UCL Fundamental of Nutrition and Metabolism - MEDC0034 Lecture 2024 PDF

Fundamental of Nutrition and Metabolism - MEDC0034 Energy Metabolism II: Perspective of Exercise Dr Adrian Slee Email: [email protected] Todays Lecture Review of Muscle Physiology Muscle Metabolism Endurance and HIIT Exercise...

Fundamental of Nutrition and Metabolism - MEDC0034 Energy Metabolism II: Perspective of Exercise Dr Adrian Slee Email: [email protected] Todays Lecture Review of Muscle Physiology Muscle Metabolism Endurance and HIIT Exercise Muscle Adaptations Lactate and Fatigue Muscle Damage & Repair Muscle Protein Turnover & Protein Intake Additional Reading for Lecture Strongly suggest you familiarise yourself with some muscle physiology, e.g. fiber architecture, fiber types and muscle contraction etc. And link to some basic metabolism reading. Textbooks for Metabolism Revision – online versions in UCL Library Other Textbooks for Metabolism Revision – online versions in UCL Library MUSCLE AND EXERCISE METABOLISM Structure of Skeletal Muscle Tissue A single muscle fiber and bundles of fibers are surrounded by connective tissue. Note the blood supply, e.g. transport of nutrients and waste products. Not seen in figure dystrophin protein links thin filaments to the sarcolemma. Desmin protein desmi  Skeletal Muscle Structure β ECM Laminin- Sarcoglyca 2 α- ns Sarcospa Dystroglycan DAPC n Sarcolemma Mechano- transduction β-Dystroglycan Apparatus Sarcoplas Dystrophi Syntrophi m/ n ns Cytoplasm Costamere Dystrobrev s in Costamere F- s Actin Myofibrillar Contractile Apparatus Myosi M-Line Titi 8 n (Myosin, C- n Z-line/ protein, M- (including disc desmin protein) and α-actinin) From: Slee, 2005 Sarcomere- Reminder of some basics… For movement, physical activity and exercise to take place, skeletal muscle must contract. This requires ATP for this to take place. (e.g. ATP binds to myosin and hydrolysis by myosin ATPase). See video: https://www.youtube.com/watch?v=BVcgO 4p88A Reminder of some basics… Don’t forget also about the basics of neuromuscular activation, e.g. motor units. Activation of neuromuscular junction, acetylcholine and Na+-K+ pump, linked to membrane depolarization. Linked to Ca2+ release from sarcoplasmic reticulum. See video: https://www.youtube.com/watch?v=sZuy35 Different types of fibers Type I (red) and Type II (white) fibersType IIb Type IIa Type It is typical of human muscles I that they contain all fiber types, but in different proportions in (overall) fast and slow muscles Fiber types characterized using ATPase histochemistry, myosin heavy chain and metabolic Fiber Type Classification Myosin ATPas e Myosin Heavy Chain From: Scott W, Stevens J, Metaboli Binder-Macleod SA. c skeletal muscle Human SO: Slow Oxidative; FOG: Fast Oxidative fiber type enzyme Phys classifications. Glycolytic; FG: Fast Glycolytic Differences in Fibers For example, the rate of ATP hydrolysis in fast twitch fibers is far greater (2-3 times more) than slow fibers. Rate and strength of contraction is different depending on type and myosin heavy chain isoform. Metabolic enzyme capacity is far higher in Type I fibers due to the presence of more mitochondria. Mitochondria in Skeletal Muscle In skeletal muscle there are populations of subsarcolemm al and intermyofibrill ar mitochondria. Bishop et al. PHYSIOLOGY 34: 56 –70, 2019. Effects of Exercise Training Note that training can have a powerful effect on hypertrophy/growth of type I/II muscle fibers. – Depends on training type, e.g. Type I and aerobic training Also, a transition between fiber types, e.g. Type IIa to IIb. Increase in size and protein content of tissue. – E.g. resistance training and type II fiber hypertrophy Increase in mitochondria with aerobic Exercise Metabolism There are TWO key aspects to muscular alterations during exercise. 1) Metabolic alterations (changes in muscle metabolism -> increased energy demand, ATP production, nutrient utilization during exercise) 2) Muscle damage and repair (covered at end of lecture) MUSCLE METABOLISM  ATP Adenosine triose phosphate or ATP is essentially the molecular currency of energy transfer in the cell. Produced from the breakdown of food- nutrients by metabolism. ATP is used for processes like: – Muscle contraction – Ion pumps – Enzyme regulation – Protein turnover – e.g. energy costs From: Hargreaves and Spriet, 2020. Nature Metabolism, VOL 2: 817–  Fuel Sources During Exercise Muscle can utilise different intramuscular and extramuscular fuel sources, e.g. Glycoge n (muscle ) Glycoge n (liver) From: Hargreaves and Spriet, 2020. Nature Metabolism, VOL 2: 817– 828 Fuel Selection During Exercise The fuel selection during exercise depends on the intensity of the exercise and ATP demands. E.g. in low intensity exercise, when O2 is present the ATP turnover is lower, hence more efficient fuel sources can be used such as fats (TGs). Rate of ATP production is an important factor. As is location and speed of delivery. – E.g. in lower intensity exercise adipose tissue Comparison of fuel sources – rate of ATP production and total P available Example: Intense Exercise – Intense (rapid/forceful) muscle contraction induces extremely high rates of ATP turnover. This is sustained by different energy systems. From: Hargreaves and Spriet, 2020. Nature Metabolism, VOL 2: 817– 828 Creatine phosphate as a buffer Efforts to regenerate ATP quickly… ATP 5 mmol/kg muscle Creatine 17 mmol/kg muscle phosphat e The presence of creatine phosphate increases the ability to maintain contraction for x4 longer Attempt to keep ATP constant. Concentration of ATP and creatine phosphate (PCr) during maximal muscle stimulation Effects of intense exercise to fatigue: ATP turnover Creatine P P ATP Baker et al, J Nutr Metab. 2010:  Myosin ATPase ATP ADP + Pi + H+ + Energy Myosin ATPase is responsible for breaking ATP down and releasing free energy during muscle contraction. Another mechanism to regenerate ATP Note that the Adenylate Kinase enzyme ADP + ADP ATP+ catalyses the reaction: AMP From: Dzeja and Terzic, 2009. Int J Mol Sci; 10(4): 1729– 1772.  Myosin Note: these ATPase byproducts have been linked to fatigue in muscle ATP ADP + Pi + H+ + Energy Myosin ATPase is responsible for breaking ATP down and releasing free energy during muscle contraction. Note that the Adenylate Kinase enzyme catalyses the reaction: ADP + ADP ATP+ AMP Muscle contraction – biochemical aspects [ATP] within muscle cells will only allow :- 1 second on maximal contraction 4 seconds of running This means that continuous ATP generation is required – and quickly! After starting vigorous exercise, ATP generation has to increase x 1000! Creatine phosphate acts as an initial buffer – E.g. hence why creatine supplementation is useful aid for athletes lactic acid and(high intensity exercise) glycogen breakdown. Note: predominant activation of glycogen breakdown In fast twitch muscle fibres as exercise intensity increases. Glycoge n granule mitochondria myofib ril Exercise and muscle glycogen breakdown Electron micrograph of muscle stained for glycogen Calcium flux also affects TCA cycle activity – e.g. consider muscle contraction  Energy Intensity, Energy Expenditure and Fuel Selection 1) Note the increase in EE with exercise intensity. 2) note the fuel selection and contribution 3 7 of muscle glycogen. From: Van Loon et al, Homeostasis of ATP concentration Glycogen is storage form of glucose To maintain ATP levels nutrient breakdown can be accelerated, e.g. by adrenaline. Ability to switch fuels, e.g. from fat to glucose as vice versa. Switch Triacylglycerol, TAG is fuels the storage form of fatty  Intramuscular Triglyceride Note: fat droplets in muscle surrounding mitochondria. Fats are stored in muscle and are an important fuel source, especially during endurance Exercise has a powerful effect on GH release and increases in relation to the exercise intensity, measured as lactate levels (lactate threshold) in the blood. Exercise and Glucose uptake Compared to rest exercise has a potent effect on increasing glucose uptake. This is also intensity and duration dependent. Potential Sites of Regulation  Before Exercise & Exercise Training Blood Flow Hexokinase Glucose Glucose Glucose-6- Phosphate Extracellular Skeletal Muscle Cell 4  After Exercise Training Increase in GLUTs Increase in Hexokinase enzyme number and activity Hexokinase Glucose-6- Glucose Phosphate Blood Glucose Flow Hexokinase Glucose-6- Glucose Phosphate Hexokinase Glucose-6- Glucose Phosphate Extracellular Skeletal Muscle Cell 4 Effects of Exercise Training Effects on GLUT-4 Gene Expression Via AMPK activation and Ca2+/Calmoduli n kinase there is an increase in GLUT- 4 gene expression Current Research on Glucose and Fatty Acid Uptake in Muscle (& similarities to glucose Metabolism)/ See Glatz et al, 2010 Muscle contraction causes increase in AMP/ATP ratio. Activation of AMPKinase. Activates pathways for glucose and fatty acid transport into the cell. Potent antdiabetic effect. Exercise and Glycogen Super-compensation Exhaustive one-legged exercise for 2.5 hours in 9 healthy male participants. Followed by 5 day CHO supercompensation regime, the subjects consumed a eucaloric diet composed of 80 E% carbohydrates, 10 E % fat and 10 E% protein. Muscle biopsies taken and protein expression MOLECULAR METABOLISM 16 (2018) 24-  Glycogen super- compensation Increased glucose uptake Glycoge n depletio n Heightened Glycogen Synthase (GS) activity MOLECULAR METABOLISM 16 (2018) 24-34 Note: enhanced GLUT protein expression GLUT1 and 4. and Hexokinase I and II expression. MOLECULAR METABOLISM 16 (2018) 24- “Prolonged exercise training increases intramuscular lipid content and perilipin 2 expression in type I muscle fibers of patients with type 2 diabetes” by Shaw et al, 2012 6 months of endurance exercise (e.g. walking, cycling) in obese male T2DM patients (n=10). Muscle biopsies taken from Vastus Laterialis at different time points. Investigating oxidative capacity (cytochrome c oxidase, COX), IMTG content and Perilipin. Note that training improved Shaw et al, Am J Physiol Endocrinol Metab. 2012 Nov 1; 303(9): E1158– E1165 They also measured Perilipin (protein associated with lipid droplet associated with insulin sensitivity) Adaptations to Training With endurance training there is a greater reliance on fat as fuel, from IMTGs in particular. Less reliance on carbohydrate and glycogen. “glycogen sparring” Attempt to increase resistance to fatigue. Note that the ability to store glycogen in muscle is enhanced however. The Athletes Paradox – studied extensively by Goodpaster, Kelley and colleagues. They showed that insulin sensitivity/resistance is closely correlated with lipid content in muscle in obese/diabetic people. However, endurance trained athletes have BOTH high lipid content and insulin sensitivity! Termed: The Athletes Paradox Insulin sensitivity Lipid content in muscle The Athletes Paradox What this means… As previously described today, when people do endurance training the muscles adapt to preferentially use fat as fuel. Fat content in muscle increases (can double) and can muscle glycogen (carbohydrate). However, fat oxidation and turnover also doubles. For example, mitochondria increase in size and number and enzyme activity increases. For example: succinate dehydrogenase activity increases in muscle. SDH is found in the krebs cycle and is a marker of oxidative capacity. Markers of oxidative capacity and mitochondrial function HIGH INTENSITY INTERVAL TRAINING (HIIT) HIIT Research has shown now from animal and human studies that HIIT exercise is more effective and productive in enhancing beneficial adaptations in skeletal muscle. Improved VO2max for example. Mitochondrial biogenesis. Activation of Type II fibers as well as Type HIIT - Definitions Torma at al. Sports Medicine and Health Science 1 (2019) HIIT – Energy Demands & Intensity Torma at al. Sports Medicine and Health Science 1 (2019) Higher intensity training increases capillarization in muscle Short periods of Type Type training, I II e.g. 4 weeks can significantly increase capillarization. Implications for Effects of HIIT on Metabolism Burst of high intensity activity activates type II fibers. Increase in ATP turnover and AMPK activation. Ca2+ sensitive pathways activated. Other metabolites, ROS, lactate, Cr and Pi etc. Increases mitochondrial biogenesis (note however, controversial topic-as difficult to measure accurately and different study Bishop et al. PHYSIOLOGY 34: 56 –70, 2019. Bishop et al. PHYSIOLOGY 34: 56 –70, Bishop et al. PHYSIOLOGY 34: 56 –70, 2019.  Effects of HIIT - Metabolism Bursts of higher intensity exercise leads to greater type II fiber activation/recruitment. Increased AMPK activation. Increased glycogen depletion. MICT vs HIIT on Mitochondrial Function McInnis and Gibala. J Physiol595.9 (2017) pp 2915–2930 Training Effects One thing to consider is the change in gene expression and mitochondrial protein synthesis using the same relative intensity of exercise. Lactate & Fatigue Another key by-product of higher intensity exercise is lactate. Is lactate good or bad? Causes fatigue? Controversial Topic Lactate and High Intensity Exercise Lactate production increases in muscle due to increased glycolytic flux. Increases intramuscular and extracellular blood lactate levels. Associated with fatigue. ATP Hydrolysis and H+ Ions Originally suggested that lactic acid and/or the H+ ions cause fatigue (e.g. from earlier studies). Infact, the increase in intramuscular H+ ions are principally from increased rate of ATP hydrolysis. Lactate Reality Check Mitochondrial Lactate Oxidation Brooks, 2020: Lactate Reality Check Instead of being the cause of fatigue, lactate is actually critical for reducing intramuscular H+ ion accumulation. It is transported out of the cell via monocarboxylate (MCT) transporters (up- regulated with exercise training), and H+ are co- transported out with lactate. It is oxidised by neighbouring tissues and in muscle during rest. Other tissues such as the brain, heart and liver use lactate., e.g. gluconeogenesis in the liver.  Lactate as a Signalling Molecule – links with hypoxia inducing factor (HIF-1) In high intensity exercise HIF-1 transcription factor is up- regulated. Linked to lactate production and MCT Nalbandian and Takeda, Biology expression 2016, 5, 38  Lactate as a Signalling Molecule – links with peroxisome proliferator activated receptor gamma coactivator (PGC1a) = transcription factor Exercise is known to activate the PGC1a transcription factor. There is a relationship between lactate and PGC1a. Nalbandian and Takeda, Biology 2016, 5, 38 Novel Actions of Lactate – Appetite Suppression in Exercise Lactate may suppress ghrelin production in the stomach. And impact POMC/AgRP neurons in hypothalam FATIGUE Fatigue There are many potential causes of muscle fatigue: – Glycogen depletion – Reduction in phosphocreatine – Accumulation of byproducts (H+, Pi, ROS, Mg2+ ) – AMP deamination to IMP and NH3 Central fatigue in the CNS may be due to: – Low blood glucose – BCAA/tryptophan balance Fatigue Causes – Peripheral and Central Increase in H+ ions- controversial topic, but may have small impact upon reducing contraction. Increase in Pi –potentially inhibiting actomyosin ATPase. Reactive oxygen species (ROS) production by muscle, e.g. superoxide (O2-.) produced by mitochondria are thought to decrease force production by muscle. E.g. by affecting calcium release from the SR and direct effects on actin and myosin. ROS and force production Powers and Jackson. Physiol Rev 88: 1243–1276, 2008 MUSCLE DAMAGE & REPAIR, PROTEIN TURNOVER & INTAKE Muscle Damage and Repair This concept is the cornerstone to understanding ‘load-induced tissue strain’ and muscle hypertrophy. E.g. effects of resistance training on muscle protein content and muscle growth over time. Muscle damage is required to provoke an anabolic response in muscle. However, it depends on the type  Muscle Damage and Repair We wont go into any depth here as it there is a lecture later in the term but to say that during heavy eccentric contractions (lengthening contractions, e.g. downhill running) the muscle can experience damage and trauma. This has a significant impact upon local immuno- inflammatory response, growth factor release and protein turnover. Z-disc streaming Normal and sarcomere Muscle Damage Sites of cytoskeletal disruption following eccentric exercise Loss of dystrophin, desmin, Z-disc and sarcomere disruption. Leads to loss 93 in muscle Effects of extreme Eccentric Exercise Note the process of damage and repair. Loss of functional cells. Infiltration with immune cells. Tissue repair Infiltrating immune cells Things to Consider Muscle protein synthetic response to resistance exercise. Release of local growth factors. Inflammatory immune cell activation. Importance of protein intake. Would anti-inflammatory medication and nutrients be useful? Muscle Protein Synthetic (MPS) Response Resistance training has a particular impact on type II fibers stimulating muscle protein synthesis, e.g. via mTOR pathway activation. Research shows that this is active post exercise and sensitive to nutrition (e.g. amino acids). Hence, chronic training combined with nutrition may lead to increases in muscle protein content and muscle hypertrophy. – Increase in actin and myosin muscle architecture and strength. – As opposed to endurance exercise mostly Blunting of MPS during exercise Research has shown that MPS is suppressed during exercise (e.g. resistance training). Processes not completely understood. Potentially relates to ATP demands and effects of AMPK activation. 9 Rose and Richter, 2009. J Appl Physiol 106: 1702– 1711 7 MPS in Trained (T) and Un-Trained (UT) There are differences in post- exercise MPS stimulation depending on training status. In resistance exercise. UT have greater MPS – e.g. rapid gains From: Burd et al, 2009. J Appl Physiol 106: 1692–1701. 9 8 Fed, Fasted and Resistance Training Effects on MPS and MPB Key points to note is that MPS is stimulated in the fed state. MPB is also suppressed. Effects of amino acids and insulin in muscle. From: Burd et al, 2009. J Appl Physiol 106: 1692– 9 9 Fed, Fasted and Resistance Training Effects on MPS and MPB From isotope studies it has been found that MPS is maximally stimulated by protein intake of 0.24-0.4 g/kg body mass. E.g. for a 100 kg person = ~24-40 g/meal. Persists for 2-3 hours. In combination with 10 RT, leads to net From: Burd et al, 2009. J Appl Physiol 106: 1692– 0 Time course of MPS response with resistance training As previously mentioned MPS can be raised for 24- 48 hours post-exercise. This period is sensitive to nutrition and amino From: Burd et al, 2009. J Appl Physiol 106: 1692– 10 1 4 8 Current Recommendations Note use of leucine and EAAs. For muscle protein synthesis stimulation And fuel in enduranc e 4 exercise. 9 Current Recommendations NOTE: also the importance stated of whole food sources of protein that contain all of the EAAs, e.g. meat, eggs, dairy etc. 5 0 Thank you & Questions