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Key Concepts the energy systems responsible for ATP generation during exercise are high energy phosphates, glycolysis and oxidative metabolism the relative ATP generating power and capacity of these energy systems are inversely related during high intensity exercise, rest-exercise transitions and prolonged endurance exercise, the contribution of the energy systems is determined by exercise intensity and duration the relative importance of CHO and fat for oxidative metabolism is determined primarily by exercise intensity and duration, with training status, preceding diet, environmental temperature, sex and age exerting modifying influences muscle glycogen and blood-borne glucose are major CHO fuels for contracting skeletal muscle muscle glycogenolysis, muscle glucose uptake, CHO oxidation and liver glucose output during exercise are influenced by intensity and duration muscle glycogenolysis is regulated by local and hormonal factors muscle glucose uptake is regulated at several steps, but increased blood flow and GLUT4 translocation reduce delivery and sarcolemmal transport as barriers liver glucose output is subject to multiple, redundant controls the interaction of pyruvate oxidation and lactate production and the importance of PDH activity in determining rate of CHO oxidation training reduces reliance on CHO as fuel source mechanisms include increased mitochondrial density and changes in hormones free fatty acids (FFA) derived from adipose tissue and muscle triglycerides are the major lipid substrate for contracting skeletal muscle key lipases (ATGL and HSL) break down adipose tissue and muscle triglycerides muscle takes up FFA via both simple and facilitated diffusion, the latter mediated transport proteins FFA availability, FFA transport capacity and muscle oxidative capacity are the major determinants of fat oxidation training increases lipid oxidation both FFA uptake and oxidation and muscle triglyceride utilisation

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Overview of Exercise Metabolism The energy systems in skeletal muscle are: high energy phosphates anaerobic glycolysis (glucose lactate) oxidative metabolism of CHO and fat (with only a very minor contribution from protein) Substrate level phosphorylayion PCr + ADP + H+ ATP + creatine (catalyzed by creatine kinase 2ADP ATP + AMP (catlaysed by adenylate kinase) Glycogen + 3ADP + 3Pi 2Lactate + H+ + 3ATP (glycolysis) Oxidative phosphorylation requires O2, ADP and Pi, and electron donors (NADH, FADH2) produced from CHO and fat metabolism Glucose + 6O2 + 36ADP 6CO2 + 6H2O + 36ATP Palmitate + 23O2 + 130ADP 16CO2 + 16H2O + 130ATP The respiratory exchange ratio (RER = VCO2/VO2) can be calculated from pulmonary gas exchange measurements of oxygen uptake (VO2) and carbon dioxide production (VCO2) to estimate the contribution of CHO and fat to oxidative metabolism: RER = 1.0 = 100% CHO (6CO2/6O2) RER = 0.7 = 100% fat (16CO2/23O2) The power of an energy system is the rate of ATP generation; the capacity is the total amount of ATP that can be produced the two parameters are inversely related: Power: PCr > Glycolysis > CHO oxidation > fat oxidation Capacity: fat oxidation > CHO oxidation > Glycolysis > PCr During the transition from rest to exercise, and from low intensity exercise to higher intensity, there is a lag in oxygen uptake (oxygen deficit) during this period the energy deficit is covered by PCr breakdown and glycolysis. During high intensity, short duration (sprint) exercise, the major energy systems are PCr and glycolysis, with a progressive rise in oxidative metabolism of glycogen. Refer to Figure 7a in the article by Michelle L. Parolin, Alan Chesley, Mark P. Matsos, Lawrence L. Spriet, Norman L. Jones, and George J. F. Heigenhauser. Regulation of skeletal muscle glycogen phosphorylase and PDH during maximal intermittent exercise. Am J Physiol Endocrinol Metab November 1, 1999 277:E890-E900: http://ajpendo.physiology.org/content/277/5/E890.long

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trans formati o n %) of Ph t o its m re cc tive a fo rm was ous studies using submaximal exercise intensi15 , 43 ).ched In the present the and hen c eo Ph osa a tivati o n. nd rea a peak (46.8 study, 5.3 the O2 max shoPrevi wn that ties ranging felevated r o m 30 to 90 % V initial 6s ofwithin bouo ts 1 and remained until s. have activati on of Phos is in excess of the estimated ux bo ut rapid 1 and elevated until 15 s. a c tivati o n of Ph o s is in ex c ess of the estimated ux 2 os s of to its m oreremained a ctive a fo rm was Previ o us studies using submaximal exer c ise intensi -f and rea c hed a peak ( 46.8 5.3 %) within the have ties ranging rom 30 to 90% V 2 max This rapid transformati on was probably due to Ca through the enzyme and that gly cogen olyti cO ux thr ough shown that 2 pid trans rmati on 5.3 was pro bably due to Ca ough the enzyme and glyco c ux thr oo ugh gen peak (fo 46.8 %) within the O olyti have sh wn that ties thr ranging fr om 30 tothat 90% V
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2 max initial 6 s of bout 1 and remained elevated until 15 s. activation of Phos is in excess of the estimated ux for high intensity exercise ! and that glycogenolytic ux through nd remained until fo 15 s. ao ctivati on pr ofFuels Ph os is in ex co ess of the thr estimated ux 2 This elevated rapid trans rmati n was o bably due t Ca ough the enzyme 2

ation was probably due to Ca

through the enzyme and that glycogenolytic ux through

Fuels for high intensity exercise!

es from PCr maximal isokinetic cycling. Fig. 7. ATP turnover rates from PCr d oxidative hydr olysis, glycolysis, and oxidative h time inter (B ) bouts ph of osphorylation during each time inter-

TP turnover rates from PCr Fig. 7. ATP turnover rates from PCr s, glycolysis, and oxidative hydr olysis, glycolysis, and oxidative ylation during each time inter rst (A ) and third (B ) bouts ph of osphorylation during each time intersokinetic cycling. val in the rst (A ) and third (B ) bouts of

val in the rst (A ) and third (B ) bouts of maximal isokinetic cycling.

M.L. Parolin et al. Am. J. Physiol. 277: E890-E900, 1999 (with permission, American Physiological Society)

M.L. Parolin et al. Am. J. Physiol. 277: E890-E900, 1999 (with permission, American Physiological Society) During more prolonged, s ubmaximal exercise, the major fuels for oxidative metabolism are muscle glycogen, blood glucose (derived from liver glycogen and gluconeogenesis, and the gut when glucose is ingested), and fatty acids derived Fuels for endurance exercise ! from triglycerides stored in the muscle and adipose tissue.
LIVER GLYCOGEN (200-400 kcal) GLUCOSE MUSCLE GLYCOGEN (1000-3000 kcal)

Fuels for endurance exercise!

Glycerol FFA

Lactate

LIVER GLYCOGEN (200-400 kcal)

MUSCLE TG (2000-3000 kcal)

GLUCOSE Lactate The relative contribution of CHO and fat is primarily determined by exercise intensity and duration. Glycerol Refer to Figure 8 in the article by J. A. RFFA omijn, E. F. Coyle, L. S. Sidossis, A. MUSCLE TG Gastaldelli, J. F. Horowitz, E. Endert, and R. R. Wolfe. Regulation of endogenous (2000-3000 kcal) fat and carbohydrate metabolism in relation to exercise intensity and duration. ADIPOSE TISSUE TG Am J Physiol Endocrinol Metab kcal) September 1, 1993 265:E380-E391: (50,000-100,000 http://ajpendo.physiology.org/content/265/3/E380.reprint Fuels for endurance exercise - intensity!

ADIPOSE TISSUE TG (50,000-100,000 kcal)

MUSCLE GLYCOGEN (1000-3000 kcal)

4!

J.A. Romijn et al. Am. J. Physiol. 265: E380-E391, 1993 (with permission, American Physiological Society)

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J.A. Romijn et al. Am. J. Physiol. 265: E380-E391, 1993 (with permission, American Physiological Society)

Refer to Figure 3 in the article by Damien J. Angus, Mark A. Febbraio, and Mark Hargreaves. Plasma glucose kinetics during prolonged exercise in trained humans when fed carbohydrate. Am J Physiol Endocrinol Metab September 1, 2002 283:E573-E577: http://ajpendo.physiology.org/content/283/3/E573.long Fuels for endurance exercise - duration!

D.J.$Angus$et$al.$$Am.$J.$Physiol.$283:$573:577,$2002$ (with$permission,$American$Physiological$Society)$ Factors influencing substrate metabolism during exercise: exercise intensity exercise duration training status preceding diet environmental temperature sex age These effects are mediated by substrate availability, hormone levels and the biochemical characteristics of skeletal muscle. CHO Metabolism During Exercise Muscle glycogen and blood-borne glucose (derived from liver glycogen and gluconeogenesis, and the gut when glucose is ingested) are the key CHO substrates utilized during exercise. Lactate, a breakdown product of glycolysis (derived from glycogen and glucose), is a substrate for oxidation within skeletal muscle, as well as for gluconeogenesis in the liver. Again, the major determinants of the rates of muscle glycogen use and glucose uptake are exercise intensity and duration. Muscle glycogenolysis (breakdown) is catalyzed by the enzyme glycogen phosphorylase which is regulated by local factors within the contracting skeletal muscle and the circulating hormone adrenaline.

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Regulation of muscle glycogenolysis during exercise: calcium inorganic phosphate circulating adrenaline muscle [glycogen] blood FFA availability temperature Following endurance training, muscle glycogen use is reduced lower aerobic utilization and lactate production. Major sites of regulation of glucose uptake during exercise: delivery blood flow and [glucose] sarcolemmal glucose transport GLUT4 translocation, glucose gradient metabolism activation of glycolytic and oxidative enzymes Increased muscle blood flow and rapid GLUT4 translocation during exercise, essentially remove delivery and transport as limiting factors. Regulation of muscle glucose uptake during exercise: increased muscle blood flow and glucose delivery GLUT4 translocation to sarcolemma (and t-tubules) increased glucose disposal notably increased hexokinase activity blood [glucose] FFA availability?? glucose fatty acid cycle muscle [glycogen] insulin (additive to exercise) adrenaline?? Contraction signaling to glucose transport (GLUT4 translocation) during exercise: calcium CaMKII, PKC AMPK nitric oxide reactive oxygen species Following endurance training, glucose uptake and oxidation by skeletal muscle are reduced. The pattern of liver glucose output during exercise is very similar to that of muscle glucose uptake, being influenced by both exercise intensity and duration. Most of the glucose output is derived from liver glycogenolysis as exercise duration increases, there is a greater contribution from gluconeogenesis.

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Regulation of liver glucose output during exercise: feedforward and feedback mechanisms decreased insulin increased glucagon increased adrenaline sympathetic nerves?? liver [glycogen] blood [glucose] The rate of carbohydrate oxidation during exercise is related to the activity of the pyruvate dehydrogenase enzyme complex its activation is related to exercise intensity and duration. Muscle and blood lactate increase exponentially during exercise of increasing intensity. Regulation of lactate metabolism during exercise: production is determined by the balance between rates of pyruvate formation and oxidation blood lactate levels are determined by the rates of lactate production and clearance muscle oxidative capacity LDH isoenzyme profile oxygen supply to contracting skeletal muscle adrenaline muscle [glycogen] Fat Metabolism During Exercise Fatty acids, derived from adipose tissue triglycerides and transported in the plasma bound to albumin and from intramuscular triglycerides, are the key fat substrates for contracting skeletal muscle during exercise. Fatty acids from triglycerides within circulating chylomicrons and very low density lipoproteins only contribute to a very small extent. Initially, the intramuscular triglycerides are utilized and there is a progressive increase in plasma fatty acid oxidation if the mobilization of fatty acids into the blood is inhibited, there is a greater reliance on intramuscular triglycerides. Glycerol is released into the circulation from both adipose tissue and contracting skeletal muscle and is often used as a measure of overall lipolysis. Triglycerides are broken down by lipases that are generally specific for triglycerides (adipose triglyceride lipase ATGL), diglycerides (hormone sensitive lipase HSL) and monoglycerides (monoglyceride lipase MGL). Both ATGL and HSL are regulated by phosphorylation.

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Regulation of adipose tissue lipolysis during exercise: mediated by ATGL and HSL -adrenergic stimulation decreased plasma insulin adipose tissue blood flow FFA/albumin ratio blood [glucose] and [lactate] caffeine Regulation of skeletal muscle lipolysis during exercise: mediated by ATGL and HSL -adrenergic stimulation (via PKA) calcium via ERK blood [glucose] plasma FFA availability For many years it was thought that fatty acid uptake into contracting skeletal muscle occurred by simple diffusion; however, it has become clear that there is a major component that occurs by facilitated diffusion, mediated via a number of fatty acid transporters. Determinants of skeletal muscle fatty acid uptake during exercise: arterial plasma [FFA] ability of muscle to oxidise fatty acids sarcolemmal, cytosolic and mitochondrial fatty acid transporters (FABP, FAT/CD36, FATP) carnitine and CPT activity -oxidative capacity mitochondrial density and HAD activity Carnitine is critical for the transport of long chain fatty acids into the mitochondria and interacts with the enzymes CPT and CAT. There is also evidence that the fatty acid transporter FAT/CD36 is also involved in the mitochondrial uptake of fatty acids. Medium chain triglycerides (MCTs) do not rely on the carnitine-CPT system and can be taken up directly by the mitochondria for this reason there has been interest in including MCTs in sports supplements to enhance fat oxidation, although results are equivocal and they can cause gastrointestinal distress at higher concentrations. Carnitine is at the crossroads of CHO and fat metabolism and can act as a buffer for acetyl units generated during high rates of carbohydrate breakdown, resulting in increased acetylcarnitine and reduced free carnitine this is one potential explanation for the reduction in fat oxidation at higher exercise intensities when there is a greater reliance on CHO.

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Why is fat oxidation reduced with increasing exercise intensity? reduced plasma fatty acid availability associated with reduced adipose tissue blood flow which impairs fatty acid mobilization increased glycolytic flux inhibits CPT activity and mitochondrial fatty acid uptake due to increased malony-CoA and decreased pH reduced carnitine availability oxidation of CHO requires less oxygen for given ATP production Following endurance training, there is increased fat oxidation both plasma FFA and intramuscular triglyceride oxidation are increased. Muscle adaptations that facilitate increased fat oxidation include: increased mitochondrial density and HAD activity increased expression of sarcolemmal, cytosolic and mitochondrial fatty acid transporters increased CPT activity Reading Jeukendrup, A.E. Performance and endurance in sport: can it all be explained by metabolism and its manipulation? Dialogues in Cardiovascular Medicine. 17: 40- 45, 2012. http://www.dialogues-cvm.com/past-issues/2012_17_1/63_04/ Discussion Topic Carbohydrate availability and utilization are critical for strenuous (>75% Wmax) exercise. Abbreviations ADP adenosine diphosphate AMP adenosine monophosphate AMPK AMP-activated protein kinase ATGL adipose triglyceride lipase ATP adenosine triphosphate CaMKII CAT CHO CoA CP (PCr) CPT Cr ERK calcium/calmodulin-dependent kinase II carnitine acyltranferase carbohydrate co-enzyme A creatine phosphate (phosphocreatine) carnitine palmitoyltransferase creatine extracellular signal-regulated kinase

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ETC FABPc FADH2 FAT/CD36 FATP FFA FT G-1-P G-6-P GLUT4 Gly GLY GNG HAD HSL IM IMTG LDH LFA LT MCT NAD NADH NO OM PDC PDH PKA PKC PM Rd Rox ROS SR ST TCA TG

electron transport chain. fatty acid binding protein (cytosolic) flavin adenine dinucleotide fatty acid transporter fatty acid transport protein free fatty acid fast twitch fibre glucose-1-phosphate glucose-6-phosphate glucose transporter isoform 4 glycogen glycogenolysis gluconeogenesis -hydroxy acyl-CoA dehydrogenase hormone sensitive lipase inner mitochondrial membrane intramyocellular triglyceride lactate dehydrogenase long chain fatty acid lactate threshold monocarboxylate transporter oxidised nicotinamide adenine dinucleotide reduced nicotinamide adenine dinucleotide nitric oxide outer mitochondrial membrane pyruvate dehydrogenase complex pyruvate dehydrogenase protein kinase A protein kinase C plasma membrane rate of disappearance/disposal rate of oxidation reactive oxygen species sarcoplasmic reticulum slow twitch fibre tricarboxylic acid triglyceride/triacylglycerol

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The University of Melbourne - 2013