Muscle Energetics and Metabolism PDF

Muscle Energetics, aerobic and anaerobic metabolism What are the mechanisms by which muscle fibers obtain energy to power contractions? ATP: an Energy Carrier • ATP functions as the most important energy intermediate ATP consists of a molecule of adenosine (adenine + ribose) to which 3 phosphat...

Muscle Energetics, aerobic and anaerobic metabolism What are the mechanisms by which muscle fibers obtain energy to power contractions? ATP: an Energy Carrier • ATP functions as the most important energy intermediate ATP consists of a molecule of adenosine (adenine + ribose) to which 3 phosphate groups are attached Removal of 1 phosphate = ADP Removal of 2 phosphates = AMP ATP has a large free energy of hydrolysis ATP and muscle contraction - Sustained muscle contraction uses a lot of ATP energy. - Muscles store contraction. enough energy to start - Muscle fibers must generate more ATP as contraction goes on. Energy Supply in Muscle Energy stored as ATP is used to power muscular activity (During sprint exercise ATP turnover can increase 100-fold above rest) Three basic energy systems exist in muscle cells to re-plenish ATP: 1. ATP-PC system 2. Anaerobic Glycolysis Anaerobic system 3. Oxidative system (Aerobic system) ATP sources during exercise (I) ATP sources during exercise (II) ATP sources during exercise (III) Contributions of CP (light green), glycolysis (medium green) and oxidative phosphorylation (dark green) to ATP turnover during maximal exercise. Muscle samples were obtained before and during 30 s of all-out cycling exercise. Dw, dry weight. Hargreaves M and Spriet LL (2020) Nature Metabolism 2:817–828 Energy Supply in Muscle (I) Energy stored as ATP is used to power muscular activity Three basic energy systems exist in muscle cells to re-plenish ATP: 1. ATP-PC system: provides energy for a short duration, high intensity work, by re-plenishing ATP rapidly 2. Anaerobic Glycolysis: Provides energy through the breakdown of glucose to create ATP for moderate-intensity and duration work (3—50 seconds) 3. Oxidative system: Uses substrates with the aid of oxigen to generate ATP ATP and CP: “ready-to-use” energy reserves Adenosine triphosphate (ATP): – the active energy molecule Creatine phosphate (CP): – the storage molecule for excess ATP energy in resting muscle The phosphocreatine (ATP-PC) system Phosphocreatine (CP or Pcr) is a phosphorylated creatine molecule that serves as a rapidly usable reserve of highenergy phosphates in skeletal muscle, heart and brain to recycle ATP • • • The ATP-PC system uses the creatine kinase reaction to maintain concentrations of ATP It replenishes ATP rapidly and is an immediate source of energy for muscle contraction Small amount: only provides ATP for a few seconds The phosphocreatine (ATP-PC) system Synthesis of ATP in mitochondria in closely coupled to that of phosphocreatine ATP + creatine CK ADP + phosphocreatine PC CK PC P + creatine + energy Energy + P + ADP ATP CK = creatine kinase Energy Supply in Muscle (II) Energy stored as ATP is used to power muscular activity Three basic energy systems exist in muscle cells to re-plenish ATP: 1. ATP-PC system: provides energy for a short duration, high intensity work, by re-plenishing ATP rapidly 2. Anaerobic Glycolysis: Provides energy through the breakdown of glucose to create ATP for moderate-intensity and duration work (3—50 seconds) 3. Oxidative system: Uses substrates with the aid of oxigen to generate ATP Lactic Acid System During very intense work most ATP is derived from the breakdown of phosphocreatine (PCr) and glycogen to lactate Lactate is the final product of anaerobic glycolysis reduction to lactate is the major fate for pyruvate in low O2 conditions In exercising muscle: high NADH/NAD+ favors lactate production by lactate dehydrogenase (LDH) During intense exercise lactate accumulates in muscle causing a drop in the pH (lactate diffuses into the bloodstream and is taken up from the liver) Energy Supply in Muscle (III) Energy stored as ATP is used to power muscular activity Three basic energy systems exist in muscle cells to re-plenish ATP: 1. ATP-PC system: provides energy for a short duration, high intensity work, by re-plenishing ATP rapidly 2. Anaerobic Glycolysis: Provides energy through the breakdown of glucose to create ATP for moderate-intensity and duration work (3—50 seconds) 3. Oxidative system: Uses substrates with the aid of oxygen to generate ATP Generates a lot of ATP, but slowly Aerobic metabolism of fatty acids in the mitochondria is the primary energy source of the resting muscle Overview of muscle metabolism − The muscle’s major fuels are glucose (from glycogen), fatty acids and ketone bodies. − Although TAGs are a more efficient form of energy storage, glycogen is the major energy reservoir in the muscle, because it can be mobilized more rapidly than fat, and glucose can be metabolized anaerobically, whereas fatty acids cannot. − The muscle cannot export glucose, since it lacks glucose-6-phosphatase. Therefore, G6P from glycogen enters glycolysis in the muscle. − Although it can synthesize glycogen from glucose, the muscle does not participate in gluconeogenesis, because it lacks the required enzymes. − Therefore, muscle carbohydrate metabolism serves muscle only. − The heart muscle relies on aerobic metabolism, is rich in mitochondria and preferentially uses fatty acids as fuel at rest (glucose during heavy work). Energy Systems during Exercise Anaerobic systems are used when working intensely Aerobic systems are used when working for longer durations (over 3 minutes) Energy Systems during Exercise The extent to which each substrate contributes to ATP production depends primarly on the intensity of muscular activity and secondarily on the duration. At no time, during exercise or rest, does any single energy system provide the complete supply of energy. Fat begins to contribute as a fuel after 20 minutes of exercise Protein become an important fuel source when glycogen stores are depleted (about 2 hours of exercise) Energy Systems during Exercise (II) Mobilization of extramuscular substrates is critical to maintain skeletal muscle metabolism during prolonged exercise • Liver increases the release of glucose into the circulation (derived first from glycogenolysis and then gluconeogenesis) • Adipose tissue increases the hydrolysis of triglycerides and release of FFAs High exercise intensity: ↑ aerobic glycolysis ↓ lipid oxidation Moderate exercise intensity: ↓aerobic glycolysis ↑ lipolysis and fat oxidation How is Fuel Selection Measured? The respiratory quotient (RQ) or respiratory exchange ratio (RER) is the amount of carbon dioxide (CO2) expired divided by the amount of oxygen (O2) consumed, measured during rest or at a steady state of exercise It reflects the substrate being oxidized for energy GLUCOSE 6O2 + C6H12O6 6CO2 + 6H20 + 38 ATP RER = 6CO2 / 6O2 =1 FATTY ACIDS 23O2 + C16H32O2 16CO2 + 16H20 + 129 ATP RER = 16CO2 / 23O2 =0.7 Respiratory Exchange Ratio (RER) • RER is the ratio between CO2 released (VCO2) and oxygen consumed (VO2) • At rest the average RER is 0.75: the body is burning approximately 85% fat and 15% carbohydrate • As exercise intensity increases, so does RER: RER of 0.95? RER of 0.8? Fuel Utilization during Exercise Carbohydrates are a major macronutrient source for the metabolic production of ATP § Stored as glycogen in muscle and liver § Glycogenolysis is the primary regulator of blood glucose Carbohydrates used during exercise come from both glycogen stores in muscle tissue and blood glucose § The relative contribution of muscle glycogen vs blood glucose depends on the intensity and duration of exercise § After the first hour of submaximal exercise, carbohydrate metabolism shifts from muscle glycogen to glycogenolysis in the liver § Gluconeogenesis also contributes to blood glucose (formation of glucose from non glucose sources (lactate, amino acids, glycerol) Muscle Glycogen Storage • Approximately 300-400 g of glycogen are stored in skeletal muscle and 70 to 100 g are stored in liver. • During high intensity activity muscle glycogen is the predominant fuel source • Liver glycogen is more important during mediumintensity activity Fuel Utilization during Exercise: Fats Fats are mainly stored as triglycerides (TAGs) in adipocytes: need to be broken down to free fatty acids (FFAs) and glycerol • During low-intensity exercise, circulating FFAs from adipocytes are the primary energy source • During higher intensities muscle glucose metabolism increases • As duration increases, the role of plasma FFAs as a fuel sources increases Fuel Utilization during Exercise: Proteins • Protein play a minor role in the fueling of muscle during exercise • Skeletal muscle can directly metabolize certain amino acids (AAs) to produce ATP • AAs can be oxidized to produce ATP or used as a substrate (alanine) for gluconeogenesis Lactate as a fuel • Lactate is usually considered as a waste product of glycolysis • Lactate can play a role in glucose production in the liver (gluconeogenesis) During exercise some of the lactic acid produced by skeletal muscle is transported to the liver via the bloodstream and converted to glucose Glucose is then released from the liver and travels back to the muscle where it can be used as an energy source CORI CYCLE Muscle Fatigue The build up of lactate leads to lowers the pH causing muscle fatigue (exhaustion and pain) Muscle fatigue is the inability to contract even in the presence of stimuli Muscle fatigue can also be due to: -depletion of metabolic reserves -damage to sarcolemma and sarcoplasmic reticulum The recovery period The time required after exercise for muscles to return to normal, when oxygen becomes available and mitochondrial activity resumes. Cori cycle - the removal and recycling of lactic acid by the liver - liver oxidizes lactic acid to pyruvate that is converted to glucose - glucose is released to recharge muscle glycogen reserves Oxygen debt - after exercise, the body needs more oxygen than usual to normalize metabolic activities, resulting in heavy breathing Fuel Utilization during Exercise Control systems ensure rapid ATP provision and the maintenance of the ATP content in muscle cells. Many signals generated in contracting skeletal muscle during exercise (Ca2+; ADP, AMP, Pi and altered energy charge) can activate kinases and signalling cascades During muscle contraction ATP is hydrolyzed to ADP ADP is converted to ATP + AMP by the adenylate kinase (AK) AMP is a key metabolic sensor regulating the activity of metabolic enzymes Allosteric regulation of PFK Active site ATP F6P ATP T R ATP AMP ADP F2,6P Regulatory site • The metabolic flux through glycolysis may vary by 100-fold, however [ATP] changes by <10% • In the muscle small changes in [ATP] result into large variations of [AMP], through the adenylate kinase reaction, and, ultimately, larger allosteric effect on PFK AMP-dependent protein kinase (AMPK) • AMP-dependent protein kinase (AMPK) activates metabolic breakdown pathways that generate ATP while inhibiting biosynthetic pathways that use ATP, so as to spare ATP for more vital processes • AMPK initiates phosphorylation cascades that ramp up glycolysis and fatty acid oxidation • AMPK is activated when the cell has high AMP:ATP ratio • The AMPK’s kinase domain must be phosphorylated to become active (binding of AMP to the g subunit causes a conformational change that exposes Thr172 in the activation loop of the a subunit, thus promoting its phosphorylation and increasing its activity by at least 100 times). • The major AMPK kinase is liver kinase B1 (LKB1) constituvely active in muscle AMPK Regulation of Metabolism in Skeletal Muscle AMPK increases the expression of GLUT4 as well as its recruitment to the muscle cell plasma membrane, thus facilitating the insulin-dependent entry of glucose into the cells (glucose uptake). AMPK-dependent phosphorylation inhibits acetyl-CoA carboxylase (ACC). The resulting decrease in [malonyl-CoA] reliefs inhibition on carnitine acyltransferase I, thus ultimately leading to augmented entry of acyl-CoA into the mitochondrion (FA oxidation). Muscle fibers and muscle performance Muscle performance Power: the maximum amount of tension produced Endurance: the amount of time an activity can be sustained Power and endurance depend on: 1. the types of muscle fibers 2. physical conditioning Skeletal Muscle Fiber Types (I) Skeletal muscle fibers can be classified based on two criteria: 1. How fast fibers contract 2. Mechanism of ATP regeneration There are three main types of skeletal muscle fibers: 1. Slow oxidative fibers - are slow to contract (slow to fatigue) - have small diameter, more mitochondria - use aerobic oxidation to produce ATP 2. Fast glycolytic fibers - contract very quickly - have large diameter, large glycogen reserves, few mitochondria - primarily use anaerobic respiration to produce ATP - have strong contractions (fatigue quickly) 3. Fast oxidative fibers -have more capillaries than fast glycolytic fibers (slower to fatigue) -primarily use aerobic respiration to produce ATP Skeletal Muscle Fiber Types (II) Slow oxidative fibers • • • • • • Aerobic (FAs and glucose) High levels of myoglobin Large number of mitochondria Low glycogen content Slow rate of fatigue Good for endurance activities Skeletal Muscle Fiber Types (III) Fast glycolytic fibers • • • • • • Anaerobic Low levels of myoglobin Few mitochondria High glycogen content Fatigues quickly Short term intense exercise Skeletal Muscle Fiber Types (IV) Fast oxidative fibers have characteristics of both muscle types (intermediate fibers): • Produce ATP relatively quickly and can produce relatively high amounts of tension • Because they are oxidative, they are more fatigue-resistant that fast glycolytic fibers • Are used primarily for movements, such as walking, that require more energy than postural control but less energy than an intense exercise bout Comparing skeletal muscle fibers Usain Bolt Eliud Kipchoge Cardiac Muscle Metabolism Cardiac muscle contracts for longer than skeletal muscle and never rests: • Cardiac muscle has a high mitochondrial density • Fast production of ATP High resistance to fatigue To meet this constant demand, cardiac muscle uses the rich supply of O2 delivered by the coronary circulation to generate ATP through aerobic respiration Readings Metabolic communication during exercise https://www.nature.com/articles/s42255-020-0258-x Skeletal muscle energy metabolism during exercise https://www.nature.com/articles/s42255-020-0251-4