G Model YPRRV 687 1–8

Paediatric Respiratory Reviews xxx (2009) xxx–xxx

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

12 Mini-symposium 3

4 Bioenergetic provision of energy for muscular activity Greg D. Wells 1,*, Hiran Selvadurai 2, Ingrid Tein 3 5 6 1 Department of Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Canada & Department of Anesthesiology, The Toronto General Hospital, Canada 7 2 Paediatrics & Child Health, Children’s Hospital, Westmead, Canada 8 3 Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada

ARTICLE INFO SUMMARY

Article history: A complex series of metabolic pathways are present in human muscle that break down substrates from Available online xxx nutritional sources to produce energy for different types of muscular activity. However, depending on the activity in which an individual is engaged, the body will make use of different energy systems that Keywords: have been adapted for the particular activity. More specifically, utilization of bioenergetic substrates Q1 depends on the type, intensity, and duration of the exercise. The aerobic oxidative system is used for physiology longer duration activities of low to moderate intensity, the anaerobic glycolytic system is used for short aerobic to moderate duration activities of higher intensity, and the high energy phosphagen system is used for anaerobic short duration activities of high intensity. The efficiency and effectiveness of these pathways can be respiratory enhanced through physical activity and training. It is these bioenergetic pathways that are the focus of this review. ß 2009 Published by Elsevier Ltd. 8 9 31 INTRODUCTION can be enhanced through physical activity and training. It is these 32 10 bioenergetic pathways that are the focus of this review. 33 11 Humans are capable of performing amazing feats. Sprinters run 12 down the track with astonishing speed and power; power lifters AN OVERVIEW OF MUSCLE PHYSIOLOGY 13 make hundreds of kilograms look like a sack of potatoes; 34 14 swimmers traverse an entire lake or channel against the elements; Muscle tissue - the contraction specialist - provides a prime 35 15 hurdlers gracefully clear all obstacles in their way; and some example of how the structure of a tissue is well-adapted to perform 36 16 basketball players even seem to defy the laws of gravity. Before a specific function. With approximately 324 muscles, and with 37 17 muscles can produce movement by pulling on their attachments to muscle constituting 30-35% and 42-47% of body mass in women 38 18 bones, they must first obtain a source of energy to sustain such a and men, respectively the importance of muscular activity is 39 19 movement. A complex series of metabolic pathways are present in obvious. The various types of muscle tissue support numerous life 40 20 human muscle that break down substrates from nutritional functions such as ventilation, physical activity and exercise, 41 21 sources to produce energy for different types of muscular activity. digestion, and of course, pumping life-sustaining blood throughout 42 22 However, depending on the activity in which an individual is the body via specialized cardiac muscle. (also 43 23 engaged, the body will make use of different energy systems that termed striated muscle) connects the various parts of the skeleton 44 24 have been adapted for the particular activity (see Fig. 1).1 More through one or more connective tissue tendons and is the type of 45 25 specifically, utilization of bioenergetic substrates depends on the muscle used to produce movement during exercise. During muscle 46 26 type, intensity, and duration of the exercise.2 The aerobic oxidative contraction, skeletal muscle shortens and, as a result of the 47 27 system is used for longer duration activities of low to moderate tendinous attachments, functions to move the various parts of the 48 28 intensity, the anaerobic glycolytic system is used for short to skeleton with respect to one another via joints. This allows changes 49 29 moderate duration activities of higher intensity, and the high in position of one skeletal segment in relation to another, thus 50 30 energy phosphagen system is used for short duration activities of creating movement. Skeletal muscle is comprised of numerous Q251 31 high intensity. The efficiency and effectiveness of these pathways multinucleated cylinder-shaped cells called muscle fibres (myofi- 52 brils), and each fibre is made up of a number of myofilaments. 53 UNCORRECTEDPhysically, they PROOF range in size from under a hundred microns in 54 diameter and a few millimeters in length to a few hundred microns 55 * Corresponding author. Division of Respiratory Medicine, Rm. 4534, The Hospital across and a few centimetres in length. Each cell (fibre) is 56 for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. 57 Tel: +1 416 710 4618; Fax: +1 416 813 5109. surrounded by a connective tissue sheath called the sarcolemma, E-mail addresses: [email protected] (G.D. Wells), and a variable number of fibres are enclosed together by a thicker 58 [email protected] (H. Selvadurai), [email protected] (I. Tein). connective tissue sheath (the perimysium) to form a bundle of 59

1526-0542/$ – see front matter ß 2009 Published by Elsevier Ltd. doi:10.1016/j.prrv.2009.04.005

Please cite this article in press as: Wells GD, et al. Bioenergetic provision of energy for muscular activity. Paediatr. Respir. Rev. (2009), doi:10.1016/j.prrv.2009.04.005 G Model YPRRV 687 1–8

2 G.D. Wells et al. / Paediatric Respiratory Reviews xxx (2009) xxx–xxx

Figure 1. Contributions of the three energy systems to activities of different durations and power outputs. 59

60 fibres called fascicles. Each fibre contains not only the contractile Figure 2. An electron micrograph of the inside of a muscle fibre. The actin and 61 machinery needed to develop force (sarcomeres), but also the cell myosin filaments, mitochondria (white arrows) and lipid droplets (black arrows) 62 organelles necessary for (mitochondria). Each are clearly visible (Images courtesy of M. Tarnopolski). 63 fibre is activated through electrical impulses transmitted by 91 64 nerves, the motor nerves and motoneurons in particular. A group of fibres. Each of the fibre types can be described on the basis of its 92 65 fibres activated via the same nerve is termed a motor unit. Also predominant metabolic pathway by which it derives energy, with 93 66 located outside each fibre is a supply of capillaries from which the the type I slow twitch fibres being described as oxidative (Type I or 94 67 cell obtains nutrients and eliminates waste. SO), and the fast twitch fibres being subdivided into two sub- 95 68 Within each myofibril, a number of contractile units called groups, fast twitch oxidative-glycolytic (Type IIa or FOG) and fast 96 69 sarcomeres, are organized in series, i.e., attached end to end. Each twitch glycolytic (Type IIb or FG). Each of the three fibre types 97 70 sarcomere is comprised of three types of protein myofilaments: the described above have distinctive morphological, contractile, and 98 71 thick filament system is composed of myosin protein which is metabolic characteristics (see Table 1). 99 72 connected from the M-line to the Z-disc by the protein titin. It also 73 contains myosin-binding protein C which binds at one end to the THE CHEMISTRY OF ENERGY PRODUCTION IN HUMAN MUSCLE 74 thick filament and the other end to the protein actin. The thin 100 75 filaments are assembled by actin monomers bound to nebulin, in a All energy in the human body is derived from the breakdown of 101 76 process that also involves tropomyosin. Nebulin and titin give complex nutrients such as carbohydrates, fats, and proteins.3 The 102 77 stability and structure to the sarcomere (see Fig. 2). When a signal end result of the breakdown of these substances is the production 103 78 comes from the motor nerve activating the fibre, the neurotrans- of the (ATP) molecule, the energy currency 104 79 mitter acetylcholine is released and travels across the neuromus- of the body. ATP provides all the energy for fuelling biochemical 105 80 cular junction. The action potential then travels along T processes of the body such as muscular work or the digestion of 106 81 (transverse) tubules until it reaches the sarcoplasmic reticulum. food. The capacity to perform muscular work (work = force exerted 107 82 The action potential from the motor neuron changes the x distance moved) is dependent on supplying sufficient energy at 108 83 permeability of the sarcoplasmic reticulum, allowing the flow of the required rate for the duration of the activity. 109 84 calcium ions into the sarcomere. Outflow of calcium from the Energy is liberated for work when the chemical bond between 110 85 sarcoplasmic reticulum allows the heads of the myosin filaments ATP and its sub-group is broken through hydrolysis 111 86 to temporarily attach themselves to the actin filaments, a process when catalyzed by the enzyme ATPase: 87 termed ‘‘cross bridge formation’’. The movement of the cross ATPbreakdown : ATP þ!ADP þ Pi þ Energy (1) 88 bridges causes a movement of the myosin filaments in relation to 112113114 89 the actin filaments, leading to shortening of the sarcomere, and ATP is broken down in a process called ‘‘ATP turnover’’. Water 115

90 muscle contraction. Human skeletal muscle is composed of a (H2O) hydrolyzes the unstable chemical bonds of the phosphate 116 91 mixture of two contractile fibre types: slow twitch and fast twitch groups of the ATP molecule, yielding an inorganic phosphate 117

Table 1 Functional Characteristics of Human Muscle Fibres

Fibre Type Type I Type IIa Type IIb

Alternate name Slow Oxidative Fast Oxidative Glycolytic Fast Glycolytic Primary source af ATP AerobicUNCORRECTED Oxidation Aerobic Oxidation & AnaerobicPROOF Anaerobic Glycolysis Myosin- ATPase activity Low High High Glycolytic enzyme content Low Intermediate High Glycogen content Low Intermediate High Number of mitochondria High High Low Myoglobin content High Intermediate Low Capillary density High Intermediate Low Speed of contraction Slow Fast Fast Rate of fatigue Slow Intermediate Fast

Please cite this article in press as: Wells GD, et al. Bioenergetic provision of energy for muscular activity. Paediatr. Respir. Rev. (2009), doi:10.1016/j.prrv.2009.04.005 G Model YPRRV 687 1–8

G.D. Wells et al. / Paediatric Respiratory Reviews xxx (2009) xxx–xxx 3

Table 2 Characteristics of the 3 energy systems

Characteristic High energy phosphate Anaerobic glycolytic Aerobic oxidative

Fuel source(s) stored ATP, phosphocreatine (PCr) stored glycogen, blood glucose glycogen, glucose, fats, proteins Enzyme sytem used in breakdown ATPase HK, PFK, LDH, PDH, others CS, MDH, SDH, others Muscle fibre type(s) recruited Type I, Type IIa, Type IIb Type I, Type IIa, Type IIb Type I, Type IIa Power output requirement high moderate - high low - moderate Metbolic byproducts ADP, P, Cr CO2, H2O maximum rate of ATP production (mmol/min) 3.6 1.6 1 Time to maximal ATP production 1 sec 5-10 sec 2-3 min Maintenance time of maximal ATP production 6-10 sec 20-30 sec 3 min Time to exhaustion of system 12-15 sec 45-90 sec theoretically unlimited Ultimate limiting factor(s) Depletion of ATP/PCr stores Lactic acid accumulation Depletion of carbohydrate stores, insufficient oxygen, heat accumulation Time for total recovery (sec) 3 min 1-2 hr 30-60 min Time for one half recovery (sec) 20-30 sec 15-20 min 5-10 min

Relative % ATP contribution to efforts of 10 sec 50 35 15 Relative % ATP contribution to efforts of 30 sec 15 65 20 Relative % ATP contribution to efforts of 2 min 4 46 50 Relative % ATP contribution to efforts of 10 min 1 9 90

117 136 118 molecule (Pi) and (ADP). The released reactions below: 119 energy is about 38-42 kilojoules (kJ) or 9-10 kilocalories (kcal) per ATPresynthesis : ADP þ Pi þ energy ! ATP (2) 120 mole of ATP.4 137138 121 The body harnesses this energy when the free Pi group is ATPresynthesis : PCr þ ADP þ energy ! ATP þ Cr (3) 122 transferred to another molecule. When this other molecule is 139140141 123 joined with the new free phosphate group, it is said to be The regeneration of ATP, however, requires energy. This energy 142 124 phosphorylated. All muscular work done in the body depends upon is supplied by the breakdown of complex food molecules such as 143 125 these phosphorylated molecules. For example, ATP powers the carbohydrates and fats in metabolic energy systems of the human 144 126 movement of muscles by transferring to contractile body. These energy systems will now be presented in more detail. 145 127 proteins, which leads to the contraction of muscle fibres.4 128 When the body performs work, it needs a continuous supply of THE ENERGY SYSTEMS 129 ATP, but the initial stores of ATP in the muscles are used up very 146 130 quickly. Therefore, ATP must be regenerated. ATP is a renewable The turnover and resynthesis of ATP involves three energy 147 131 resource that can be regenerated by the recombination of ADP and systems, each of which employs a different means of energy 148 132 Pi. The metabolic process that results in the recombination of ADP production. These energy systems are (1) the high-energy 149 133 and Pi to form ATP is termed ATP resynthesis (see Eq. (2)). ATP can phosphagen system, (2) the anaerobic glycolytic system, and (3) 150 134 also be resynthesized through the combination of phosphocreatine the aerobic oxidative system (Table 2 and Fig. 3). These sources of 151 135 (PCR) and ADP as shown in Eq. (3). This reaction can occur at a very energy for muscular contraction and other types of work are 152 136 fast pace in the body. The resynthesis of ATP is described in the designated as aerobic or anaerobic, depending on whether they 153

UNCORRECTED PROOF

Figure 3. A general representation of aerobic, anaerobic and high energy phosphate bioenergetic pathways.

Please cite this article in press as: Wells GD, et al. Bioenergetic provision of energy for muscular activity. Paediatr. Respir. Rev. (2009), doi:10.1016/j.prrv.2009.04.005 G Model YPRRV 687 1–8

4 G.D. Wells et al. / Paediatric Respiratory Reviews xxx (2009) xxx–xxx 153 154 require the presence of oxygen to provide energy. The high-energy 155 phosphagen and the anaerobic glycolytic systems do not use 156 oxygen. The aerobic oxidative system depends on oxygen to 157 produce energy. The three bioenergetic systems that are used in 158 human physiology to produce energy for muscular activity are 159 explained in detail in the following sections.

The High-Energy Phosphate System 160 161 The high-energy phosphate system (also known as the 162 phosphagen or anaerobic alactic system) is characterized by the 163 substrates that the system uses to produce energy. This system can 164 provide energy for muscles in the initial 1 to 15 seconds of high 165 intensity activity.5 The high-energy phosphate substrates that are 166 the primary energy source for the high-energy phosphate system 167 are adenosine triphosphate (ATP) and phosphocreatine (PCr). 168 During the initial stages of high intensity exercise, ATP is broken 169 down via the enzyme ATPase, and phosphocreatine is broken down 170 via the enzyme creatine kinase to supply inorganic phosphate for 171 ATP resynthesis (Eqs. (2) and (3), respectively).6 172 The high-energy phosphate system can produce very large 173 amounts of energy in a short duration of time (from 2.4 mmol/kg/s 174 in sedentary people to 10-15 mmol/kg/s in athletes).7,14 The high- 175 energy phosphate system can supply energy until the intramus- 176 cular stores of ATP are decreased and, thereafter, for as long as 177 there is a local supply of phosphocreatine to resynthesize ATP from 178 ADP. The total muscle stores of ATP (3.5-7.5 mmol/kg) and creatine 179 phosphate (16-28 mmol/kg) are small and are depleted rapidly in 180 high intensity work.7,14 Therefore, the initial concentrations of 181 high-energy phosphates in the muscle are limiting factors in an 182 individual’s ability to perform short-term high intensity work. 183 Once the stores of phosphocreatine are depleted, ATP resynthesis 184 must occur through anaerobic glycolysis or aerobic oxidation, and 185 the power output drops accordingly. 186 The high-energy phosphate system is the primary energy 187 system that is used in sporting events such as weight lifting, high 188 jump, long jump, 100-metre run, or 25-metre swim. These high 189 power output activities require a high rate of energy production as Figure 4. The steps of anaerobic glycolysis. Adapted from McArdle W D et al., 190 the work is done over a short time interval (power = work / time). It 200714. 191 is also used for high intensity activities of daily living such as 192 jumping, or short runs. If individuals are to continue the activity 193 beyond a 15-second period, they must produce energy from 215 194 another system at a lower power output. steps of the anaerobic glycolytic pathway13 (see Fig. 4). This 216 195 Training may result in changes in levels of stored ATP and PCr in biochemical process results in the release of energy in the form of 217 196 muscle. Strength training (repeated muscular efforts against a ATP, which is then used for muscle contraction. During glycolysis 218 197 resistance or opposing force) may result in increases of approxi- certain enzymes break down the chemical bonds in glucose in the 219 198 mately 20% in ATP, and PCr.8 Sprint training (short high intensity absence of oxygen (hence the term anaerobic). Each molecule of 220 199 intervals separated by long rest periods) does not appear to result glucose ultimately yields 2 lactic acid molecules and 2 molecules of 221 200 in increased stores of ATP or PCr.9 Strength and sprint training ATP, the latter is then used for muscle contraction. 222 201 modalities also appear to affect the enzymes associated with the Although the peak rate of energy production is high (1.6 mol 223 202 high energy phosphate system, more specifically ATPase and ATP . min-1), the system is inefficient, as only 2 mols of ATP are 224 203 creatine kinase.10–12 produced for every one mol of glucose that is broken down.14 Most 225 of the energy generated in glycolysis does not result in ATP 226 The Anaerobic Glycolytic System resynthesis. Instead it is dissipated as heat. Further, two molecules 227 204 of ATP contribute to the initial of the glucose 228 205 The body relies primarily on anaerobic metabolism for the molecule, glycolysis generates a net gain of two ATP molecules. 229 206 energy required to perform intensive exercise of greater than 12- This represents an endergonic conservation of 14.6 kcal/mol. 230 207 15 seconds and less than 3 minutes duration.4 Anaerobic glycolysis Glycolysis generates only about 5 % of the total ATP generated 231 208 is the primary energy system that is used in sportingUNCORRECTED events such as during the complete PROOF breakdown of the glucose molecule. However, 232 209 the 800-metre run, 200-metre swim, downhill ski racing, and owing to the high concentration of glycolytic enzymes and the 233 210 1500-metre speed skating and in other activities such as sprints speed of these reactions, significant energy for muscle action is 234 211 during soccer or hockey games. Metabolically, energy production generated rapidly during glycolysis.14 Further, when the rate of 235 212 via glycolysis is accomplished in the cytoplasm of skeletal muscle muscle work is high, pyruvate can accumulate faster than the 236 213 by the catabolism of carbohydrate, in the form of blood glucose or aerobic oxidative system can process, and is then converted into 237 214 muscle glycogen (the storage form of glucose, consisting of many lactic acid. The conversion of pyruvate to lactic acid production is 238 215 molecules of glucose), to pyruvate.3 through 10 separate but linked used to maintain the rate of anaerobic glycolysis and energy 239

Please cite this article in press as: Wells GD, et al. Bioenergetic provision of energy for muscular activity. Paediatr. Respir. Rev. (2009), doi:10.1016/j.prrv.2009.04.005 G Model YPRRV 687 1–8

G.D. Wells et al. / Paediatric Respiratory Reviews xxx (2009) xxx–xxx 5 239 279 240 production.15 This process has recently been reviewed16 and was maximal efforts alternating with 2-3 minutes of rest) can increase 280 241 the subject of a comprehensive symposium.17 the rate of flux through the glycolytic pathway, thus increasing the 281 242 The exercise intensity at which lactic acid begins to accumulate ATP production rate, but also increasing the rate of lactic acid 282 243 within the blood has been commonly referred to as the anaerobic production.21 This increased flux through the glycolytic pathway is 283 244 threshold.18 In practical terms, the anaerobic threshold can be accomplished through upregulation of anaerobic enzymes. Muscle 284 245 thought of as the point during exercise when the person begins to and blood buffering capacity can also be increased through 285 246 feel discomfort and a burning sensation in their muscles. It can be anaerobic sprint or interval training.22 Trained individuals have 286 247 identified during clinical incremental exercise tests as the point also been shown to remove lactate faster from exercising muscle, 287

248 when carbon dioxide production (VCO2) exceeds oxygen con- suggesting an increase in the number and/or efficiency of the 288 249 sumption (VO2) with the resulting respiratory exchange ratio (RER) lactate transporters present in the specific muscle tissue (Type I or 289 250 greater than one. Some investigators believe that accumulation of Type II).23 Aerobic endurance training can also increase the rate of 290 251 lactic acid, which breaks down into lactate and hydrogen ions, will lactate elimination by increasing the rate of pyruvate processing in 291 252 eventually contribute to . However, this would not the Krebs cycle in mitochondria. This increases the work rate that 292 253 account for the muscle fatigue, cramps and contractures seen can be achieved exclusively through aerobic metabolism, and thus 293 254 during high-intensity, short-burst exercise in people with glyco- decreases the production of lactic acid for a given work level.24 294 255 lytic/glycogenolytic disorders, in which glycolysis, and thus lactate Aerobic endurance training can result in other adaptations that can 295 256 production, is blocked. Thus, there are likely many different lead to an increased rate of lactate removal from the muscle 296 257 variables in the microenvironment of the muscle that contribute to following training, including increased muscle blood flow and 297 258 muscle fatigue under different conditions. For example, hydrogen increased ability to metabolize lactate in the heart, the liver and in 298 259 ions may interfere with the actin-myosin coupling and thereby non-working muscle. Blood flow is increased in trained individuals 299 260 ultimately impede muscle contraction. Further, the pH change through an increase in the number of blood vessels in the muscle, 300 261 associated with the accumulation of hydrogen ions may decrease altered neural and endocrine function, more red blood cells, 301 262 the rate of glycolysis through its effect on the rate-limiting enzyme greater total blood volume, and increased cardiac output.25 302 263 phosphofructokinase (PFK). These mechanisms are reviewed in 264 detail elsewhere.19 The Aerobic Oxidative System 265 Lactic acid accumulation is a commonly measured variable in 303 266 sports physiology and typical values range from 2 mmol/L at rest, The aerobic oxidative energy system is a very important energy 304 267 to 4 mmol/L in moderate sustainable exercise to 16 mmol/L in system in the human body, as it is the primary source of energy for 305 268 maximal (i.e. 2 minute maximal effort sprint- a very broad range of activities. Daily activities such as walking, 306 269 ing). Efficient lactate removal from the Type II glycolytic muscle jogging, swimming, household chores, and walking up stairs all use 307 270 fibres, where lactic acid is predominantly produced, to Type I energy provided by the aerobic oxidative system. Exercise that is 308 271 oxidative fibres, where lactate can be oxidized in mitochondria, performed at an intensity lower than that of the anaerobic 309 272 can allow individuals to continue to exercise at higher intensities threshold relies exclusively on the aerobic system for energy 310 273 for longer periods of time. This transfer of lactic acid in and out of production. Thus, blood lactate levels remain relatively low (2– 311 274 muscle fibres is accomplished via monocarboxylate lactate 6 mmol/L blood) during purely aerobic exercise. As the duration of 312 275 transporters on the surface of the muscle cell.20 A graphical intensive activity increases, the relative contribution of the aerobic 313 276 representation of the physiology of lactic acid transport is oxidative system to total energy production increases (see Fig. 1).26 314 277 presented in Fig. 5. During intense exercise, well trained individuals can elevate their 315 278 Exercise training has significant effects on the anaerobic rate of oxygen consumption up to 20 times above resting values.27 316 279 glycolytic system. High intensity interval training (e.g. 60 second Under conditions of heavy exercise, the skeletal muscle cells set 317

UNCORRECTED PROOF

Figure 5. Representation of lactate transport metabolism in different muscle fibre types. Adapted from20.

Please cite this article in press as: Wells GD, et al. Bioenergetic provision of energy for muscular activity. Paediatr. Respir. Rev. (2009), doi:10.1016/j.prrv.2009.04.005 G Model YPRRV 687 1–8

6 G.D. Wells et al. / Paediatric Respiratory Reviews xxx (2009) xxx–xxx

Figure 6. A graphical representation of the steps in the Krebs cycle. Krebs cycle substrates are presented in black, enzymes are indicated in green, and metabolic by-products in blue.

317 353

318 the aerobic demand for oxygen, as 90% of the oxygen in the body is oxygen flux (VO2) can be thought of as current, and total oxygen 354 319 consumed in the mitochondria in the muscle cell. The aerobic transport (cardiac output) as voltage. Since voltage = current x 355

320 energy system is the primary energy system that is used in exercise resistance, the equation becomes VO2 = cardiac output x (arterial- 356 321 provided that (a) the working muscles have sufficient mitochon- venous O2 difference). The relative contribution of the individual 357 322 dria to meet energy requirements, (b) sufficient oxygen is supplied steps in the respiratory pathway has been a subject of some debate, 358 323 to the mitochondria, and (c) enzymes or intermediate products do however, using the above electrical circuit model, it has been 359 324 not limit the rate of energy flux through the Kreb’s cycle and shown that for humans exercising in normoxia, approximately 75% 360

325 respiratory chain – the bioenergetic pathways that produce ATP of VO2max is set by central O2 transport and the remaining 25% by 361 326 within the mitochondria. the periphery.28 Thus, it is now generally accepted that it is the 362 327 The pathway for oxygen transport involves three main integrated, interactive steps in the respiratory pathway that help 363 27 328 structures; the lungs, the circulation, and the muscle. Oxygen set VO2max. 364 329 follows a simple linear pathway without branches. Respiration is a In human muscle mitochondria, a complex biochemical 365 330 regulated process matched to the instantaneous demands of process known as oxidative phosphorylation is used to 366

331 aerobic metabolism: as muscle ATP consumption increases, O2 resynthesize ATP. Mitochondria are energy-generating orga- 367 332 demand is increased proportionally.27 Increases in oxygen trans- nelles in the muscle fibres that contain a system of enzymes, 368 333 port that occur during exercise are brought about as a result of an coenzymes, and activators that carry on the oxidation of 369 334 increase in ventilation and uptake of oxygen into the blood, an nutrients and release ATP for use in aerobic work. Oxidative 370

335 increased cardiac output and O2 transport by the blood, and an phosphorylation consists of pathways that include the Krebs 371 336 increased extraction of O2 by the muscle due to increased O2 (also known as the citric acid) cycle (see Fig. 6) and the electron 372 337 metabolism in the mitochondria. Respiration is a limited function, transport chain. The processes combine ADP and Pi through 373 338 and the limit of the maximal rate of oxygen that can be consumed biochemical steps in the presence of oxygen to synthesize ATP. 374

339 to produce energy in the muscle is termed VO2max. Any additional Both carbohydrates (glycogen and glucose) and fats (triglycer- 375 340 energy requirements beyond that intensity will be fulfilled via ides and fatty acids) provide molecules that are used in oxidative 376

341 anaerobic metabolism. VO2max is higher in athletes than non- phosphorylation. The system is highly efficient; the energy yield 377 342 athletes, and to an extent is malleable and can be elevated by from the metabolism of glucose as the substrate is 36 ATP 378 343 training.27 molecules in conditions of adequate oxygen supply (18 times the 379 344 Further, the pathway for oxygen transport from the environ- yield from the anaerobic system). Fats are an important energy 380 345 ment to the mitochondria in the skeletal muscle cells is linear. The source for athletic events that require large outputs of energy 381 346 actual process of respiration is the integratedUNCORRECTED function involving over a long period PROOF of time. For example, the oxidation of an 18- 382 347 the coordinated action of all of the structures that make up the carbon fatty acid molecule produces 147 molecules of ATP. Water 383

348 pathway for delivery of O2 from the lungs to the respiratory chain and carbon dioxide are given off as by-products of this reaction. 384 349 enzymes in the mitochondria of the muscle cell.27 A metaphor for Fats are an ideal molecule for storage of energy (each gram of 385 350 understanding the respiratory pathway can be developed using an lipid yeilds approximately 9.4 kilocalories of energy, more than 386 351 electric circuit as the example. In this case the individual steps can twice the amount found in carbohydrates or proteins. A normal 387 352 be viewed as resistors in series, and the total resistance can be person has enough energy stored as fats to run hundreds of miles, 388

353 estimated by the difference in arterial and venous O2 levels. The but only enough stored carbohydrate to run about 20 miles! In 389

Please cite this article in press as: Wells GD, et al. Bioenergetic provision of energy for muscular activity. Paediatr. Respir. Rev. (2009), doi:10.1016/j.prrv.2009.04.005 G Model YPRRV 687 1–8

G.D. Wells et al. / Paediatric Respiratory Reviews xxx (2009) xxx–xxx 7

Figure 7. The oxygen transport pathway and related adaptations to aerobic endurance training.

389 421422 390 addition to the efficient provision of energy for muscular 2. Increased vascularization (number of blood vessels and 423 391 contraction, the aerobic system is used to re-establish cellular capillaries) within skeletal muscle26 and heart muscle.33 424 392 homeostasis in muscle tissue after intensive exercise bouts. More Increased capillarization is a benefit as it allows for a greater 425 393 specifically, removal of lactic acid from muscle tissue is surface area and reduced distance between the blood and the 426 394 accomplished largely via conversion of lactate back to pyruvate surrounding tissues, thus increasing diffusion capacity of 427 395 and then subsequent processing of pyruvate in the Krebs cycle. oxygen and carbon dioxide, as well as easing the transport of 428 396 The lactic acid, once produced in type II muscle fibres, is actively nutrients to cells.34 429430 397 transported into the blood and into type I fibres where lactate can 3. Decreased blood pressure.35 431432 398 be metabolized back to . 4. Increased total blood volume36 and the number and total 433 399 Endurance exercise is the method of training that is most volume of red blood cells through stimulation of erythropoiesis 434 400 effective for eliciting adaptations in the aerobic oxidative energy (formation of new red blood cells) in the bone marrow.37 435436 401 system. It consists of sustained low to moderate intensity activity 5. Increased number and size of mitochondria within the muscle 437 402 (50–75% of maximum heart rate) of long duration, typically in fibres.38,39 438439 403 excess of 20 minutes and as long as several hours. Aerobic 6. Increased activity of aerobic enzymes such as AMP kinase40 and 440 404 endurance exercise stimulates positive adaptations throughout the Krebs cycle enzymes38 which can be observed as an increased 441

405 entire cardiovascular system, making it an excellent intervention arterial-venous O2 difference, and 442443 406 for improving health and performance and for preventing or even 7. Preferential use of fats over glycogen during exercise.41 444 407 treating various diseases, particularly obesity29 and Type II In summary, aerobic endurance training stimulates many positive 445 408 diabetes.30 The major adaptations that occur in the human body adaptations in aerobic oxidative metabolism and the cardiovascular 446 409 with aerobic endurance training are summarized in Fig. 7. system as a whole. Optimal health and performance depend upon 447 410 Endurance training increases the maximal aerobic power of a these adaptations. It is important that health professionals under- 448 411 sedentary individual by 15-25% regardless of age. Genetics plays a stand these adaptations in order to be able to impart this knowledge 449 412 large role in determining the rate of adaptation, with some to the general population and to encourage individuals to adopt 450 413 individuals adapting quickly and others moreUNCORRECTED slowly.31 Endurance lifestyles that PROOF will improve their health and quality of life. 451 414 training has many effects on aerobic metabolism and related physiological functions: Summary of Energy Systems Physiology 415416 452 417 1. Increased cardiac output. The increase in cardiac output may The function of muscles is to convert chemical energy from food 453 418 arise due to an increase in the size of the heart cavities into mechanical energy, allowing individuals to perform muscular 454 419 (ventricles and atria) as well as an increase in the contractility of work. Fats, carbohydrates and proteins are the basic interrelated 455 420 the walls of the heart.32 fuel sources that are available to muscles to perform this function. 456

Please cite this article in press as: Wells GD, et al. Bioenergetic provision of energy for muscular activity. Paediatr. Respir. Rev. (2009), doi:10.1016/j.prrv.2009.04.005 G Model YPRRV 687 1–8

8 G.D. Wells et al. / Paediatric Respiratory Reviews xxx (2009) xxx–xxx 507 456457 High energy phosphates contribute anaerobic energy to the muscle 15. di Prampero PE, Ferretti G. The energetics of anaerobic muscle metabolism: A 508 reappraisal of older and recent concepts. Respir Physiol 1999 Dec 1; 118: 103–115. 509 458 system. Very high power outputs can be produced on demand, but 16. Myers J, Ashley E. Dangerous curves. A perspective on exercise, lactate, and the 510 459 these outputs can only be maintained for very short durations. anaerobic threshold. Chest 1997 Mar; 111: 787–795. 511 460 Small amounts of blood glucose and large amounts of muscle 17. Brooks GA. Current concepts in lactate exchange. Med Sci Sports Exerc 1991 Aug; 23: 512 895–906. 513 461 glycogen can also supply energy rapidly. High power outputs can 18. Svedahl K, MacIntosh BR. Anaerobic threshold: The concept and methods of measure- 514 462 be maintained in this fashion through anaerobic glycolysis ment. Can J Appl Physiol 2003 Apr; 28: 299–323. 515 463 accompanied by lactic acid production. Lower power outputs for 19. Noakes TD. Physiological models to understand exercise fatigue and the adaptations 516 464 sustained periods of time can be maintained by aerobic oxidation that predict or enhance athletic performance. Scand J Med Sci Sports 2000 Jun; 10: 517 123–145. 518 465 of glycogen with limited production of lactate. Fuel stored as fat is 20. Bonen A. Lactate transporters (MCT proteins) in heart and skeletal muscles. Med Sci 519 466 also available to the mitochondria for oxidation and is limited to Sports Exerc 2000 Apr; 32: 778–789. 520 467 slow production of ATP at low power outputs for sustained periods 21. Laursen PB, Jenkins DG. The scientific basis for high-intensity interval training: 521 Optimising training programmes and maximising performance in highly trained 522 468469 of time. endurance athletes. Sports Med 2002; 32: 53–73. 523 22. Parkhouse WS, McKenzie DC. Possible contribution of skeletal muscle buffers to 524 enhanced anaerobic performance: A brief review. Med Sci Sports Exerc 1984 Aug; 525 REFERENCES 470 16: 328–338. 526 471 23. Juel C. Current aspects of lactate exchange: Lactate/H+ transport in human skeletal 527 472 1. Abernethy PJ, Thayer R, Taylor AW. Acute and chronic responses of skeletal muscle to muscle. Eur J Appl Physiol 2001 Nov; 86: 12–16. 528 473 endurance and sprint exercise. A review. Sports Med 1990 Dec; 10: 365–389. 24. Tomlin DL, Wenger HA. The relationship between aerobic fitness and recovery from 529 474 2. Morton RH, Hodgson DJ. The relationship between power output and endurance: A high intensity intermittent exercise. Sports Med 2001; 31: 1–11. 530 475 brief review. Eur J Appl Physiol Occup Physiol 1996; 73: 491–502. 25. Delp MD. Differential effects of training on the control of skeletal muscle perfusion. 531 476 3. Hargreaves M. Skeletal muscle metabolism during exercise in humans. Clin Exp Med Sci Sports Exerc 1998 Mar; 30: 361–374. 532 477 Pharmacol Physiol 2000 Mar; 27: 225–228. 26. Xu F, Rhodes EC. Oxygen uptake kinetics during exercise. Sports Med 1999 May; 27: 533 478 4. Wilmore JH, Costill DL (eds). Physiology of sport and exercise 3rd Edition. : Human 313–327. 534 479Q3 Kinetics. 27. Hoppeler H, Weibel ER. Limits for oxygen and substrate transport in mammals. JExp 535 480 5. Hultman E, Bergstrom J, Anderson NM. Breakdown and resynthesis of phosphor- Biol 1998 Apr; 201(Pt 8): 1051–1064. 536 481 ylcreatine and adenosine triphosphate in connection with muscular work in man. 28. di Prampero PE. Metabolic and circulatory limitations to VO2 max at the whole animal 537 482 Scand J Clin Lab Invest 1967; 19: 56–66. level. J Exp Biol 1985 Mar; 115: 319–331. 538 483 6. Homma T, Hamaoka T, Sako T, Murakami M, Esaki K, Kime R et al. Muscle oxidative 29. Bonen A, Dohm GL, van Loon LJ. Lipid metabolism, exercise and insulin action. Essays 539 484 metabolism accelerates with mild acidosis during incremental intermittent isometric Biochem 2006; 42: 47–59. 540 485 plantar flexion exercise. Dyn Med 2005 Feb 20; 4: 2. 30. Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane 541 486 7. Terjung RL, Clarkson P, Eichner ER, Greenhaff PL, Hespel PJ, Israel RG et al. American Database Syst Rev 2006 Jul 19; 3:CD002968. 542 487 college of sports medicine roundtable. the physiological and health effects of oral 31. Macarthur DG, North KN. Genes and human elite athletic performance. Hum Genet 543 488 creatine supplementation. Med Sci Sports Exerc 2000 Mar; 32: 706–717. 2005 Apr; 116: 331–339. 544 489 8. MacDougall JD, Ward GR, Sale DG, Sutton JR. Biochemical adaptation of human 32. Cox ML, 926–931. 545 490 skeletal muscle to heavy resistance training and immobilization. J Appl Physiol 1977 33. Gielen S, Hambrecht R. Effects of exercise training on vascular function and myo- 546 491 Oct; 43: 700–703. cardial perfusion. Cardiol Clin 2001 Aug; 19: 357–368. 547 492 9. Dawson B, Fitzsimons M, Green S, Goodman C, Carey M, Cole K. Changes in 34. Suter E, Hoppeler H, Claassen H, Billeter R, Aebi U, Horber F et al. Ultrastructural 548 493 performance, muscle metabolites, enzymes and fibre types after short sprint training. modification of human skeletal muscle tissue with 6-month moderate-intensity exer- 549 494 Eur J Appl Physiol Occup Physiol 1998 Jul; 78: 163–169. cise training. Int J Sports Med 1995 Apr; 16: 160–166. 550 495 10. Costill DL, Coyle EF, Fink WF, Lesmes GR, Witzmann FA. Adaptations in skeletal 35. Cox KL. Exercise and blood pressure: Applying findings from the laboratory to the 551 496 muscle following strength training. J Appl Physiol 1979 Jan; 46: 96–99. community setting. Clin Exp Pharmacol Physiol 2006 Sep; 33: 868–871. 552 497 11. Mohr M, Krustrup P, Nielsen JJ, Nybo L, Rasmussen MK, Juel C et al. Effect of two 36. Kubukeli ZN, Noakes TD, Dennis SC. Training techniques to improve endurance 553 498 different intense training regimes on skeletal muscle ion transport proteins and fatigue exercise performances. Sports Med 2002; 32: 489–509. 554 499 development. Am J Physiol Regul Integr Comp Physiol . 37. Szygula Z. Erythrocytic system under the influence of physical exercise and training. 555 500 12. Vikne H, Refsnes PE, Ekmark M, Medbo JI, Gundersen V, Gundersen K. Muscular Sports Med 1990 Sep; 10: 181–197. 556 501 performance after concentric and eccentric exercise in trained men. Med Sci Sports 38. Taylor AW, Bachman L. The effects of endurance training on muscle fibre types and 557 502 Exerc 2006 Oct; 38: 1770–1781. enzyme activities. Can J Appl Physiol 1999 Feb; 24: 41–53. 558 503 13. Spriet LL, Howlett RA, Heigenhauser GJ. An enzymatic approach to lactate production 39. Hoppeler H, Fluck M. Plasticity of skeletal muscle mitochondria: Structure and 559 504 in human skeletal muscle during exercise. Med Sci Sports Exerc 2000 Apr; 32: 756– function. Med Sci Sports Exerc 2003 Jan; 35: 95–104. 560 505 763. 40. Hardie DG. AMP-activated protein kinase: A key system mediating metabolic 561 506 14. McArdle WD, Katch FL, Katch VL. Exercise physiology: Energy, nutrition and responses to exercise. Med Sci Sports Exerc 2004 Jan; 36: 28–34. 562 507 human performance, 5th Edition ed. McArdle WD, Katch FL, Katch VL, editors. 41. Jeukendrup AE. Modulation of carbohydrate and fat utilization by diet, exercise and 563 508 Lippincott Williams & Wilkins; 2007. environment. Biochem Soc Trans 2003 Dec; 31(Pt 6): 1270–1273. 564

UNCORRECTED PROOF

Please cite this article in press as: Wells GD, et al. Bioenergetic provision of energy for muscular activity. Paediatr. Respir. Rev. (2009), doi:10.1016/j.prrv.2009.04.005