Oxidative Systems for Muscle Energy 1 PDF

BMS201 Lecture No: Title: Oxidative systems for muscle energy 1 Instructor Name: Dr Wael Elayat Medicine and Surgery Program Spring 2024 ILOs By the end of this lecture, you should be able to: 1- Identify sources of free fatty acids for muscle...

BMS201 Lecture No: Title: Oxidative systems for muscle energy 1 Instructor Name: Dr Wael Elayat Medicine and Surgery Program Spring 2024 ILOs By the end of this lecture, you should be able to: 1- Identify sources of free fatty acids for muscle use. 2- Identify stages of fatty acid oxidation. 3- Describe steps of fatty acid activation, mitochondrial transport, reaction of beta oxidation  Introduction Oxidative system (aerobic pathway) produces 95% of ATP during rest and light to moderate and prolonged exercise e.g. posture, marathon, climbing hills. Energy is produced by oxidative phosphorylation (in electron transport chain). This requires a supply of oxygen and occurs when O2 delivery can keep up with O2 use. Muscles which have a high demand for oxygen as a result of sustained contraction (e.g.to maintain posture) store it attached to the heme moiety of myoglobin are red (leg of chicken), whereas muscles with little or no myoglobin are white. Fuels for oxidative system are: stored glycogen, then glucose (blood), pyruvic acid from glycolysis, and free fatty acids.  Fatty acids (FAs) Oxidation Fatty acids are oxidized in several tissues, including liver, muscle, and adipose tissue, by the pathway of β-oxidation. Neither erythrocytes nor brain can use fatty acids and so continue to rely on glucose during fasting. Erythrocytes lack mitochondria, and fatty acids are not used by the brain as fuel, as fatty acids can not cross blood brain barrier. Free fatty acids in plasma are a major source of energy for muscle during rest, under marathon condition and in prolonged starvation. Sources of FA for muscle use 1- Plasma free fatty acids. 2- Adipose tissue TAG. Adipose tissue TAG a- Release of fatty acids from TAG The mobilization of stored fat requires the hydrolytic release of fatty acids and glycerol from their TAG form. This process is initiated by hormone-sensitive lipase, which removes a fatty acid from DAG after the effect of adipose tissue lipase. b- Activation of hormone- sensitive lipase (HSL):  HSL - This enzyme is activated when phosphorylated by cAMP– dependent protein kinase. - cAMP is produced in the adipocyte when one of several hormones (such as epinephrine) binds to receptors on the cell membrane, and activates adenylyl cyclase. - In the presence of high plasma levels of insulin and glucose, HSL is dephosphorylated, and inactivated.  C- Transportof adipocyte fatty acids - The free fatty acids move through the cell membrane of the adipocyte, and bind to plasma albumin. 1-They are transported to the tissues as muscle. 2-Enter cells. 3- Get activated to their CoA derivatives and are oxidized for energy production.  Oxidation of fatty acids 1- β -Oxidation of fatty acids in the mitochondria, which is the major pathway for catabolism of fatty acids. 2- Peroxisomal β -Oxidation of fatty acids in the peroxisome, which is a minor pathway for catabolism of very long chain fatty acids. 3- Peroxisomal α oxidation of fatty acids: which is a minor pathway for oxidation of branched chain FA, phytanic acid.  In class assessment 1- Fatty acids are regarded as: a) Immediate source of energy. b) Potential source of anaerobic energy for muscle. c) Potential source of aerobic energy for brain. d) Potential source of aerobic energy for RBCs. e) Potential source of aerobic energy for muscle. 1- β -Oxidation of fatty acids i- Definition: - The major pathway for catabolism of fatty acids. ii- Site: - It occur in the mitochondria. iii- Steps: - Two-carbon fragments are successively removed from the carboxyl end of the active fatty acid (fatty acyl COA) producing acetyl CoA, NADH, and FADH2. Oxidation of FAs pass through 3 stages. a- Activation of FA b- Transport of long chain activated FA into mitochondria c- Reactions of beta oxidation a- Activation of FA Fatty acid + ATP + CoASH ——> Acyl-CoA + PPi + AMP - This reaction is catalyzed by the enzyme acyl-CoA synthetase (thiokinase) which is located on the outer mitochondrial membrane. - This reaction occurs in cytoplasm. - The resulting pyrophosphate (PPi) is degraded to 2 inorganic phosphates and a large amount of energy is released in the form of heat. b- Transport of long chain fatty acids into mitochondria Short chain fatty acids (2-4 carbons) and medium chain fatty acids (6-12 carbons) diffuse freely into mitochondria to be oxidized. Medium-chain fatty acids are plentiful in human milk. Long chain fatty acids (14-20 carbons) are transported into the mitochondrion by a carnitine shuttle to be oxidized. Very long chain fatty acids enter peroxisomes for oxidation. b- Transport of long chain fatty acids into mitochondria  The entry of long-chain acyl groups into the mitochondrial matrix can be prevented by Malonyl CoA (initiator of FA synthesis), it inhibits CAT-I.  Therefore, turning on the fatty acid synthesis pathway and turning off the -oxidation pathway  Carnitine Sources: 1- Diet (Meat products). 2- Endogenous source: It can be synthesized from lysine and methionine by an enzymatic reaction in the liver and kidney. N.B.: Although muscle contains around 97% of total body carnitine, yet it can not synthesize it.  Clinical significance of carnitine 1- Primary carnitine deficiency. a- CATI/CPT1 deficiency: affects the liver. b- CATII/CPTII deficiency: can affect muscle. 2- Secondary carnitine deficiency. Decreased synthesis: liver disease, malnutrition, vegetarian. Increased demands: pregnancy, trauma, infection. Increased loss: hemodialysis.  c- Oxidation Reactions - β Oxidation involves cyclic removal of two carbons, in the form of acetyl CoA from the carboxyl end of acyl CoA. Several enzymes collectively called fatty acid oxidase participate in this process which occurs in the mitochondria. A repeating sequence of 4 reactions: Oxidation =Dehydrogenation (FAD linked dehydrogenase). Hydration. Oxidation=Dehydrogenation (NAD linked dehydrogenase). Thiolytic cleavage. c- Oxidation Reactions  References: Lippincott Illustrated Review Integrated system Lippincott Illustrated Review 6th edition Oxford Hand book of Medical Science 2nd edition Clinical Key Student THANK YOU