the myocardium and is either stored as glycogen, or broken down by glycolysis to pyruvate . Lactate is extracted from the blood, converted to pyruvate in the cytosol, and further oxidized to acetylCoA in the mitochondrial matrix. In the normal healthy human heart, pyruvate is derived in approximately equal proportions from glycolysis and lactate uptake. Pyruvate is oxidized to acetyl-CoA in the mitochondria by the enzyme pyruvate dehydrogenase The rate of flux of pyruvate to acetyl-CoA is determined by the amount of active enzyme present in the tissue and the concentration of CoA, NAD+ and pyruvate, and the products: acetyl-CoA and NADH.
Flux of pyruvate to acetyl-CoA is inhibited by acetyl-CoA and NADH, and thus high rates of fatty acid oxidation result in elevated NADH : NAD+ ratio and acetyl-CoA : free CoA ratio, which strongly inhibit flux through PDH The amount of active enzyme is also under acute allosteric control by PDH kinase, which phosphorylates and inhibits PDH. The activity of PDH kinase is stimulated by increases in the NADH : NAD+ and acetyl-CoA : free CoA ratios, and thus high rates of fatty acid oxidation stimulate PDH kinase and inhibit the rate of glucose and lactate oxidation by the heart. Conclusion Myocardial ischaemia of moderate severity dramatically alters fuel
metabolism, reducing the rate of oxygen consumption and ATP production. This leads to a fall in ATP content, high rates of glycolysis, pyruvate formation and lactate accumulation, and a fall in intracellular pH. The myocardium continues to derive most of its energy (5070%) from the oxidation of fatty acids. Despite the high rate of lactate production during ischaemia, pyruvate oxidation is inhibited by fatty acid oxidation, which contributes to the accelerated lactate production, intracellular acidosis and general disruption to cell homeostatis. Ischaemia-induced dysfunction can be minimized by metabolic agents that partly inhibit fatty acid oxidation, and increase the combustion of glucose and lactate.
Disclaimer . These slides have been prepared and approved by the Student Assessment Division of the Texas Education Agency. If any slide is amended or revised for use in local or regional trainings, please remove this slide as well as...
An adequate amount of all 20 amino acids is required to build proteins for growth and to replace the proteins that are turned over. However, only 8 of these (9 in children) cannot be produced by the body and must...
There are around 25 000 species of fish. They are divided into three classes. BONY FISH (OSTEICHTHYES) OSTEON = bone. JAWLESS FISH (AGNATHA) A = without, GNATHOS = jaw. CARTLIAGINOUS FISH (CHONDRICHTHYES) CHONDROS = cartilage. Fish. Bony Fish have skeletons...
Research Mission and Vision. Research Mission: The mission of the Research Department is to work collaboratively to support all stakeholders by collecting, maintaining, and reporting accurate data, facilitating testing, and using current technology in order to provide useful and timely...
Access to Recovery - ATR - is a nationwide initiative of the Substance Abuse & Mental Health Services Administration (SAMHSA) Center for Substance Abuse Treatment (CSAT). The program issues vouchers to clients for the purchase of clinical treatment and recovery...
After 3 months pass, the worker savings nothing and instead spends all her monthly income. Here is the classic textbook example of time inconsistency (from Mankiw's intermediate macro text and other textbooks): The government announces a policy of not negotiating...
Ready to download the document? Go ahead and hit continue!