9 Muscles and Muscle Metabolism

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. MDufilho 4/14/2017

Muscle Metabolism: Energy for Contraction ATP only source used directly for contractile activities Move and detach cross bridges, calcium pumps in SR, return of Na+ & K+ after excitation-contraction coupling Available stores of ATP depleted in 4–6 seconds 4/14/2017 MDufilho

Muscle Metabolism: Energy for Contraction ATP regenerated by: Direct phosphorylation of ADP by creatine phosphate (CP) Anaerobic pathway (glycolysis  lactic acid) Aerobic respiration 4/14/2017 MDufilho

Direct phosphorylation Figure 9.19a Pathways for regenerating ATP during muscle activity. Direct phosphorylation Coupled reaction of creatine Phosphate (CP) and ADP Energy source: CP Creatine kinase Creatine Oxygen use: None Products: 1 ATP per CP, creatine Duration of energy provided: 15 seconds 4/14/2017 MDufilho

Anaerobic pathway Glycolysis and lactic acid formation Figure 9.19b Pathways for regenerating ATP during muscle activity. Anaerobic pathway Glycolysis and lactic acid formation Energy source: glucose Glucose (from glycogen breakdown or delivered from blood) Glycolysis in cytosol 2 Pyruvic acid net gain Released to blood Lactic acid Oxygen use: None Products: 2 ATP per glucose, lactic acid Duration of energy provided: 30-40 seconds, or slightly more 4/14/2017 MDufilho

At 70% of maximum contractile activity Anaerobic Pathway At 70% of maximum contractile activity Bulging muscles compress blood vessels; oxygen delivery impaired Pyruvic acid converted to lactic acid Lactic acid Diffuses into bloodstream Used as fuel by liver, kidneys, and heart Converted back into pyruvic acid or glucose by liver 4/14/2017 MDufilho

Fast pathway, but does not produce much ATP 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 MDufilho 4/14/2017

Produces 95% of ATP during rest and light to moderate exercise; slow Aerobic Pathway Produces 95% of ATP during rest and light to moderate exercise; slow Series of chemical reactions that require oxygen; occur in mitochondria Breaks glucose into CO2, H2O, and large amount ATP Fuels - stored glycogen, then bloodborne glucose, pyruvic acid from glycolysis, and free fatty acids 4/14/2017 MDufilho

Aerobic cellular respiration Figure 9.19c Pathways for regenerating ATP during muscle activity. Aerobic pathway 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) Pyruvic acid Fatty acids Aerobic respiration in mitochondria Aerobic respiration in mitochondria Amino acids 32 net gain per glucose Oxygen use: Required Products: 32 ATP per glucose, CO2, H2O Duration of energy provided: Hours 4/14/2017 MDufilho

Aerobic Respiration – Krebs Cycle Occurs in the mitochondrial matrix and is fueled by pyruvic acid (from glucose) and fatty acids 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 MDufilho 4/14/2017

Coenzyme A shuttles acetic acid to an enzyme of the Krebs cycle Each acetic acid is decarboxylated and oxidized, generating: 3 NADH + H+ 1 FADH2 2 CO2 1 ATP MDufilho 4/14/2017

Pyruvic acid from glycolysis Figure 24.7 Simplified version of the Krebs (citric acid) cycle. Glycolysis Krebs cycle Electron trans- port chain and oxidative phosphorylation Carbon atom Inorganic phosphate Coenzyme A Cytosol Pyruvic acid from glycolysis Transitional phase Mitochondrion (matrix) Oxaloacetic acid (pickup molecule) Citric acid (initial reactant) Malic acid Isocitric acid Krebs cycle Fumaric acid α-Ketoglutaric acid Succinic acid Succinyl-CoA 4/14/2017 MDufilho

Summary of ATP Production Complete oxidation of 1 glucose molecule Glycolysis + Krebs cycle + electron transport chain  CO2 + H2O  32 molecules ATP By both substrate-level and oxidative phosphorylation But, energy required to move NADH + H+ generated in glycolysis into mitochondria  final total ~ 30 molecules ATP Still uncertainty on final total 4/14/2017 MDufilho

Figure 24.12 Energy yield during cellular respiration. Mitochondrion Cytosol Electron shuttle across mitochondrial membrane Glycolysis Electron transport chain and oxidative phosphorylation 2 Acetyl CoA Krebs cycle Pyruvic acid Glucose (4 ATP – 2 ATP used for activation energy) by substrate-level phosphorylation by substrate-level phosphorylation by oxidative phosphorylation Typical ATP yield per glucose 4/14/2017 MDufilho

Energy Systems Used During Sports Aerobic endurance Length of time muscle contracts using aerobic pathways Anaerobic threshold Point at which muscle metabolism converts to anaerobic 4/14/2017 MDufilho

Figure 9.20 Comparison of energy sources used during short-duration exercise and prolonged-duration exercise. Short-duration exercise Prolonged-duration exercise 6 seconds 10 seconds 30–40 seconds End of exercise Hours ATP stored in muscles is used first. ATP is formed from creatine phosphate and ADP (direct phosphorylation). Glycogen stored in muscles is broken down to glucose, which is oxidized to generate ATP (anaerobic pathway). ATP is generated by breakdown of several nutrient energy fuels by aerobic pathway. 4/14/2017 MDufilho

Physiological inability to contract despite continued stimulation Muscle Fatigue Physiological inability to contract despite continued stimulation Occurs when Ionic imbalances (K+, Ca2+, Pi) interfere with E‑C coupling Prolonged exercise damages SR and interferes with Ca2+ regulation and release Total lack of ATP occurs rarely, during states of continuous contraction, and causes contractures (continuous contractions) 4/14/2017 MDufilho

Excess Postexercise Oxygen Consumption To return muscle to resting state Oxygen reserves replenished Lactic acid converted to pyruvic acid Glycogen stores replaced ATP and creatine phosphate reserves replenished All require extra oxygen; occur post exercise 4/14/2017 MDufilho

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 4/14/2017 MDufilho

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 MDufilho 4/14/2017

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 4/14/2017 MDufilho

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 4/14/2017 MDufilho