Basics 1 - F24_merged.pdf

NUTR 4210: Nutrition, Exercise and Energy Metabolism Me: Dr. David J. Dyck … first name is fine!!! ANNU 345 [email protected] no “formal” office hours … email to set up appt, or to ask straightforward questions TA: Nicole Notaro nnotaro@uoguelp...

NUTR 4210: Nutrition, Exercise and Energy Metabolism Me: Dr. David J. Dyck … first name is fine!!! ANNU 345 [email protected] no “formal” office hours … email to set up appt, or to ask straightforward questions TA: Nicole Notaro [email protected] 1  General Content Intro, ex phys basics Carb metab: liver glucose production, muscle uptake, effects of training Fat metab: adipose and muscle lipolysis, muscle uptake, effects of training Protein metabolism: focus on resistance training Obesity and insulin resistance: models to study, assessment, mechanisms (lipids, inflammation, mitochondrial dysfunction) Tissue cross-talk: myokines, hepatokines and adipokines (focus on adipokines) Antioxidants, high-fat diets, ketogenic diets Brown adipose tissue and physiological importance Exercise as a treatment for insulin resistance: effects on muscle, liver and AT Biological sex differences in exercise metabolism 2  OR …. If we get REALLY bored: Why can’t the Leafs win? 1967 3  NUTR 4210: Nutrition, Exercise and Energy Metabolism Grading will be 3 exams 2 midterms (Oct 7, Nov 11 in class) Final (Dec 9 @ 8:30am) Exam weighting: 40 / 35 / 25 (best to worst) Exams will be mainly MC, possibly some very short answer Exams will be in class and closed book Exams are NOT cumulative 4  What CAN Exercise Do? More Like What CAN’T Exercise Do! Exercise in a Pill??? AMPK mimetics 5 Basic Exercise Physiology and Metabolism Concepts Models (Rodent) Energy Expenditure Body Composition Cardiovascular Responses Endocrine Responses 6 How do we study exercise using animal models? Swimming: Pros: Often very strenuous form of exercise; consequently you can see robust adaptations in various tissues Relatively inexpensive Cons: Can be extremely stressful and may not mimic exercise in humans (catecholamine experiment?) Some animals “float” Hard to quantify the amount of exercise completed 7 Treadmill Running Pros: Mimics human exercise studies in that you can control intensity and duration of exercise Cons: Some animals are not good runners, how can this be controlled for? Can still be stressful, but not as much as swimming Cost, >$10K/treadmill 8 Voluntary Wheel Running Pros: Inexpensive, not stressful, easy to perform Cons: Relevance to humans might be a bit limited as mice can run for >8hrs/night difficulty in controlling for exercise volume (but easy to quantify); can employ a wheel lock 9 In Situ Rat Hindlimb Perfusion Pros: very tight control over perfusate composition; can stimulate sciatic nerve for contractions Cons: less physiological, “lab-made perfusate”; non-physiological stimulation conditions (twitch/tetanic; reverse recruitment, etc) Ex vivo isolated muscle incubation Pros: very tight control over incubation medium composition; can also stimulate to contract Cons: “Even less physiological; disrupted blood and neural supply; limited by diffusion; only some muscles suitable 10  ENERGY What is energy? Is this an energy drink ? What about this ? 160 mg caffeine in 16 oz (473 ml) Energy is defined as the capacity to do work 11  ENERGY BALANCE ENERGY IN ENERGY OUT FOOD & DRINK METABOLIC & CELLULAR FUNCTION basal metabolism thermic effect of food physical activity POSITIVE ENERGY BALANCE NEGATIVE ENERGY BALANCE Weight gain / obesity Weight loss 12  ENERGY BALANCE First law of thermodynamics Energy cannot be created or destroyed Energy stored = Energy Intake – Energy Expended There is no way around this! argues that diet composition isn’t likely the issue per se (??) Excess energy preferentially stored as TAGs in adipocytes Lean adults have ~75,000 kcal stored as TAGs in adipocytes Compare this to ~3,000 kcal of glycogen in liver and muscle Sadly, energy mobilization during negative balance also comes from lean tissue i.e. protein! 13 WHAT COMPRISES TOTAL DAILY ENERGY EXPENDITURE (TDEE)? 1. Resting Energy Expenditure (REE) - 60 to 75% of TDEE Energy needed to keep the body alive at complete rest while awake Basal metabolic rate (BMR) *strict/controlled measurement conditions* Resting metabolic rate (RMR) (~10% greater than BMR) 2. Thermic Effect of Food (TEF) - 5 to 10% of TDEE Stimulated by protein, caffeine May be reduced in obesity 3. Physical Activity - 15 to 30% of TDEE Highly variable! 14  Total Energy Expenditure is Related to Muscle Mass and Decreases After Age 60 A B 30 30 Males Females 25 25 Older Adults mean±sd Adults TEE (MJ/d) TEE (MJ/d) Juveniles 20 20 Neonates 15 15 10 10 5 5 0 0 0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90 Fat Free Mass (kg) Age (yr) Total energy expenditure from 6421 participants 64% female 29 countries Age: 8 days – 95yrs Pontzer et. al 2021 15  Total Energy Expenditure Decreases After Age 60 Even After Adjusting for LBM 100 125 150 175 200 A Adjusted TEE (%) 75 50 mean±sd Males Females 25 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 Age (yr) When energy expenditure is adjusted for fat-free (lean body) mass, males and females are nearly identical only decreases slightly after age 60 (both male and female) Pontzer et. al 2021 16 Humans Accumulate Fat Mass With Age (up to ~60 yrs) … Total and Lean Mass Increase up to ~25 yrs Pontzer et. al 2021 17  ENERGY EXPENDITURE ACROSS THE LIFESPAN Key takeaways TEE increases with amount of fat-free mass (i.e. muscle) TEE is higher in males due to greater muscle mass TEE and fat-free mass fairly stable until ~60 years old BUT, fat mass increases up to age 60 Age-related fat gain in adulthood up to 60 yrs is probably not due to a decrease in total in energy expenditure… but most likely greater energy intake! 18  WHAT HAPPENS WITH WEIGHT LOSS? “Biggest Loser Competition”: Lost ~60kg on average! 6 years later: Significant weight regain (bad!) Still maintain some weight loss (good!) Perhaps surprisingly, lean mass well preserved (good!) Fothergill et al. Obesity. 2016 19  WHAT HAPPENS WITH WEIGHT LOSS? “Biggest Loser Competition” 6 years later: Starting RMR: 2607 kcal RMR STILL blunted! (actually a bit worse!) 30wk RMR: 1996 kcal 6 yr RMR: 1903 kcal Interestingly, turns out that the weight regain (at 6 yrs) was not significantly correlated to this metabolic reduction at 30wks Not sure why. Perhaps because they maintained physical activity? Starting TEE: 3804 kcal/d Starting PA: 5.6 kcal/kg/day 30wk TEE : 3002 kcal/d 30wk PA: 10.0 kcal/kg/day 6 yr TEE : 3429 kcal/d 6 yr PA: 10.1 kcal/kg/day Fothergill et al. Obesity. 2016 20  Measuring Total Energy Expenditure Direct Calorimetry All metabolic processes in the body generate heat (we’re around 50% efficient biochemically) Heat production can be used as a measure of energy expenditure 21  Making ATP is Inefficient could also be fatty acid, or amino acid oxidation ATP stores are VERY small – enough for only 2-3 seconds of intense muscular contraction ! Coupling of these reactions is NOT efficient. Approximately 60% of the energy released by the oxidation of a substrate is lost as HEAT – only 40% is used for biological work. 22 Direct Calorimetry Measures the heat a person generates in a sealed chamber Heat produced is proportional to the amount of energy expended Heat energy is measured as a change in temperature USDA, Maryland, USA 23  Disadvantages www.cals.wisc.edu/ Expensive! Need O2 source, CO2 absorber Can’t apply to field settings Isn't very practical 24  Indirect Calorimetry Estimating energy expenditure by measuring oxygen consumption (VO2) Principle: As the body’s energy expenditure increases, the use of oxygen increases proportionately (to a threshold). Open-circuit spirometry: breathe ambient room air “metabolic cart” flow meter to measure volume of air analyzers for measuring the percentage of oxygen and carbon dioxide in the air (inspired / expired) computer for calculations 25 The Old School Using a Douglas Air Collection Bag! 26  Indirect Calorimetry At rest… Resting Metabolic Rate (RMR) 27 Indirect Calorimetry …with exercise This is an open-circuit “metabolic cart” system Disadvantages Hyperventilate? Airtight? Mask comfort? 28  Advantages Portable versions to Can also determine EE in a determine the wide variety of substrates (fat/ activities carb) being oxidized! (Respiratory Exchange Ratio; VCO2/VO2) 29  What About Animal Studies? Comprehensive Lab Animal Monitoring System (CLAMS) Also indirect, but an enormous amount of information (data every 10 min, light beams to estimate physical activity) 30  This Class Calculating energy expenditure from indirect calorimetry Respiratory exchange ratio (fuel selection) VO2max and its limiting factors Classic physiological responses to exercise training 1  Basic Whole Body Metabolic Measurements VO2 is used to calculate energy expenditure How do we go from litres of oxygen to kcal? Thermal equivalents of O2: ~5 kcal per L O2 Regardless of whether fat or carbohydrate is oxidized (protein is ignored) E.g. if exercising for 60 min with a VO2 of 3.8 L/min: ~5 kcal/L X 3.8 L/min X 60 min = 1140 kcal (energy expended) 2  Substrate Utilization (RER, RQ) VCO2 / VO2 reflects blend of fat and carb; assumes no protein also assumes that VO2 and VCO2 represent mitochondrial events (see below) C6H12O6 + 6 O2 → 6 CO2 + 6 H2O (RER = 6 CO2 / 6 O2 = 1.00) C16H32O2 + 23 O2 → 16 CO2 + 16 H2O (RER = 16 CO2 / 23 O2 = 0.70) *Difference is at PDH (pyruvate dehydrogenase) whole body (RER) vs. mitochondrion (RQ) RQ – respiratory quotient; occurs at the level of the mitochondrion - difficult to measure! RER - respiratory exchange ratio: measured at the level of the lungs (mouth) i.e. a whole body phenomenon - may be affected by acid/base disturbances, etc. i.e. may NOT equal RQ! (think of some situations!) 3 CO2 + H2O < -- > H2CO 3 < -- > H+ + HCO3 -  Using an RER Table Example. A person consumes 3.8L O2/min and expires 2.89L CO2/min RER = VCO2 / VO2 = 2.89L / 3.8L = 0.76 What is the energy expenditure for 1 hour? 4.751kcal for 1L O2 x 3.8L x 60min = 1083kcal or…. 6.253kcal for 1 L CO2 x 2.89L x 60min = 1084 kcal What is the percent substrate utilization? 81% fat, 19% carb 4  Another Example… A person consumes 16L O2/h and expires 15L CO2/h Q1. What percent fat are they using? Q2. What is the energy (kcal) expended per hour? Q3. Approximately how many kcal should this person consume in a day to maintain neutral energy balance? RER = 15/16 = 0.94 (19% fat) O2: 16 L/h x 4.97 kcal/L = 79.5 kcal = ~80 kcal/h CO2: 15L/h x 5.29 kcal/L = 79.4 kcal = ~80 kcal/h Using either O2 or CO2 data should give same answer! But you need the RER! Or, “ballpark it” just using O2 if you don’t have the table …. 16 x 5 = 80 Finally, 24hrs x 80 kcal/h = 1,920 kcal 5  Rest vs. Exercise Primary fuel at rest Fat oxidation Low energy expenditure Not exclusively fat oxidation at rest (certain tissues require glucose) … ~85% fat, 15% carbohydrate Fuels during Exercise Depends on intensity, duration, diet, training status In general, more intense and less trained = more carb Greater duration and more trained = more fat More on this a bit later! 6 The “Fat Burning” Zone? 40-60% VO2 max Exercise with no caloric restriction …. seems like high intensity is actually best! 7 Vissers et al. PLoS One. 2013. The “Fat Burning” Zone? 40-60% VO2 max Body weight loss, fat loss, preservation of fat free mass are similar following moderate continuous exercise vs. HIIT programs (12 wks) with similar caloric expenditures 8 D’Amuri et al. BMJ Open. 2021.  VO2max Maximum O2 consumption/aerobic capacity Standardized, progressive test until failure Optimal test length ~10-12min Criteria: plateau in VO2 with increasing work rate respiratory exchange ratio value >1.15 RPE of 19 or 20 maximal HR in last stage (within 10 bpm of age-predicted) blood lactate concentration of > 8 mmoles/L A general indicator of aerobic fitness (and health!) Expressed as Absolute (L/min) Relative (ml/kg/min) *cardiorespiratory fitness may be the single best indicator of survival in patients with cardiovascular disease 9 http://www.sport-fitness-advisor.com/VO2max.html 10  Oskar Svendsen 194 mL/kg/min 240 ml/kg/min measured at 97.5 mL/kg/min >250 ml/kg/min >660 ml/kg/min May be close to theoretical limit. Their muscle cells are so dense that adding more mitochondria would take 11 away sarcomeres!  VO2 max expressed in relative terms (ml/kg/min) Cardiorespiratory Fitness Classification: VO2max (ml/kg/min) Age (yr) Poor Fair Good Excellent Superior WOMEN 20-29 35 36-39 40-43 44-49 50+ 30-39 33 34-36 37-40 41-45 46+ 40-49 31 32-34 35-38 39-44 45+ 50-59 24 25-28 29-30 31-34 35+ 60-69 25 26-28 29-31 32-35 36+ 70-79 23 24-26 27-29 30-35 36+ MEN 20-29 41 42-45 46-50 51-55 56+ 30-39 40 41-43 44-47 48-53 54+ 40-49 37 38-41 42-45 46-52 53+ 50-59 34 35-37 38-42 43-49 50+ 60-69 30 31-34 35-38 39-45 46+ 70-79 27 28-30 31-35 36-41 42+ 12 What limits VO2 max? O2 Supply O2 Demand (central) (Peripheral) 13 Bengt Saltin World-renowned Scandinavian exercise physiologist Concluded that oxygen supply (delivery) is likely the major limit to endurance performance i.e. VO2max 14 What limits VO2 max? O2 Supply (central) 15  Phlebotomy eliminates the maximal cardiac output response to six weeks of exercise training Bonne et al. Am J Physiol Reg Integr Comp Physiol. 306(10): R752-R760, 2014. Phlebotomy, removed ~380 mL of whole blood 9 untrained male Pretraining Posttraining Phlebotomy - 6 weeks of endurance training (ET) Rest Body mass, kg 78 :± 10 74 :± 10* Pre = pre-ET Hb ma ss , g Hb ma s s , g/kg 849 :± 145 10.9 :± 1.0 894 :± 129* 12.1 :± 1.2* Post = post-ET [Hb], g/l 14.8 :± 0.5 14.7 :± 0.7 14.9 :± 0.6 45.1 :± 2.1‡ Phlebotomy = post-ET w/ blood Hct, % Exercise 43.1 :± 1.0 44.3 :± 1.8* Watt ma x , W 275 :± 49 340 :± 37* 317 :± 31†‡ volume reduced to pre-ET values V˙O 2m a x , ml/min 3,665 :± 539 4,024 :± 615* 3,689 :± 631† RER 1.49 :± 0.18 1.41 :± 0.18 1.43 :± 0.14 V˙E, l/min 162 :± 30 148 :± 23 134 :± 20 A A C 28 * † 8000 * † 150 * † 7500 26 Cardiac Output (l · min-1) 140 7000 24 Blood Volume (ml) Stroke Volume (ml) 130 6500 120 22 6000 110 20 5500 100 18 5000 90 16 4500 80 14 4000 70 Pre Post Phlebotomy Pre Post Phlebotomy Pre Post Phlebotomy Qmax and VO2max were normalized to pre-training values when the training induced increase in BV was restored to pre-training values via phlebotomy 16 Argues the increase in blood volume, rather than structural changes in heart, are more important  Maximal heart rate does not limit cardiovascular capacity in healthy humans: insight from right atrial pacing during maximal exercise Munch et al. J Physiol 592(2):377-390, 2014. Right atrium Methods: Atrial pacing - 12 endurance trained male cyclists - Increment cycling with and without Radial artery Blood sampling + atrial pacing blood pressure - Increase HR by ~20 beats Pulmonary artery Femoral vein Blood sampling + Exercise-cycling Blood sampling + blood pressures blood pressure Femoral vein Saline infusion + thermistor for blood flow 100 % measurement 85 % 70 % 40 % 55 % Warm up 25 % -3 0 2 4 6 8 10 12 Table 1. Heart rates during incremental cycling and one-legged knee-extensor exercise with and without right atrial pacing ( % maximal workload) Baseline 25% 40% 55% 70% 85% 1 00 % Cycling Control trial 87 ± 6 121 ± 5 140 ± 4 152 ± 4 168 ± 3 178 ± 2 184 ± 2 Pacing trial 109 ± 4∗ 138 ± 3∗ 157 ± 3∗ 171 ± 3∗ 187 ± 4∗ 200 ± 3∗ 206 ± 3∗ 17 Maximal heart rate does not limit cardiovascular capacity in healthy humans: insight from right atrial pacing during maximal exercise Munch et al. J Physiol 592(2):377-390, 2014. An increase in HR did not alter Q due to a proportional decrease in SV Q = SV x HR HRmax does not limit cardiac performance in trained humans 18  Central Circulation Cardiac Output (stroke volume x heart rate) O2 delivery/supply (improved with endurance training!) 70-85% of limitation Stroke volume is main limiting factor HRmax does not limit cardiovascular capacity O2 Carrying Capacity blood doping studies, erythropoietin (EPO), ↑ red blood cells 19  Skeletal Muscle – Are there peripheral limitations to VO2 max? 20 O2 Demand (Peripheral) 21  Improved aerobic performance in endurance training vs. sprint interval training 20 healthy, young, males and females 3 sessions/week for 6 weeks of either: 30-60 min at 65% VO2max 4-6 30-second “all-out” bouts with 4 min recovery Compared improvements in performance, central, and peripheral adaptations Performance: Time trial, VO2max Central: cardiac output, stroke volume Peripheral: arterial-venous O2 difference Macpherson et al., Med Sci Sports Exerc. 43(1):115-122, 2011. 22 Performance: Centrally: Peripherally: Both improved Only Endurance Only SIT SIT: muscle has adapted by extracting more O2! 23 And …. the one-legged kicking exercise model: A favorite of some famous Danish researchers! Allows training of one leg but not the other in the same individual Can determine VO2 in one leg by using arterial and venous catheters What do you think limits VO2 max in a single exercising leg? 24 Classic Training Adaptations RATS Treadmill training 2hrs/day, 5 days/week, 6 weeks Has been cited >1600 times. Likely one of the most influential papers in the field 25 The Same Phenomenon is Seen in Humans Treadmill training 2hrs/day, 60-70% VO2 max, 7-10 days Indices of mitochondrial content are increased in skeletal muscle after exercise … and it happens quickly!!!! 26 Use it or lose it! The authors of this study took trained subjects and then “de-trained” them for ~12 weeks! Biggest drop is ~25% 27  Use it or lose it! Reductions in mitochondrial content also occur – although a bit larger 28 But the Really Scary One??? Insulin Response! insulin-stimulated glucose uptake in rat muscle Open = uptake Closed = GLUT4 29 An “old” Holloszy study (?)  Mechanisms of training-induced increases in mitochondria and GLUT4 Localized changes in contracting skeletal muscle are likely the primary drivers of exercise-induced increases in mitochondrial enzymes There are many potential signaling factors : increases in calcium perturbations in high energy phosphate levels (ATP, ADP, AMP, PCr, Cr) reactive oxygen species 30  Recap Energy expenditure can be calculated using energy equivalents to O2 and CO2 (need RER), or estimated simply from O2 RER assumes aerobic steady state and estimates the balance of carb and fat. It assumes no protein. VO2 max is generally limited by cardiac output, and more specifically, stroke volume. In some cases, peripheral (muscle) oxygen utilization can be the limiting factor. Exercise training increases mitochondria in skeletal muscle. This has been one of the most reproducible findings in the field of exercise biochemistry in both rodents and humans Increases in skeletal muscle mitochondrial content occur rapidly, and so do reductions in mitochondrial enzymes when exercise is stopped Increases in mitochondrial content serve to provide ATP to contracting skeletal muscle Changes in insulin response (training / detraining) occur VERY fast! 31 Endocrine Responses During Exercise 1  Basically, It’s a Stress Response …. Many hormones increase, ONE decreases Anterior pituitary: GH, ACTH, prolactin, TSH Posterior pituitary: ADH Thyroid: T3 and T4 Parathyroid: PTH Adrenals: Epi, norepi, cortisol, aldosterone Pancreas: Insulin (decrease), glucagon Kidney: Renin Liver: Follistatin, GDF-15, others Muscle: IL-6, irisin 2  How Does the Body Meet the Challenge of Increased Energy Demand During Exercise? Hormones Maintenance thermal / fluid regulation Fuel Mobilization cardiovascular, renal liver, adipose, muscle Delivery Fuel Utilization cardiovascular skeletal muscle 3 1. Fuel (Substrate) Mobilization liver, adipose, muscle Norepinephrine Epinephrine Glucagon Insulin 4  Catecholamines Norepinephrine (nmol/L) Two main forms Norepinephrine (NE) - released from sympathetic nervous system (SNS) Epinephrine (Epi) - adrenal medulla; release stimulated by NE During exercise Epinephrine (nmol/L) Exponential increase in circulating levels Norepinephrine circulates at much higher levels 5 Exercise Training Blunts Catecholamine Response J Appl Physiol. 43(6):953-958, 1977 6  Catecholamines - Liver During exercise, catecholamines have many functions Increased hepatic glucose production Due to epi and norepi (mainly alpha receptors) Increased glycogenolysis Early response Increases gluconeogenesis Production of glucose from non-glucose sources, like glycerol, amino acids, lactate, etc. Later response due to availability of non-glucose sources Muscle, AT: mainly beta 2 receptors, some beta 1 Alpha: NE > E Liver: mainly alpha (1, 2) receptors B1: NE = E B3 mainly in BAT B2 E >>>>>> NE 7  Catecholamines - Liver In mice, liver sensitivity to epi/norepi (glycogen breakdown) is reduced by exercise training Is this a problem? What might be the compensations? 8  Catecholamines – Adipose tissue Lipolysis is the sequential breakdown of triglycerides to fatty acids and glycerol Adipose triglyceride lipase* Hormone sensitive lipase* Monoglyceride lipase Rapid and robust increase in lipolysis during exercise Even walking increases lipolysis Fatty acids have 3 ’fates’ Oxidized within adipose tissue (