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Click for larger image	Cori Cycle Muscular Activity and the Cori Cycle: Muscular activity or its anticipation leads to the release of epinephrine by the adrenal medulla. Epinephrine markedly stimulates glycogen breakdown(glycogenolysis) in muscles and, to a lesser extent, in the liver. Muscular activity quickly uses stored ATP as the energy source and more ATP must be generated by the breakdown of glycogen. The sequence of epinephrine stimulating events is outlined in the graphic on the left and explained in the following sections. The reaction cascade sequence is as follows: 1) Epinephrine binds to a receptor on the muscle cell membrane and stimulates adenyl cyclase in the membrane. 2) Adenyl cyclase in the membrane catalyzes the formation of cyclic AMP from ATP. 3) The increase of cyclic AMP activates a protein kinase. The binding of cyclic AMP to an enzyme is an allosteric control where the enzyme is "switched on" for activity. 4) The protein kinase causes phosphorylations (addition of phosphate) on a series of phosphorylation enzymes which activates them to finally produce glucose-1-phosphate. 4a) At the same time that enzymes are being activated for glycogen breakdown, glycogen synthetase enzyme must be inactivated. Glycogenesis must be "switched off" and glycogenolysis "switched on." 5) Glucose-6-phosphate is the final result of the initial stimulation by epinephrine or other hormones such as glucagon. If this happened to a muscle cell, then the glycolysis pathway is the next step in the sequence. If this happened to a liver cell stimulated by glucagon, then glucose is produced to enter the blood stream.
Click for larger image	Cori Cycle: During muscle contractions, ATP is constantly being used to supply energy and more ATP is produced to replenish supplies. Link to details of muscular contraction with Myosin. Graphic on ATP-actin-myosin contraction. At first glycolysis produces pyruvic acid which is then converted into acetyl CoA and is metabolized in the citric acid cycle to make ATP using the electron transport chain. If muscular activity continues, the availability of oxygen for use at the end of the electron transport chain becomes the limiting factor and the cells soon exhaust their supplies of oxygen. When this happens, the citric acid cycle is inhibited and causes pyruvic acid to accumulate. See graphic on the left. However, glycolysis continues even under anaerobic conditions even though the citric acid cycle works only under aerobic conditions. Epinephrine at (1) stimulates the enzymes to work on glycogen as discussed in the above panel. Glycogenolysis at (2) is stimulated to make more glucose-6-phosphate. When the cells become anaerobic, glycolysis (3) continues if pyruvic acid is converted to lactic acid (4). Remember that the synthesis of lactic acid requires NADH from Step 5 in glycolysis and produces NAD+ so that Step 5 can continue. The formation of lactic acid buys time and shifts part of the metabolic burden to the liver. Quiz: What usually happens to NADH from Step 5?   Answer Under aerobic conditions, there is a connection to the electron transport chain. But if not oxygen this is inhibited. Starting with glycogen to make glucose-6-phosphate, how many ATP are made using anaerobic glycolysis?   Answer step = -1 ATP step 6 = +2 ATP step 9 = +2 ATP Therefore , you get a NET 3 ATP. Link to a simple animation: Cori Cycle
Click for larger image	Cori Cycle (cont.): Even though not as much ATP can be furnished by glycolysis alone, it is a significant source of ATP when muscular activity continues for any length of time. The final limiting factor in continued muscular activity is the build up of lactic acid. The lactic acid eventually produces muscular pain and cramps which force discontinuation of activity. Usually before this happens and after activity has ceased, lactic acid diffuses out of the muscle cells and into the blood where it enters the liver. The body is very efficient in that lactic acid is sent in the blood (5) to the liver which can convert it back to pyruvic acid (6) and then to glucose through gluconeogenesis (8). The glucose can enter the blood (9) and be carried to muscles and immediately used. If by this time the muscles have ceased activity, the glucose can be used to rebuild supplies of glycogen through glycogenesis (10). This recycling of lactic acid is referred to as the Cori Cycle. The Cori cycle also operates more efficiently when the muscular activity has stopped. At this time the oxygen debt can be made up so that the citric cycle and electron transport chain also begin to function again. In order for most of the lactic acid to be converted to glucose, some must be converted to pyruvic acid and then to acetyl CoA (7). The citric acid cycle and electron transport chain must provide ATP to "fuel" the gluconeogenesis of the remainder of the lactic acid to glucose. Glucagon Protein - Chime in new window