Substrate Utilization During Exercise Carb F24 PDF

Substrate Utilization During Exercise Carbohydrates Lipids Proteins (very little) 1  Basic Points About Fuel Sources in Exercise Plasma-derived substrates (glucose, fatty acids) Supply most of the energy at lo...

Substrate Utilization During Exercise Carbohydrates Lipids Proteins (very little) 1  Basic Points About Fuel Sources in Exercise Plasma-derived substrates (glucose, fatty acids) Supply most of the energy at low intensity exercise Intramuscular substrates (glycogen, triglycerides) More important at higher intensities (65% VO2max and up) In later stages of exercise plasma substrates become more important, as endogenous sources decline In general: Carbohydrate - more contribution with increased intensity, less contribution as exercise duration increases Fat – more contribution with increased duration, less contribution as exercise intensity increases 2 Substrate Utilization During Exercise Where is it coming from? Carbohydrate: Liver (hepatic glucose production; glycogenolysis and gluconeogenesis) Muscle glycogen Fat: Adipose tissue (lipolysis) Intramuscular triacyglycerol 3  The Liver and Blood Glucose Control Hepatic glucose production (HGP) Need to maintain blood glucose concentration at ~4 - 5 mM Some tissues depend on glucose neural (can also use ketones) red blood cells (lack mitochondria) What happens during exercise? Maximum leg glucose uptake can reach ~2 mmol/min - but total blood glucose content is only about 25 mmoles (5 mmol/L x 5 L) you could theoretically deplete all blood glucose in ~12 min of exercise! 4  How does the liver maintain blood glucose? Catecholamines, glucagon Liver mainly alpha receptors GNG glycogenolysis Liver glucose production 5  Liver Glycogenolysis and Gluconeogenesis with Exercise: Contribution to HGP gluconeogenesis Increasing intensity * Due to rapid restoration of hepatic blood flow upon end of exercise, there is an increased supply of gluconeogenic precursors that are still elevated in the blood - the consequence is a "spike" in gluconeogenesis in recovery from exercise. 6  Hepatic Glycogenolysis ▪ Glycogen phosphorylase ▪ Hormonal control (e.g. glucagon, insulin, catecholamines) breakdown of glycogen to G-1-P in liver G-6-P can be converted to glucose and exported to the systemic circulation to maintain blood glucose (via GLUT2) in muscle this reaction does not occur can deplete liver glycogen in ~1 hr 7  Gluconeogenesis (GNG): Glucose Synthesis from Non-Carbohydrate Sources Pyruvate, lactate, glycerol some AA Liver glucose 8 Exercise Training Increases GNG Young and old rats trained 5 days/wk, 8-10 weeks. Hepatocytes were isolated and epinephrine stimulated glucose production was measured in the presence of lactate Gluconeogenesis is increased. Remember that glycogenolysis is reduced. 9  In Liver, Glucagon and Catecholamines Increase cAMP Key GNG + Key GNG enzyme enzyme Key glycolysis enzyme Key (phosphofructokinase) glycolysis enzyme cAMP simultaneously increases gluconeogenesis and decreases glycolysis 10  Muscle Glycogen Utilization Content vs duration Rate vs intensity Rate of utilization tends to be exponential rate of depletion is fastest at onset (~first 15-20 min) Glycogen "sparing" means to reduce rate of glycogen utilization during initial period of exercise What leads to glycogen sparing? Why is this important? aerobic training finite fuel; “sparing” of it can increased lipid availability lead to prolonged time to fatigue 11  Exercise Training Adaptations and Whole-Body Substrate Oxidation Training shifts substrate use towards fat … note that this is only assessed up to ~80% VO2 max 12 Hansen et al. 1996 Dietary Manipulation of Muscle Glycogen Exercise to exhaustion to first deplete glycogen, and then given various diets for three days. Glycogen restoration greatest with high carbohydrate diet 13  Maintaining Blood Glucose During Exercise … Benefits of Ingesting Glucose. Subjects cycled at ~70% VO2peak while ingesting either placebo OR 8% CHO beverage. McConell et. al. Journal of Applied Physiology. 87: 1083-1086, 1999. 14  What Happens if I Eat Lots of Sugar Right Before I Exercise? Glucose crash and earlier time to fatigue ! What hormone is responsible for this disastrous outcome???? 15  Skeletal Muscle Glycolysis: initial reactions for complete oxidation of glucose to CO2, H2O; ends at pyruvate “Anaerobic glycolysis”: increasing Lactate acidity with high intensity PDH dehydrogenase exercise…fatigue Examples? 1 to 2 min duration e.g. 200-400 m sprints, repeated sprints (soccer), 100m hard effort swim 16  Lactic acid Lactate dehydrogenase Lactic acid is formed (LDH) when oxygen is insufficient, OR simply when the production of NADH & pyruvate exceeds capacity of PDH* at pH of 7, lactic acid instantly dissociates into lactate and H+ Is lactate “bad”??? 17  Lactate…An Important Metabolite When muscle lactate levels are high, such as LDH in high intensity exercise, lactate moves out of muscle cells into the blood…where does it go? e.g. liver, heart What happens to it? converted to pyruvate and used aerobically to produce ATP Also, used in the liver for gluconeogenesis (Cori Cycle… next slide) Lactate is a key gluconeogenic precursor! 18  Muscle doesn't have the enzymes capable of glucose synthesis from lactate! The Cori Cycle GNG Net consumption of Glycolysis 4 ATP; energetically costly for the liver! Start here **If muscle activity has stopped, glucose is used to replenish supplies of glycogen through glycogenesis (synthesis of glycogen)** 19 The development of acidosis during intense exercise has traditionally been explained by the increased production of lactic acid, causing the release of a proton and the formation of the acid salt sodium lactate. On the basis of this explanation, if the rate of lactate production is high enough, the cellular proton buffering capacity can be exceeded, resulting in a decrease in cellular pH. These biochemical events have been termed lactic acidosis. The lactic acidosis of exercise has been a classic explanation of the biochemistry of acidosis for more than 80 years. This belief has led to the interpretation that lactate production causes acidosis and, in turn, that increased lactate production is one of the several causes of muscle fatigue during intense exercise. This review presents clear evidence that there is no biochemical support for lactate production causing acidosis. Lactate production retards, not causes, acidosis. Similarly, there is a wealth of research evidence to show that acidosis is caused by reactions other than lactate production. Every time ATP is broken down to ADP and P(i), a proton is released. When the ATP demand of muscle contraction is met by mitochondrial respiration, there is no proton accumulation in the cell, as protons are used by the mitochondria for oxidative phosphorylation and to maintain the proton gradient in the intermembranous space. It is only when the exercise intensity increases beyond steady state that there is a need for greater reliance on ATP regeneration from glycolysis and the phosphagen system. The ATP that is supplied from these non-mitochondrial sources and is eventually used to fuel muscle contraction increases proton release and causes the acidosis of intense exercise. Lactate production increases under these cellular conditions to prevent pyruvate accumulation and supply the NAD(+) needed for phase 2 of glycolysis. Thus increased lactate production coincides with cellular acidosis and remains a good indirect marker for cell metabolic conditions that induce metabolic acidosis. If muscle did not produce lactate, acidosis and muscle fatigue would occur more quickly and exercise performance would be severely 20 impaired.  Lactate and Acidosis Lactic acid → *Lactate + H+ Pyruvate + NADH + H+ → Lactate + NAD+ ** ATP + Cr -→ PCr + ADP + H+ *Theoretically, accumulation of strong anions (-ve charge) like lactate or chloride cause metabolic acidosis (Stewart acid-base chemistry) **Some argue that the hydrolysis of ATP is the most significant cause of H+ accumulation at very high metabolic rates … and the accumulation of lactate is just “going along for the ride” i.e. association, not cause 21  Muscle Soreness and Lactic Acid Does lactate cause muscle soreness in the days after strenuous exercise? NO! What is the cause? Microscopic damage to muscle fibres, particularly “eccentric” muscle contractions Triggers an inflammatory-repair response that leads to pain! Called delayed onset muscle soreness (DOMS) What about the acute burning sensation? That’s tougher … might be H+, osmotic change due to metabolite buildup (inc. lactate) 22  Summary So Far … Carbs contribute more with increasing exercise intensity Carb is stored in liver and muscle; liver releases glucose via GNG and/or glycogenolysis Training increases epi-induced GNG, but reduces glycogenolysis Training shifts substrate use towards fat, sparing muscle glycogen Lactate is not the villain it’s made out to be! 23  J Appl Physiol 65(2):909-913, 1988 Contraction induces a rapid increase in glucose transport that can persist for an hour or more after cessation Increase above basal rate 24  Additive Effect of Insulin + Exercise on Glucose Uptake into Muscle Glucose transport can be stimulated by two separate pathways in skeletal muscle. One pathway is activated by insulin and the other by contractile activity. Constable et al. 1993 25  Insulin insulin and contractions/exercise operate Insulin Receptor through distinct mechanisms muscle contraction/hypoxia IRS AMPK    PI 3-kinase PI 3-kinase AMPK dependent dependent signals AMPK PDK signals independent Signals (e.g. Ca2+, ROS) Akt PKC GLUT 4 AS160 26 Wortmannin is a PI3 kinase inhibitor PI3 phosphatidylinositol kinase 27  AMPK may mediate effects of muscle contractions on skeletal muscle glucose uptake What is 5' AMP-activated protein kinase (AMPK)? A cellular "energy sensor” Responds to a decrease in energy status – increase in AMP, increase in Cr/PCr, also decrease in glycogen) Net response of AMPK activation? Stimulates ATP-producing pathways and simultaneously inhibits ATP consuming pathways AMPK activation increases glucose uptake and fatty acid oxidation (some controversy – wait until next course!) 28  Exercise-Induced Insulin Sensitivity Richter et al. J Clin Invest 69(4):785-793, 1982 Hindlimb perfusion model! Exercise causes a leftward shift in the insulin dose-response curve. This indicates an improvement in insulin sensitivity. 29 Post-Exercise Insulin Sensitivity The effects of exercise on insulin sensitivity can last for several hours and can be impacted by the intensity and duration of exercise as well as post-exercise nutrition. Richter et al. J Clin Invest 69(4):785-793, 1982 30 Time Course of Glucose Uptake After Contraction Loss of contraction-stimulated glucose uptake replaced by increase in insulin stimulated glucose uptake. What’s the purpose?? Contraction stimulated glucose uptake Insulin sensitivity rest Stop exercise 31  What Effect Does Exercise Training Have on Skeletal Muscle Glucose Transport? Exercise trained rats for 2 days by swim training 6 hrs/day! mRNA expression protein content 32 Ren et al. J Biol Chem 269(20): 14396-401, 1994 Exercise Increases the Amount of GLUT4 … AND Glucose Transport The increase in GLUT4 allows for an increase insulin mediated glucose transport 33 Rapid Reversion After Cessation of Exercise! insulin-stimulated glucose uptake in rat muscle 34 What About Humans? 35 What About Humans? 36  A Single Bout of Exercise Increases Total Muscle GLUT-4 Content in Humans Cycling 1 hour at 65% VO2 max Take home point: Even a single bout of exercise increases human skeletal muscle GLUT-4 protein content Greiwe et al. 2000 37  Skeletal Muscle Glucose Uptake Summary Insulin and contraction/exercise appear to operate through distinct mechanisms (i.e. can be additive) Both involve movement of GLUT4 to plasma membrane Increase in glucose transport can persist for several hours post exercise but then subsides This is replaced by an increase in muscle insulin sensitivity (hours to days) GLUT4 protein content is rapidly increased with exercise 38