Exercise Physiology MPB 326 David Wasserman, PhD Light Hall Rm 823 3-7336

The Remarkable Thing about Exercise

The Great Debate Top-down Feedback control

Energy Metabolism and the Three Principles of Fuel Utilization

The need for energy starts when calcium is released from the sarcoplasmic reticulum of contracting muscle

The Working Muscle The presence of Ca++ allows for the interaction of two major proteins in the muscle, actin and myosin. In the resting state, these proteins (which have a natural affinity for each other) are prevented from coming into contact. Two other proteins, troponin and tropomyosin, form a complex weave between the actin and myosin, and prevent contact. When Ca++ enters the picture, the shape of the troponin-tropomyosin complex changes, and now actin and myosin can come into contact with each other. Muscle contraction stops when Ca++ is removed from the immediate environment of the myofilaments. The sarcoplasmic reticulum actively pumps Ca++ back into itself and this requires utilization of ATP. Troponin-tropomyosin reassume their inhibitory position between the actin and myosin molecules once Ca++ is removed.

Energy for Contraction The shape of the myosin molecule is very complex. Actually, a globular head on myosin attaches to a long stalk on the major portion of the myosin molecule. Numerous heads exist on a single myosin molecule. This head is flexible and attaches to the actin molecule. The head allows for energy requiring movement of the actin molecule along the myosin molecule. It can be considered a ratchet because it detaches from the binding site on actin after the power stroke, goes back to its original orientation, and attaches to another binding site on actin, further down the molecule. This process slides the actin filament along the myosin filament and is known as the sliding filament theory of muscle contraction. It was initially proposed by A.F. Huxley in 1957. Energy for the reorientation and movement of the myosin head comes from the molecule ATP. Oddly enough, stopping the process of muscle contraction also requires energy. The saying 'it takes energy to relax', is certainly true for skeletal muscle. Muscle contraction stops when Ca++ is removed from the immediate environment of the myofilaments. The sarcoplasmic reticulum actively pumps Ca++ back into itself and this requires utilization of ATP. Troponin-tropomyosin reassume their inhibitory position between the actin and myosin molecules once Ca++ is removed. It is important to remember that the above scenario applies for groups of individual

Muscle relaxation requires energy too!

Where does this ATP come from?

Sources of ATP Stored in muscle cell (limited) Synthesized from macronutrients Common Processes for ATP production Anaerobic System a. ATP-PC (Phosphagen system)   b. Anaerobic glycolysis (lactic acid system) Aerobic System a. Aerobic glycolysis b. Fatty acid oxidation c. TCA Cycle

ATP-PCr (Phosphagen system) Stored in the muscle cells (PCr > ATP) ATP + H2O  ADP + Pi + E (ATPase hydrolysis) PCr + ADP  ATP + Cr (creatine kinase reaction) ADP + ADP  ATP + AMP (adenylate kinase) PCr represents the most rapidly available source of ATP a) Does not depend on long series of reactions b) No O2 transportation required c) Limited storage, readily depleted ~ 10 s

Glycolysis Glucose + 2 ADP + 2 Pi + 2 NAD+ 2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O

Lactate Dehydrogenase Hypoxic conditions Pyruvate + CoA + NADH + H+ Lactate + NAD+

Pyruvate Dehydrogenase Lots of Oxygen Pyruvate + CoA + NADP+ Acetyl-CoA + CO2 + NADPH

Pyruvate Dehydrogenase Pyruvate + CoA + NADP+ Acetyl-CoA + CO2 + NADPH

TCA Cycle Acetyl-CoA + 3 NAD+ + FAD + GDP + Pi + 2H20 CoASH + 3 NADH + 3H+ + FADH2 + GTP + 2CO2

Beta Oxidation of Fatty Acids 7 FAD + 7 NAD+ + 7 CoASH + 7 H2O + H(CH2CH2)7CH2CO-SCoA 8 CH3CO-SCoA + 7 FADH2 + 7 NADH + 7 H+

Summary of ATP Production via Lipid Oxidation ATP Balance Sheet for Palmitic Acid (16 carbon) ATP Activation of FA chain -1 ß oxidation (16 Carbons / 2) –1 = 7 (at 5 ATP each) 35 Acetyl-CoA (16 Carbons / 2) = 8 (at 12 ATP each) 96 Total per chain 130

Electrochemical Energy and ATP Synthesis

Energy for “Burst” and Endurance Activities Rate of ATP Production (M of ATP/min) phosphagen system ..............4 anaerobic glycolysis..………2.5 aerobic system.......................1 How long Can it Last? phosphagen system...8 to 10 sec anaerobic glycolysis…1.3 to 1.6 min aerobic system.........unlimited time (as long as nutrients last)

Aerobic Energy During low intensity exercise, the majority of energy is provided aerobically Energy produced aerobically requires O2 Therefore, O2 uptake can be used as a measure for energy use

Exercise Testing in Health and Disease

Oxygen Uptake and Exercise Domains 4 2 150 Work Rate (Watts) I N C R E M T A L Moderate Heavy 300 VO2 (l/min) Severe

Anaerobic Threshold Concept Exercise 15 Heart Disease Blood Lactate mM 10 Onset of lactic acidosis Athlete 5 There is a work rate below which the energy requirement can be satisfied oxidatively and above which the working muscle becomes heavily reliant on anaerobic glycolysis with the resulting increase in blood lactate. This point is used clinically as a marker of dis 50 100 150 200 250 Rest Period Exercise (watts)

Anaerobic Threshold in Some Elite Long Distance Athletes can be close to Max Exercise 15 Onset of lactic acidosis Blood Lactate mM 10 Bill Rodgers 5 There is a work rate below which the energy requirement can be satisfied oxidatively and above which the working muscle becomes heavily reliant on anaerobic glycolysis with the resulting increase in blood lactate. This point is used clinically as a marker of dis Basal Oxygen Uptake 20 40 60 80 100 Oxygen Uptake (% maximum)

Oxygen Deficit and Debt

Oxygen Uptake and Exercise Domains L O A D Severe 4 Heavy 2 Moderate 12 24 Time (minutes)

Lactate and Exercise 12 Blood Lactate mM 6 12 24 Time (minutes)

Three Principles of Fuel Utilization during Exercise Maintaining glucose homeostasis Using the fuel that is most efficient Storage Metabolic Preserving muscle glycogen core

Glucose homeostasis is usually maintained despite increased glucose uptake by the working muscle Moderate Exercise 1 8 Blood Glucose 6 ( mg / dl ) 4 2 5 R a t e s o f G l u c o s e 4 E n t r y a n d E n t r y 3 R e m o v a l f r o m t h e B l o o d 2 R e m o v a l ( m g • k g - 1 • m i n - 1 ) 1 - 3 3 6 T i m e ( m i n )

Carbohydrate Stores after an Overnight Fast Sedentary Liver Glycogen Blood Glucose Muscle Glycogen 100 grams 400 grams 4 grams Blood glucose is preserved at the expense of glycogen reservoirs. This is illustrated by the response to exercise. In the normal postabsorptive state. There are about 100 g of glycogen in the liver and 400 g of glycogen in muscle. With exercise CHO oxidation by the working muscle can go up by tenfold and yet after 1 h, 4 grams of glucose is maintained in the blood at the expense of liver and muscle glycogen stores. Even after 2 h the amount of glucose in the blood is constant. Even after glycogen stores get criticallly low liver gng willl kick in and limit the fall in glucose. Only after extremely long duration exercise will the blood glucose levels fall to critically low levels. 32

Carbohydrate Stores after an Overnight Fast 1 hr of Exercise Liver Glycogen Blood Glucose Muscle Glycogen 400 grams 4 grams Blood glucose is preserved at the expense of glycogen reservoirs. This is illustrated by the response to exercise. In the normal postabsorptive state. There are about 100 g of glycogen in the liver and 400 g of glycogen in muscle. With exercise CHO oxidation by the working muscle can go up by tenfold and yet after 1 h, 4 grams of glucose is maintained in the blood at the expense of liver and muscle glycogen stores. Even after 2 h the amount of glucose in the blood is constant. Even after glycogen stores get criticallly low liver gng willl kick in and limit the fall in glucose. Only after extremely long duration exercise will the blood glucose levels fall to critically low levels. 100 grams 33

Carbohydrate Stores after an Overnight Fast 2 hr of Exercise Liver Glycogen Blood Glucose Muscle Glycogen 400 grams 4 grams Blood glucose is preserved at the expense of glycogen reservoirs. This is illustrated by the response to exercise. In the normal postabsorptive state. There are about 100 g of glycogen in the liver and 400 g of glycogen in muscle. With exercise CHO oxidation by the working muscle can go up by tenfold and yet after 1 h, 4 grams of glucose is maintained in the blood at the expense of liver and muscle glycogen stores. Even after 2 h the amount of glucose in the blood is constant. Even after glycogen stores get criticallly low liver gng willl kick in and limit the fall in glucose. Only after extremely long duration exercise will the blood glucose levels fall to critically low levels. 100 grams 34

Carbohydrate Stores after an Overnight Fast 3 hr of Exercise Liver Glycogen Blood Glucose Muscle Glycogen 400 grams 4 grams Blood glucose is preserved at the expense of glycogen reservoirs. This is illustrated by the response to exercise. In the normal postabsorptive state. There are about 100 g of glycogen in the liver and 400 g of glycogen in muscle. With exercise CHO oxidation by the working muscle can go up by tenfold and yet after 1 h, 4 grams of glucose is maintained in the blood at the expense of liver and muscle glycogen stores. Even after 2 h the amount of glucose in the blood is constant. Even after glycogen stores get criticallly low liver gng willl kick in and limit the fall in glucose. Only after extremely long duration exercise will the blood glucose levels fall to critically low levels. 100 grams 35

Carbohydrate Stores after an Overnight Fast 4 hr of Exercise Liver Glycogen Blood Glucose Muscle Glycogen 400 grams 4 grams Blood glucose is preserved at the expense of glycogen reservoirs. This is illustrated by the response to exercise. In the normal postabsorptive state. There are about 100 g of glycogen in the liver and 400 g of glycogen in muscle. With exercise CHO oxidation by the working muscle can go up by tenfold and yet after 1 h, 4 grams of glucose is maintained in the blood at the expense of liver and muscle glycogen stores. Even after 2 h the amount of glucose in the blood is constant. Even after glycogen stores get criticallly low liver gng willl kick in and limit the fall in glucose. Only after extremely long duration exercise will the blood glucose levels fall to critically low levels. 100 grams !!! 36

Contribution of different fuels to metabolism by the working muscle is determined by 3 objectives: Maintaining glucose homeostasis Using the fuel that is most efficient Storage Metabolic Preserving muscle glycogen core

The Most Efficient Fuel depends on Exercise Intensity and Duration Metabolic Efficiency CHO is preferred during high intensity exercise because its metabolism yields more energy per liter of O2 than fat metabolism. kcal/l of O2 CHO 5.05 Fat 4.74 CHO can also produce energy without O2!!! Storage Efficiency Fat is preferred during prolonged exercise because its metabolism provides more energy per unit mass than CHO metabolism. kcal/g of fuel CHO 4.10 Fat 9.45 Fats are stored in the absence of H2O.

Effects of Exercise Intensity Plasma FFA (fat from fat cells) is the primary fuel source for low intensity exercise As intensity increases, the source shifts to muscle glycogen From: Powers & Howley. (2007). Exercise Physiology. McGraw-Hill.

Effects of Exercise Duration From: Powers & Howley. (2007). Exercise Physiology. McGraw-Hill.

Fuel Selection From: Powers & Howley. (2007). Exercise Physiology. McGraw-Hill. As intensity increases carbohydrate use increases, fat use decreases As duration increase, fat use increases, carb use decreases

Contribution of different fuels to metabolism by the working muscle is determined by 3 objectives: Maintaining glucose homeostasis Using the fuel that is most efficient Storage Metabolic Preserving muscle glycogen core

Other fuels are utilized to spare muscle glycogen during prolonged exercise thereby delaying exhaustion Lactate Adipose NEFA Pyruvate Glycerol Amino Acids Muscle NEFA GLY ATP GNG GLY Glucose Liver As exercise duration increases: • More energy is derived from fats and less from glycogen. • Amino acid, glycerol, lactate and pyruvate carbons are recycled into glucose.

Contribution of different fuels to metabolism by the working muscle is determined by 3 objectives: Maintaining glucose homeostasis Using the fuel that is most efficient Storage Metabolic Preserving muscle glycogen core

Discussion Question Can you accommodate all three principles of fuel utilization? Why not? What is the Consequence?