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Chapter 9 & 24 Muscle Metabolism © Annie Leibovitz/Contact Press Images MDufilho Introduction: Muscle Metabolism – Energy for Contraction • Energy is never created nor destroyed, only stored or released • Bonds = energy – ATP is the currency for cellular energy • Energy is stored in the bonds. 10/7/2015 2 MDufilho 9.6 Energy for Contraction and ATP Providing Energy for Contraction • ATP supplies the energy needed for the muscle fiber to: – Move and detach cross bridges – Pump calcium back into SR – Pump Na+ out of and K+ back into cell after excitation-contraction coupling • Available stores of ATP depleted in 4–6 seconds • ATP is the only source of energy for contractile activities; therefore it must be regenerated quickly 10/7/2015 MDufilho 3 Providing Energy for Contraction • ATP is regenerated quickly by three mechanisms: – Direct phosphorylation of ADP by creatine phosphate (CP) – Anaerobic pathway: glycolysis and lactic acid formation – Aerobic respiration 10/7/2015 MDufilho 4 Figure 9.16a Pathways for regenerating ATP Direct phosphorylation during muscle activity. Coupled reaction of creatine phosphate (CP) and ADP Energy source: CP CP ADP Creatine kinase Creatine ATP Oxygen use: None Products: 1 ATP per CP, creatine Duration of energy provided: 15 seconds 10/7/2015 MDufilho 5 Figure 9.16b Pathways for regenerating ATP Anaerobic pathway during muscle activity. Glycolysis and lactic acid formation Energy source: glucose Glucose (from glycogen breakdown or delivered from blood) Glycolysis in cytosol 2 O2 ATP net gain Released to blood Pyruvic acid O2 Lactic acid Oxygen use: None Products: 2 ATP per glucose, lactic acid Duration of energy provided: 30–40 seconds, or slightly more 10/7/2015 MDufilho 6 Providing Energy for Contraction (cont.) • Anaerobic pathway: glycolysis and lactic acid formation (cont.) – Lactic acid • Diffuses into bloodstream • Used as fuel by liver, kidneys, and heart • Converted back into pyruvic acid or glucose by liver – Anaerobic respiration yields only 5% as much ATP as aerobic respiration, but produces ATP 2½ times faster 10/7/2015 MDufilho 7 Anaerobic Glycolysis • Fast pathway, but does not produce much ATP • Important for the first 30 – 40 sec. of strenuous activity if enzymes and fuel are available • Stored ATP, CP and glycolysis can support strenuous muscle activity for 60 sec. • At full speed lactic acid accumulates, lowering pH which halts reaction • At full speed, glucose might not be supplied fast enough 10/7/2015 8 MDufilho Providing Energy for Contraction (cont.) • Aerobic respiration – Produces 95% of ATP during rest and light-tomoderate exercise • Slower than anaerobic pathway – Consists of series of chemical reactions that occur in mitochondria and require oxygen • Breaks glucose into CO2, H2O, and large amount ATP (32 can be produced) – Fuels used include glucose from glycogen stored in muscle fiber, then bloodborne glucose, and free fatty acids 10/7/2015 MDufilho • Fatty acids are main fuel after 30 minutes of exercise9 Figure 9.16c Pathways for regenerating ATP Aerobic pathway during muscle activity. Aerobic cellular respiration Energy source: glucose; pyruvic acid; free fatty acids from adipose tissue; amino acids from protein catabolism Glucose (from glycogen breakdown or delivered from blood) O2 Pyruvic acid Fatty acids O2 Aerobic respiration in mitochondria Amino acids 32 CO2 H2O ATP net gain per glucose Oxygen use: Required Products: 32 ATP per glucose, CO2, H2O Duration of energy provided: Hours 10/7/2015 MDufilho 10 Oxidation of Glucose (cont.) • Citric acid cycle – Also called Krebs cycle – Occurs in mitochondrial matrix – Fueled by pyruvic acid from glucose breakdown and fatty acids from fat breakdown • Prep. Step - Pyruvic acid is converted to acetyl CoA • Requires oxygen, but does not directly use it • Preferred method of ATP production • During rest/light exercise AR yields 95% of ATP needed 10/7/2015 MDufilho 11 Oxidation of Glucose (cont.) • Citric acid cycle (cont.) • Transitional phase is where each pyruvic acid is converted to acetyl coenzyme A (acetyl CoA) in three steps • Each acetic acid is decarboxylated and oxidized, generating: – 3 NADH + H+ – 1 FADH2 – 2 CO2 – 1 ATP 10/7/2015 MDufilho 12 Figure 24.7 Simplified version of the citric acid (Krebs) cycle. Glycolysis Citric acid cycle Electron transport chain and oxidative phosphorylation Carbon atom Pi Inorganic phosphate CoA Coenzyme A ATP ATP ATP Cytosol Mitochondrion (matrix) Pyruvic acid from glycolysis NAD+ CO2 Transitional phase NADH + H+ CoA Acetyl CoA Oxaloacetic acid (pickup molecule) NADH + H+ Citric acid (initial reactant) CoA NAD+ Isocitric acid Malic acid NAD+ Citric acid cycle CO2 NADH + H+ a-Ketoglutaric acid Fumaric acid CoA CO2 FADH2 Succinic acid FAD CoA GTP ADP 10/7/2015 MDufilho Succinyl-CoA GDP + NAD+ NADH + H+ Pi ATP 13 Summary of ATP Production – Complete oxidation of 1 glucose molecule – Totals between substrate-level phosphorylation and oxidative phosphorylation equal 32 ATPs • Glycolysis + Krebs cycle + electron transport chain – But….energy is required to move NADH + H+ generated in glycolysis into mitochondria, which uses up ~2 ATPs, so final total is 30 ATPs produced • There is still uncertainty on final total 10/7/2015 MDufilho 14 Figure 24.11 Energy yield during cellular respiration. Electron shuttle across mitochondrial membrane Glycolysis Glucose Mitochondrion 2 NADH + H+ Cytosol Pyruvic acid 2 NADH + H+ 2 Acetyl CoA 6 NADH + H+ Citric acid cycle 2 FADH2 Electron transport chain and oxidative phosphorylation (4 ATP – 2 ATP used for activation energy) Net +2 ATP by substrate-level phosphorylation 10 NADH + H+ 2.5 ATP 2 FADH2 1.5 ATP +2 ATP by substrate-level phosphorylation + about 28 ATP by oxidative phosphorylation –2 ATP (average shuttle cost) About 30 ATP 10/7/2015 MDufilho Typical ATP yield per glucose 15 Providing Energy for Contraction (cont.) • Energy systems used during sports – Aerobic endurance • Length of time muscle contracts using aerobic pathways – Light-to-moderate activity, which can continue for hours – Anaerobic threshold • Point at which muscle metabolism converts to anaerobic pathway 10/7/2015 MDufilho 16 Figure 9.17 Comparison of energy sources used during short-duration exercise and prolongedduration exercise. Short-duration, high-intensity exercise 6 seconds 10 seconds ATP stored in muscles is used first. ATP is formed from creatine phosphate and ADP (direct phosphorylation). 10/7/2015 MDufilho 30–40 seconds End of exercise Glycogen stored in muscles is broken down to glucose, which is oxidized to generate ATP (anaerobic pathway). Prolonged-duration exercise Hours ATP is generated by breakdown of several nutrient energy fuels by aerobic pathway. 17 Muscle Fatigue • Physiological inability to contract despite continued stimulation • Usually occurs when there are ionic imbalances – Levels of K+, Ca2+, Pi can interfere with E-C coupling – Prolonged exercise may also damage SR and interferes with Ca2+ regulation and release • Lack of ATP is rarely a reason for fatigue, except in severely stressed muscles 10/7/2015 MDufilho 18 Excess Postexercise Oxygen Consumption • For a muscle to return to its pre-exercise state: – Oxygen reserves are replenished – Lactic acid is reconverted to pyruvic acid – Glycogen stores are replaced – ATP and creatine phosphate reserves are resynthesized • All replenishing steps require extra oxygen, so this is referred to as excess postexercise oxygen consumption (EPOC) – Formerly referred to as “oxygen debt” 10/7/2015 MDufilho 19 Heat Production During Muscle Activity • ~40% of energy released in muscle activity useful as work • Remaining energy (60%) given off as heat • Dangerous heat levels prevented by radiation of heat from skin and sweating • Shivering - result of muscle contractions to generate heat when cold 10/7/2015 MDufilho 20 Skeletal Muscle Cramps Cause • Insufficient blood flow or oxygen = anaerobic ATP production • Lactic acid accumulates and causes muscle irritation • Due to dehydration and insufficient K+ , Ca 2+ and rarely Na+ Prevention • Hydration, fitness and adequate diet 10/7/2015 21 MDufilho Muscular Dystrophy • Duchenne muscular dystrophy (DMD): – Most common and severe type – Inherited, sex-linked, carried by females and expressed in males (1/3500) as lack of dystrophin • Cytoplasmic protein that stabilizes sarcolemma • Fragile sarcolemma tears Ca2+ entry damaged contractile fibers inflammatory cells muscle mass drops – Victims become clumsy and fall frequently; usually die of respiratory failure in 20s 10/7/2015 MDufilho 22 Muscular Dystrophy – No cure – Prednisone improves muscle strength and function – Myoblast transfer therapy disappointing – Coaxing dystrophic muscles to produce more utrophin (protein similar to dystrophin) successful in mice – Viral gene therapy and infusion of stem cells with correct dystrophin genes show promise 10/7/2015 MDufilho 23