Muscle Metabolism Introduction 1. ATP is necessary for muscle contraction a. when a single muscle cell is contracting it can use up millions of ATP molecules per second to form and break the rigor bonds of cross-bridges (myosin head attached to thin filament) as the muscle cells contract b. even small muscles contain 1000 s of muscle cells c. ATP is also needed for maintenance of membrane potential for the generation of the muscle impulse and for the operation of Ca 2+ active transport pumps in the cistern membranes 2. Where does the ATP come from to support muscle contraction a. there are a number of sources of ATP that are engaged in a specific sequence as a muscle contracts b. Sources of ATP 1. ATP stored in muscle cells (5-10 seconds of sustained activity) 2. creatine phosphate stored in muscle cells (phosphate-storage molecule)(15-30 seconds of activity) 3. Cellular Respiration during exercise a. anaerobic (without oxygen) pathways that make ATP (glycolysis; fermentation) 1. if oxygen supply to the exercising muscle cells doesn t match the rate at which glycolysis makes pyruvate for the aerobic pathway, then some of the pyruvate is
converted to lactic acid. O 2 supply is only one of several factors that cause an increase in muscle and blood lactate levels during exercise. Some lactic acid can be produced in resting cells. 2. lactic acid is a byproduct of anaerobic cellular respiration b. aerobic pathways (with oxygen) respiration 1. makes ATP for activities lasting longer then a minute 3. the aerobic pathways of cellular respiration occur in the mitochondrion and make far more ATP then glycolysis 3. Muscle cells at rest a. store ATP that they make by cellular respiration (muscle cells have a lot of mitochondria) b. build up stores of creatine phosphate creatine + ATP creatine phosphate + ADP c. convert glucose that comes into the cell into glycogen (glycogenesis) 1. muscle cells contain a lot of glycogen 2. glycogen accounts for about 1.5% of a muscle cell s total mass 3. about 75% of the body s glycogen is stored in skeletal muscle (most of the rest is in the liver) 3. muscle cells depend on the breakdown of glycogen (glycogenolysis) during exercise to supply glucose to make ATP by cellular respiration Cellular Respiration of Glucose Overview Glucose + 6O 2 6CO 2 + 6H 2 O + 30-32 ATP 1. Glycolysis occurs in the cytoplasm a. anaerobic process that occurs in the cytoplasm b. glucose is broken down to 2 pyruvate c. results in a net gain of 2 ATP and forms 2 NADH (reduced coenzymes which carry e s to the ETC s in the mitochondria to make ATP) d. if there is enough O 2 in the cell, then all of the pyruvate goes into the mitochondria 2. Mitochondrial Stages a. all of the mitochondrial stages of cellular respiration require O 2 b. if O 2 is available, then pyruvate enters the mitochondrion and is broken down to CO 2 and H 2 O as about 30 ATP form 1. most of the ATP gained by cellular respiration (about 95%) is formed in the mitochondria 2. the CO 2 that forms is a gaseous waste product of cellular respiration. 3. CO 2 diffuses out of the cell, then into the blood. The blood takes it to the lung where it is exhaled. c. if O 2 is unavailable, then all of the mitochondrial stages of cellular respiration shut down d. CO 2 is generated in the mitochondria by the oxidation of pyruvate and the Kreb s Cycle e. most of the ATP (about 95%) that forms from the break down of glucose comes from the mitochondrial stages of cellular respiration 1. glycolysis produces 2 ATP per glucose (6%) 2. the mitochondria produce about 30 ATP per glucose (30/32=94%) f. Pathways in the Mitochondrion 1. oxidation of pyruvate (pyruvate to Acetyl CoA) 2. Kreb s Cycle 3. Electron Transport Chain and chemiosmosis g. if insufficient O 2 is available such as occurs during exercise, then some of the pyruvate does not enter the mitochondrion and gets converted to lactic acid within the sarcoplasm. 2
ATP Production by Exercising Skeletal Muscle One system blends into the next. There is considerable overlap between the 3 ATP-generating systems listed in the table below. Duration of Exercise System Description of System First 30 seconds Phosphagen System Stored ATP and CP Next 30-60 seconds Glycogen-Lactic Acid system Blood glucose and glucose from glycogen are used to make ATP by lactic acid fermentation After about a minute or more of exercise until stop exercising Aerobic Respiration After about 60 seconds of exercise the cardiopulmonary system delivers oxygen to exercising skeletal muscle fast enough to sustain aerobic cellular respiration During exercise that lasts for more than 10 minutes, more than 90% of the ATP is produced aerobically. Short Bursts of Activity Lasting about 30 seconds (e.g., weight lifting, sprinting) 1. short bursts of activity like weight lifting and sprinting are powered by the stores of ATP and CP 2. ATP is provided by the phosphagen system which consists of stored ATP and ATP made by transferring a phosphate group from creatine phosphate to ADP to make ATP a. stored ATP and Creatine Phosphate (CP) are called the phosphagen system b. They are capable of supporting muscle contraction for about a minute of brisk walking or about 6 seconds of sprinting c. the phosphagen system is important for bursts of activity during sports like football and weightlifting d. once the cytoplasmic stores of ATP and CP are gone, then the cell switches to the glycogen-lactic acid system to make ATP for about 30 seconds and then finally to aerobic respiration which can provide ATP for hours of sustained activity. 3. ATP in muscle cells: first 6 seconds of running activity a. a resting muscle stores some ATP b. this reserve is used up quickly c. when you start to exercise vigorously, this reserve is used within 6 seconds 3
4. Creatine phosphate (CP) supplies an additional 25 seconds of activity a. once the stored reserves of ATP are used up (within the first 6 seconds of exercise), the cells rely on the formation of ATP from CP b. a resting muscle has six times more CP than stored ATP c. CP is formed when muscle cells are at rest d. when needed, CP releases its stored energy to convert ADP to ATP; the ATP that forms is then used to power muscle contraction CP + ADP creatine + ATP (this reaction is catalyzed by creatine kinase) Sustained Exercise that Lasts Longer than 30 seconds 1. Once the stored ATP and CP reserves are gone (can occur within 5-10 seconds depending on the strenuousness of the exercise), ATP is made for the next 30-40 seconds by an anaerobic process called lactic acid fermentation that is part of the glycogen-lactic acid system a. as the phosphagen system is used up within the first 5-10 seconds of heavy exercise, the muscles shift to anaerobic fermentation (glycogen-lactic acid system) until the cardiopulmonary system can catch up with oxygen demand of exercising muscle. b. During next 30 to 40 seconds (after the depletion of ATP from the phosphagen system), the body uses glucose from the blood and the breakdown of muscle glycogen to make ATP by breaking it down during glycolysis to lactic acid. c. The pathway from glycogen to lactic acid is called the glycogen lactic acid system 2. the primary fuel for ATP synthesis by cellular respiration during exercise is glucose 3. most of the glucose for ATP synthesis in an active muscle comes from the breakdown of muscle glycogen 4. when an active muscle cell runs low on ATP and CP, enzymes of glycogenolysis are stimulated to convert glycogen to glucose 5. Anaerobic respiration and Lactic Acid Production during exercise a. anaerobic means without oxygen; glycolysis allows cells to generate ATP when mitochondrial activity is limited by the oxygen supply b. a muscle cell shifts to anaerobic respiration when it can t get enough oxygen into the cell to breakdown all of the pyruvate that forms at the end of glycolysis c. this occurs during strenuous exercise; break down glucose to pyruvate faster than the circulatory system can deliver oxygen to the cell d. some of the pyruvate is then fermented to form lactic acid (lactic acid fermentation) e. during strenuous activity lasting more than 30 or 40 seconds, anaerobic pathways supply most of the ATP for muscle contraction f. glycolysis (anaerobic pathway) supplies ATP at a rate that is 2.5 times faster than aerobic mitochondrial stages of cellular respiration g. activities such as soccer and tennis that involve short bursts of activity for a long period of time rely mostly on anaerobic pathways (lactic acid fermentation) to make ATP 6. Aerobic Cellular Respiration a. during low levels of prolonged activity (e.g., walking), the circulatory system provides enough O 2 for the complete respiration of glucose to CO 2 and H 2 O with the involvement of the mitochondrial stages b. well-conditioned athletes deliver more oxygen to muscle cells than those that are not conditioned 4
Muscle Fatigue 1. Muscle fatigue is the physiological inability to contract even though the muscle is receiving stimuli to do so. 2. Although many factors contribute to fatigue, it is not completely understood 3. The availability of ATP decreases during contraction, but is still available. a. Thus ATP is not a fatigue-causing factor in moderate exercise. b. a total lack of ATP results in cramping since the rigor bonds can t be broken (e.g., writer s cramp). The cramps are called contractures in which the muscle enters a state of continuous contraction for a while. 4. Several ionic imbalances contribute to fatigue a. during muscle activity, K + build up in the fluids of the T-tubules. This decreases the ability of muscle cells to release Ca 2+ from the cisterns, thus interferes with excitation-contraction coupling. b. An increase in the intracellular concentration of inorganic phosphate (P i from CP and ATP breakdown may interfere with calcium release from the SR and with myosin s power stroke. 5. Lactic acid (LA) accumulation during exercise has long been assumed to be a major cause of muscle fatigue, but that doesn t seem to be the case. a. LA does accumulate during exercise and release H + that lead to acidosis and acidosis will interfere with muscle contraction, but studies show that buffering systems within muscle cells bind up the H + to prevent ph changes. The ph of exercising muscle cells is normally regulated within normal limits. b. LA is associated with the ache that occurs as muscles are exercised. Lactic Acid Production 1. during strenuous exercise, muscle cells often do not receive enough O2 so that all of the pyruvate formed by glycolysis can enter the mitochondria. a. As a result, some of the pyruvate is converted to lactic acid (LA) b. LA production is proportional to the amount of O2 that exercising skeletal muscle cells receive during exercise 2. better conditioned athletes have efficient systems to deliver a lot of oxygen to muscle cells during exercise and produce less lactic acid than a non-conditioned individual a. more capillary beds b. higher amounts of myoglobin in the cells c. stronger heart to more efficiently pump blood to lungs and exercising skeletal muscle d. additional mitochondria to use O2 to make ATP e. increased number of RBC s 3. Some of the lactic acid produced by exercising muscle cells enters the blood stream and most of that is taken up by liver cells. Liver cells then convert the lactic acid to glucose by reversing the steps of glycolysis 4. Only relatively short, intense activity causes lactic acid to accumulate. LA is not thought to be a contributor to fatigue in low-moderate activity of any duration. 5. LA releases H+ which lower the ph in muscle cells. This contributes to fatigue. Exercise-induced muscle soreness 1. occurs 12-24 hours after exercise 2. due to microscopic damage to muscle cells (e.g., torn sarcolemma, damaged myofibrils) 3. indicated by blood levels of myoglobin and the enzyme creatine kinase 5
4. muscles repair the damage within a day or so Prolonged Muscle Activity (more than 10 minutes; distance running) 1. during prolonged muscle activity, the body gradually switches away from anaerobic pathways to aerobic pathways for making ATP a. aerobic pathways require O 2, which can come from either of 2 sources b. O 2 comes from the blood into muscle cells c. some O 2 is found stored in muscle cells where it binds reversibly to myoglobin 2. aerobic pathways supply more than 90% of the ATP required for sustained intense activity lasting more than 10 minutes 3. aerobic pathways supply almost 100% of the ATP in marathon runners Oxygen Debt (Oxygen Deficit) 1. Amount of extra oxygen used by cells of the body immediately after exercise (beyond resting oxygen consumption) to restore the body back its normal resting state. 2. The oxygen debt accumulates during exercise and it is paid back after exercise is over as one breathes heavily for a few minutes. When one finishes exercising, one might expect that the heavy breathing that occurs during exercise would immediately stop since extra oxygen shouldn t be needed to maintain a resting metabolism, but that isn t the case because of the oxygen debt. 3. After prolonged exercise, a person continues to breathe heavily for several minutes to take in extra oxygen to pay back the oxygen debt. Breathing Rate (Breaths/Min) Resting 12 Exercise 20 a. the extra O 2 allows liver (and muscle) cells to make more ATP than normal for a few minutes in order to convert lactic acid back to pyruvate. Two pyruvate molecules can then be combined into glucose. b. extra O 2 is used to oxygenate myoglobin in skeletal muscle cells; store oxygen in resting muscle cells c. extra O 2 is used to make the extra ATP in muscle cells to synthesize glycogen and creatine phosphate reserves that were used up during exercise. Restock glucose as glycogen. Most ATP used to regenerate CP. Muscle Fatigue 1. strength of contraction becomes progressively weaker until the muscle no longer responds 2. Fatigue occurs when the muscle cannot produce enough ATP to satisfy demand and/or when one is psychologically tired. 3. Contributing factors a. lack of enough O 2 to generate sufficient ATP b. glycogen depletion (decrease the rapid ATP-generating system) c. ionic imbalances K + accumulate in T-tubules as a result of repeated muscle impulses. This can interfere with the ability of muscle cells to release Ca 2+ from cisterns d. LA production that decreases ph of sarcoplasm. This can lead to a decrease in the activity of enzymes such that muscles don t contract effectively. Buffers within skeletal muscles appear to correct this reasonably well so that it is not a major cause of fatigue. e. Inorganic phosphate that forms from the breakdown of ATP 6