Physiology of Exercise PDF

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CHAPTER 2 Physiology of Exercise SKELETAL MUSCLE: MECHANICAL PROPERTIES AND Identifying the Anaerobic Threshold by Gas Exchange....... 30 FIBER TYPES.................................... 10 Anaerobic, Lactate, and Lactic Acidosis Thresholds.......... 32 BIOENERGETICS.................................... 11 Altered Physiological Responses to Exercise above Sources of High-Energy PO4 and Cell Respiration........... 11 the Anaerobic Threshold............................ 33 Phosphocreatine Splitting Kinetics....................... 13 METABOLIC-CARDIOVASCULAR-VENTILATORY COUPLING... 39 Substrate Utilization and Regulation..................... 13 Sources of Adenosine Triphosphate Regeneration Reflected OXYGEN COST OF WORK............................. 16 in V̇O2 and V̇CO2 Kinetics............................ 39 Work Efficiency and Steady-State V̇O2.................... 17 Cardiovascular Coupling to Metabolism: V̇O2 Non–Steady State................................ 17 Muscle Oxygen Supply............................. 41 Power-Duration Curve and Critical Power................. 18 Ventilatory Coupling to Metabolism...................... 43 LACTATE INCREASE................................. 18 Effect of Dietary Substrate............................. 46 Lactate Increase as Related to Work Rate................. 18 CONTROL OF BREATHING............................ 48 Lactate Increase as Related to Time...................... 19 Arterial Hydrogen Ion Regulation........................ 48 Lactate Increase in Response to Increasing Work Rate....... 20 H + Balance......................................... 48 Mechanisms of Lactate Increase......................... 20 Physical Factors...................................... 49 Oxygen Supply, Critical Capillary PO2, and Lactate Increase... 22 Reflexes Controlling Breathing during Exercise............. 49 BUFFERING THE EXERCISE-INDUCED LACTIC ACIDOSIS..... 26 GAS EXCHANGE KINETICS............................ 52 THE ANAEROBIC THRESHOLD CONCEPT................. 29 Oxygen Uptake Kinetics............................... 52 The Anaerobic Threshold and Oxygen Uptake–Independent Carbon Dioxide Output Kinetics......................... 56 and –Dependent Work Rate Zones.................... 29 SUMMARY........................................ 56 The performance of muscular work requires the physi- Blood with normal hemoglobin of adequate concentration ological responses of the cardiovascular and ventilatory An effective pulmonary circulation through which the systems to be coupled with the increase in metabolic regional blood flow is matched to its ventilation rate; efficient coupling minimizes the stress to the com- Normal lung mechanics and chest bellows ponent mechanisms supporting the energy transfor- Ventilatory control mechanisms capable of regulat- mations. In other words, cellular respiratory (internal ing arterial blood gas tensions and hydrogen ion respiration) requirements can only be met by the inter- concentration action of physiological mechanisms that link gas ex- The response of each of the coupling links in the gas ex- change between the cells and the atmosphere (external change process is usually quite predictable and can be respiration) (see Fig. 1.3). Inefficient coupling increases used as a frame of reference for considerations of im- the stress to these systems and, when sufficiently severe, paired function. can result in symptoms that impair or limit work perfor- This chapter reviews the essentials of skeletal mance. Efficient gas exchange between the cells and the muscle physiology, including the relationship between environment requires the following: structure and function, cellular respiration, substrate Appropriate intracellular structure, energy substrate, metabolism, and the effect of an inadequate O2 supply. and enzyme concentrations After considering internal (cellular) respiration, it ex- A heart capable of pumping the quantity of oxygenated amines the circulatory and ventilatory links between blood needed to sustain the energy transformations internal and external respiration, including the factors An effective system of blood vessels that can selectively that determine the magnitude and time course of the distribute blood flow to match local tissue gas exchange cardiovascular and ventilatory responses and how they requirements are coupled to the metabolic stress of exercise. Thus, 9 009-061_Wasserman_29774_Chapter_02.indd 9 9/24/11 12:22:18 AM  10 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION this chapter is comprehensive and serves as the under- stores, muscle glycogen concentration is similar in type pinning of the interpretation of the clinical problems to I and type II fibers, but the triglyceride content is two follow in subsequent chapters. Because of their multiple to three times greater in the type I slow-twitch fibers. applications and relevancies, some subtopics might be Type I slow-twitch fibers may be more efficient than repeated under major topics. Therefore, the reader may the type II fast-twitch fibers, performing more work or find the topical outline at the beginning of this chapter developing more tension per unit of substrate energy to be a useful guide. utilized.48 Considerable potential for change by specific train- ing exists in the enzyme concentrations of a particu- SKELETAL MUSCLE: MECHANICAL lar fiber. For example, a fast-twitch fiber in an endur- PROPERTIES AND FIBER TYPES ance-trained athlete could have higher concentrations of oxidative enzymes than in a chronically sedentary Human skeletal muscles consist of two basic fiber types: subject.55 These structural and functional differences types I and II (Table 2.1). These fiber types are classi- between fiber types depend to a large extent on the fied on the basis of both their contractile and biochemi- neural innervation of the fibers. A single motor neuron cal properties.118 Type I (slow-twitch) fibers take a longer supplies numerous individual muscle fibers; this func- time to develop peak tension (≈ 80 msec) following their tional assembly is termed a motor unit. These fibers are activation than type II (fast-twitch) fibers (≈30 msec). distributed throughout the muscle rather than being The slow contractile properties of type I fibers appear spatially contiguous. Fibers comprising a motor unit are to result largely from the relatively low activity of the characteristically of the same fiber type, and substrate myosin ATPase at the myofibril that catalyzes the split- depletion occurs rather uniformly within each fiber of ting of the terminal high-energy phosphate of adenosine the contracting unit. triphosphate (ATP), the lower Ca++ activity of the regula- Fiber type distribution within human skeletal tory protein, troponin, and the slower rate of Ca++ uptake muscle varies from muscle to muscle. For example, the by sarcoplasmic reticulum. These same properties appear soleus muscle typically has a much higher density of to confer a relatively high resistance to fatigue on the slow-twitch fibers (> 80%) than the gastrocnemius mus- type I fibers. cle (~50%) or the triceps brachii (~20% to 50%). The Biochemical differences between the two basic vastus lateralis muscle (~50% slow-twitch fibers) has fiber types focus chiefly on their capacity for oxidative been used widely for analysis of fiber type character- and glycolytic activities. Type I fibers, being especially istics in humans. The basic fiber type pattern of this rich in myoglobin, are classified as red fibers, whereas muscle varies in different subjects. Elite endurance ath- type II fibers, which contain considerably less myo- letes typically have a high percentage of slow-twitch fi- globin, are classified as white fibers. The type I slow- bers in this muscle (>90% is not uncommon) compared twitch fibers tend to have significantly higher levels of with untrained control subjects (~50%) or elite sprinters oxidative enzymes than the type II fast-twitch fibers, (20% to 30%). which typically have a high glycolytic activity and en- Whereas basic fiber type pattern is genetically deter- zyme profi le. The type II fibers are further classified mined, it is greatly influenced by the neural characteris- into type IIa and type IIx (formerly classified as type tics of the efferent motor neuron. When the motor nerves IIb),49 based on the greater oxidative and lesser glyco- innervating the fast flexor digitorum longus and the slow lytic potential of the type IIa fibers compared with the soleus muscles of the cat are cut and cross-spliced, the type IIx fibers (Table 2.1). With respect to substrate contractile and biochemical characteristics of the muscle Table 2.1 Characteristics of Muscle Fiber Types Slow oxidative (type 1) Fast oxidative (type IIa) Fast glycolytic (type IIx) Contraction Slow twitch Fast twitch Fast twitch Fiber size Small Intermediate Large Color Red Red White Myoglobin concentration High High Low Mitochondrial content High High Low 009-061_Wasserman_29774_Chapter_02.indd 10 9/24/11 12:22:18 AM  CHAPTER 2: PHYSIOLOGY OF EXERCISE 11 begin to resemble the features of the muscle originally Sources of High-Energy PO4 and innervated by the nerve.20 Thus, an important trophic in- Cell Respiration fluence on muscle function is conferred by its nerve sup- Energy for muscular contraction is obtained predomi- ply. Although phenotypic changes within a muscle fiber nantly by the oxidation in the mitochondria of three- can be induced by activity, with mechanical factors such carbon (pyruvate) and two-carbon (acetate) metabolic in- as stretch considered to be contributory to the fast-to- termediaries from carbohydrate and fatty acid catabolism slow shift, a typical program of exercise training does not (Fig. 2.1). A small additional amount of energy comes cause appreciable interchanges between type I and type II from biochemical mechanisms in the cell cytoplasm that fibers; however, it can cause changes within type II fibers metabolize glucose and glycosyl units (from glycogen) (e.g., from type IIx to type IIa).70 Evidence is accumu- to pyruvate (see Fig. 2.1). Both the mitochondrial and lating, however, that long-term inactivity and/or chronic cytosolic sources of energy are transformed into high- disease can result in a shift toward a greater percentage energy phosphate compounds, predominantly as creatine of type II fibers. phosphate and ATP. During the splitting of ~P from these The pattern of activation of fiber types depends on compounds, energy is released for cellular reactions such the form of exercise. For low-intensity exercise, the type as biosynthesis, active transport, and muscle contrac- I slow-twitch fibers tend to be recruited predominantly, tion. Exercise entails an acceleration of these energy- whereas the type II fast-twitch fibers (which produce yielding reactions in the muscles to regenerate ~P at the greater force) are recruited at higher work rates, espe- increased rate needed for the increased energy expendi- cially at or above 70% to 80% of the maximal aerobic ture of physical work. Thus, the cellular consumption of power.43 It should be noted that although training in- O2 is increased; this must be matched by an increased creases the percentage of type I fibers in active muscle delivery of O2 from the atmosphere to the mitochondria. and detraining reduces it, it is difficult to discern a spe- Simultaneously, CO2, the major catabolic end product of cific pathophysiology in the gas exchange response to exercise, is removed from the cell by muscle blood flow exercise detraining, other than an increase in anaerobic and eliminated from the body by ventilating the pulmo- metabolism at a lower work rate. nary blood flow. Acetate is produced from the catabolism of carbohy- BIOENERGETICS drates, fatty acids, and, in nutritionally deficient states, amino acids. It reacts with oxaloacetate in the mito- Skeletal muscle may be considered to be a machine that is chondrion, after esterification with coenzyme A (also fueled by the chemical energy of substrates derived from known as acetyl-CoA), to form citrate in the Krebs or ingested food and stored as carbohydrates and lipids in tricarboxylic acid (TCA) cycle (see Fig. 2.1). Here, cata- the body. Although protein is a perfectly viable energy bolic reactions result in CO2 release and the transfer of source, it is not used to fuel the energy needs of the body hydrogen ions (protons) and their associated electrons to any appreciable extent, except under conditions of to the mitochondrial electron transport chain, which starvation. then flow down the energy gradient of the electron The free energy of the substrate (i.e., that fraction transport chain, transferring energy to resynthesize of the total chemical energy that is capable of doing ATP from adenosine diphosphate (ADP) and inorganic work) is not used directly for muscle contraction. It phosphate (i.e., oxidative phosphorylation). At the end must fi rst be converted into and stored in the termi- of the electron transport chain, cytochrome oxidase cat- nal phosphate bond of ATP. The terminal phosphate alyzes the reaction of each pair of protons and electrons bond of this compound has a high free energy of hy- with an atom of oxygen to form a molecule of water. drolysis (ΔG) and is designated as a high-energy phos- For each transfer of a pair of protons and electrons, suf- phate bond (~P). Current estimates of ΔG per ~P for ficient energy is released to form either two or three physiological conditions such as those occurring in ATP molecules—three if the electron transport process contracting muscle are as high as 12 to 14 Kcal/ mole. begins at nicotinamide adenine dinucleotide (NAD +), Therefore, muscle is ultimately a digital device operat- but only two if it begins at fl avin adenine dinucleotide ing in discrete multiple units of ~P energy, with one (FAD) (see Fig. 2.1). ~P thought to be used per myosin cross-bridge linkage Six ATP molecules are gained during the catabolism to and subsequent release from actin. The muscle uses of glucose to pyruvate if the reduced nicotinamide ad- this energy for the conformational changes, externally enine dinucleotide ([NADH + H+]) in the cytosol, formed manifested by shortening or increasing tension. Thus, during glycolysis, is reoxidized by the proton shuttle and muscular exercise depends on the structural charac- FAD (see pathway A of Fig. 2.1).83 Of the six ATP mol- teristics of muscle and on the body’s systems, which ecules regenerated from glucose (seven from glycogen) maintain a physicochemical milieu for adequate ATP by this mechanism, two are formed in the cytosol by regeneration. the Embden-Meyerhof (glycolytic) pathway and four in 009-061_Wasserman_29774_Chapter_02.indd 11 9/24/11 12:22:18 AM  12 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION FIGURE 2.1. Scheme of the major biochemical pathways for production of adenosine triphosphate (ATP). The transfer of H+ and electrons to O2 by the electron transport chain in the mitochondrion and the “shuttle” of protons from the cytosol to the mitochondrion (pathway A) are the essential compo- nents of aerobic glycolysis. This allows the efficient use of carbohydrate substrate in regenerating ATP to replace that consumed by muscle contraction. Also illustrated is the im- portant O2 flow from the blood to the mitochondrion, without which the aerobic energy generating mechanisms within the mitochondrion would come to a halt. At the muscle sites of inadequate O2 flow to mitochondria, pathway B serves to re- oxidize NADH + H+ to NAD+. Pyruvate is converted to lactate (highly dissociated lactic acid at the cell pH), as NADH + H+/ NAD+ increases in the cytosol. the mitochondrion during the coupled reoxidation of glycosyl unit combines with inorganic phosphate, it be- cytosolic NADH + H+ by the mitochondrion, via the mito- comes ~P. Thus, there is a net yield of 37 ATP molecules chondrial membrane proton shuttle and the cytochrome from the aerobic oxidation of each glycosyl unit. Because electron transport chain.83 The shuttle accepts hydrogen 6 molecules of O2 are used for glucose (glycosyl) oxida- ions from the cytosolic [NADH + H+] and transfers them tion and 36 high-energy phosphate bonds are formed, the to mitochondrial coenzymes, NAD+ or FAD, as illustrated ratio of ~P to O2 is 6 for glucose (6.18 for glycogen). Six in Figure 2.1. This method of regenerating oxidized NAD+ molecules of CO2 and H2O are catabolic end products of in the cytosol maintains the cytosolic redox state and en- these reactions. ables glycolysis to continue. Because O2 is the ultimate Under conditions in which the mitochondrial proton recipient of the protons that are generated by glycolysis shuttles fail to reoxidize the [NADH + H+] generated by and transported into the mitochondria, this glycolysis is glycolysis at a rate sufficient to keep cytosolic [NADH + aerobic (see pathway A in Fig. 2.1). H+]/NAD+ normal (Fig. 2.1), the redox state of the cyto- The formation of acetyl-CoA from pyruvate and its sol is lowered. Because [NADH + H+] accumulates in the subsequent entry into the TCA cycle yields a total of five re- cytosol at the expense of NAD+, glycolysis would slow if duced mitochondrial NAD molecules (i.e., [NADH + H+]). it were not for an alternate pathway capable of reoxidizing Because the reoxidation of each [NADH + H+] by the elec- cytosolic [NADH + H+]. When [NADH + H+] accumulates, tron transport chain yields 3 ATP molecules, there is a pyruvate can reoxidize the [NADH + H+] back to NAD+. net gain of 15 ATP. However, 2 molecules of acetyl-CoA However, by its acceptance of the two protons, pyruvate is are formed from each glucose molecule, so the total gain reduced to lactate (see pathway B in Fig. 2.1). Thus, pyru- is 30 ATP from these reactions. When added to the 2 ATP vate oxidation of [NADH + H+] results in lactate accumu- gained from glycolysis and the 4 others obtained from re- lation. Because the breakdown of glucose or glycosyl to oxidation of cytosolic [NADH + H+] by the proton shuttle lactate occurs without use of oxygen, it is termed anaero- with the subsequent transfer of its protons and electrons bic glycolysis. The substrate price for the production of to oxygen (see Fig. 2.1), the total gain in ATP from the energy from this reaction is expensive compared with the complete oxidation of glucose is 36. However, glycogen is complete oxidation of glycogen to CO2 and H2O. The net the major carbohydrate source in the normally nourished gain in ATP is only 3 from each glycosyl unit instead of person, so an additional ~P is obtained because when a 37. For the same work rate, therefore, this pathway causes 009-061_Wasserman_29774_Chapter_02.indd 12 9/24/11 12:22:19 AM  CHAPTER 2: PHYSIOLOGY OF EXERCISE 13 intracellular concentration some five times greater than that of ATP, also serves as a mediator of ATP resynthesis through the creatine kinase reaction; that is, PCr + ADP + H+ ↔ Cr + ATP Note that the breakdown of PCr produces an alkalinizing reaction. Kushmerick and Conley called PCr a “chemical ca- pacitor” for ATP.81 The decrease in PCr concentration contributes to the O2 deficit from the start of exercise, with its contribution to the O2 deficit being proportion- ally greater the slower the time course of the V̇O2 increase. In fact, for moderate-intensity exercise, the sum of the utilization of PCr and O2 stores is sufficient to account for the entire O2 deficit. At higher work rates, however, anaerobic energy transfer from lactate production supple- ments these stored resources. In addition to serving as what has been termed an energy buffer, PCr is also thought to play an important role in the control of oxidative phosphorylation, likely in its link to local ADP: [ADP] = ([ATP][Cr])/([PCr] [H+] Keq) FIGURE 2.2. Gas exchange during aerobic (A) and aerobic plus anaerobic (B) exercise. The acid–base consequence of the latter is where Keq is the equilibrium constant of the creatine a net increase in cell lactic acid production. The buffering of the kinase reaction. ADP consequently increases as PCr de- accumulating lactic acid takes place in the cell at the site of forma- creases; thus, the ADP increase and/or PCr decrease might tion by bicarbonate. The latter mechanism will increase the CO2 pro- be the signal that triggers mitochondrial O2 uptake.169 In duction of the cell by approximately 22 mL per mEq of bicarbonate fact, the time course of the change in [PCr], measured by buffering lactic acid. The increase in cell lactate and decrease in cell nuclear magnetic resonance spectroscopy, has been shown bicarbonate will result in chemical concentration gradients, causing to be indistinguishable from that of V̇O2 (and, by exten- lactate to be transported out of and bicarbonate to be transported sion, cellular O2 consumption) in exercising humans.113 into the cell. These reactions are reversed in early recovery and consti- tute part of the repayment of the O2 debt. glycogen (and glucose) to be used at a considerably faster rate than when the production of ∼P is totally aerobic.35,60 Substrate Utilization and Regulation Moreover, the two lactic acid molecules that accumulate At this point, several terms need to be clarified for preci- when each glucose molecule or glycosyl unit undergoes sion and to avoid possible confusion (see Fig. 1.3). The anaerobic metabolism cause a disturbance in acid–base symbol V̇O2 indicates O2 uptake by the lungs per minute. balance in the cell and blood (Fig. 2.2). That the turn-on It is distinguished from O2 consumption by the cells, of anaerobic ATP production does not signal the turn-off which is symbolized by Q̇O2. The symbol V̇CO2 indi- of aerobic ATP production deserves emphasis. Both aero- cates CO2 output by the lungs per minute, distinguished bic and anaerobic mechanisms share in energy generation from CO2 production by the cells, symbolized by Q̇CO2. at high work rates, with the anaerobic mechanism provid- Thus, the substrate mixture undergoing oxidation is ing an increasing proportion of energy as the work rate characterized by the net rates of CO2 yield or production is increased. (Q̇CO2) and oxygen utilization or consumption (Q̇O2). The ratio V̇CO2 /V̇O2 as measured at the airway (i.e., the gas ex- change ratio, R) reflects Q̇CO2 /Q̇O2, the metabolic respira- Phosphocreatine Splitting Kinetics tory quotient (RQ), only when there is a steady state in Oxygen uptake (V̇O2) during exercise is inextricably linked V̇CO2 and V̇O2; that is, when CO2 is not being added to to increased rates of high-energy phosphate utilization. It or being removed from the body, CO2 stores and the O2 is the major source of resynthesis of ATP, which is used stores are constant. Thus, the new V̇CO2 and V̇O2 are equal to fuel muscular contraction through the process of oxi- to the new Q̇CO2 and Q̇O2, respectively (i.e., when Q̇CO2 = dative phosphorylation. Phosphocreatine (PCr), with an V̇CO2 and Q̇O2 = V̇O2). 009-061_Wasserman_29774_Chapter_02.indd 13 9/24/11 12:22:19 AM  14 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION During acute hyperventilation (resulting from, e.g., acute hypoxia, pain, or anxiety, or of volitional origin), considerably more CO2 is unloaded from the body CO2 stores than O2 is loaded into the O2 stores. This is be- cause hemoglobin, at sea level, is almost completely sat- urated with O2 at the end of the pulmonary capillaries and the physical solubility of O2 in blood is low; on the other hand, appreciable amounts of CO2 can be unloaded from blood and tissue stores as alveolar ventilation is increased and PaCO2 is reduced. Thus, with acute hyper- ventilation, R will exceed the metabolic RQ until a steady state (i.e., CO2 output equals CO2 production) is again attained at the new level of ventilation. Similarly, during the acute metabolic acidosis of exercise, “extra” CO2 is evolved when HCO3− buffers lactic acid (see Fig. 2.2). This will also result in R exceeding RQ until a new steady state in CO2 stores is attained (i.e., the CO2 pool size is again constant, although depleted, and CO2 output equals pro- duction), at which time R again equals RQ. Differences between R and RQ will also occur during acute hypoven- tilation and recovery from metabolic acidosis, but in the opposite direction. FIGURE 2.3. The percentage of carbohydrate substrate in the diet As seen in the following equations, carbohydrate estimated from the respiratory quotient measurement. The calories of (e.g., glycogen or glucose) is oxidized with RQ equal to energy obtained per liter of oxygen consumed for each combination is 1.0 (i.e., six CO2 molecules produced and six O2 mol- given on the right ordinate. (From Lusk G. Science of Nutrition. New ecules consumed) and, ideally, has a ∼P:O2 of 6.0 or York, NY: Johnson Reprint; 1976, with permission.) 6.18, depending on whether glucose or glycogen is the substrate: biopsies.14 Thus, to economize on O2 transport, a greater C6H12O6 + 6 O2 → 6 CO2 + 6 H2O + 36 or 37 ATP (1) proportion of carbohydrate than of fatty acids is used for energy during muscular work as compared with the Lipid (e.g., palmitate) is oxidized with RQ equal to 0.71 resting state.127 (i.e., 16 CO2 produced to 23 O2 consumed) and has a Because muscle RQ is high relative to that of most ∼P:O2 of 5.65 (i.e., 130 ATP/23 O2): other organs (with the exception of the nervous system), the total body RQ increases from a resting value of C16H32O2 + 23 O2 → 16 CO2 + 16 H2O + 130 ATP (2) approximately 0.8 (on an average Western diet) toward approximately 0.95 during moderate exercise, depending Intermediate steady-state RQ values reflect different pro- on the exercise metabolic rate (Fig. 2.4). An RQ of 0.95 portions of carbohydrate and fat being utilized in the indicates that about 84% of the substrate during exercise bioenergetic, metabolic process (Fig. 2.3). For storage is derived from carbohydrate (see Fig. 2.3). Although the economy, fat is the more efficient energy; however, for fuel mixture for the total body derives proportionally economy of O2 utilization, carbohydrate is the more ef- more from carbohydrate than from lipid stores during ficient substrate, supplying 6% to 8% more ATP per mole exercise as work rate increases (see Fig. 2.4), RQ de- of O2 with carbohydrate as compared to fat. creases slowly over time during prolonged constant-load When a steady state of gas exchange exists, R pro- exercise (Fig. 2.5). This reflects a decrease in the pro- vides an accurate reflection of RQ. During exercise, the portional utilization of carbohydrate associated with a muscle RQ can be estimated from the increase in V̇CO2 reduction in muscle glycogen stores. When muscle gly- relative to the increase in V̇O2over the range of moder- cogen becomes depleted, the exercising subject senses ate work rates. These gas exchange measurements sug- exhaustion.111 Acute ingestion of glucose may allow the gest that the muscle substrate RQ during exercise is ap- work to continue.124 proximately 0.95, when a normal diet is ingested.10,32,34 The rate of decrease in muscle glycogen during exer- This is in close agreement with the muscle substrate cise can be slowed by raising blood glucose levels with a RQ in normal humans found by Bergstrom and asso- continued infusion of glucose.3 The importance of mus- ciates based on the rate of muscle glycogen consump- cle glycogen in work tolerance is well described by the tion during exercise determined from repeated muscle experiments of Bergstrom et al.,14 who demonstrated a 009-061_Wasserman_29774_Chapter_02.indd 14 9/24/11 12:22:20 AM  CHAPTER 2: PHYSIOLOGY OF EXERCISE 15 Carbohydrates Skeletal muscle in humans contains, on average, 80 to 100 mmol (15 to 18 g) glucose per kilogram of wet weight stored as glycogen. For a 70-kg man, this amounts to ap- proximately 400 g of muscle glycogen.14 However, a con- tracting muscle can draw only on its own glycogen reserves and not on the pools in noncontracting muscles. Normally, approximately 4 to 5 g of glucose are avail- able in the blood (100 mg/100 mL). Although muscle uptake of blood glucose increases considerably during exercise, the blood concentration does not fall because of an increased rate of glucose release from the liver. The liver represents a highly labile glycogen reserve in the range of 50 to 90 g. This glycogen is broken down into glucose by glycogenolysis and released into the blood. Glucose can also be produced in the liver (gluconeogenesis) from lac- tate, pyruvate, glycerol, and alanine precursors. The rate of glucose release from the liver into the circulation depends on both the blood glucose concentration and a complex interaction of hormones such as insulin, glucagon, and the FIGURE 2.4. The steady-state R (RQ) at various levels of exercise for catecholamines epinephrine and norepinephrine.138,139 the whole body determined as the ratio of steady-state V̇CO2 to V̇O2 for As exercise intensity and duration increase, the circu- the levels of exercise indicated on the x-axis for 10 subjects. The heavy lating levels of catecholamines and glucagon increase, line is the average response. thereby maintaining the level of blood glucose despite its increased utilization by the exercising muscles. These regulatory processes maintain physiologically adequate high positive correlation between the tolerable duration concentrations of glucose, except when muscle and liver of high-intensity work and the muscle glycogen content glycogen stores become greatly depleted. before exercise. Physical fitness, in the sense of the capacity for sus- tained activity, affects the substrate utilization pattern. Lipids A fitter subject uses a greater proportion of fatty acids Skeletal muscles have access to their own intramuscular for energy than an unfit one for submaximal work.63 store of lipids, averaging 20 g of triglycerides per kilogram This mechanism conserves glycogen, allowing more work of wet weight. This source accounts for a considerable to be performed before glycogen depletion and consequent proportion of the total energy required by the muscles, exhaustion. The specific regulation of different substrates depending on the duration of exercise and the rate of is considered in the following sections. muscle glycogen depletion. FIGURE 2.5. Effect of exercise duration on the gas exchange ratio (R) for constant work rate exercise of moderate, heavy, and very heavy work intensity. Note that the R is higher for the higher work intensities, but slowly declines with time after the ini- tial increase. Results are those for a single healthy subject. The R is higher with greater exercise intensity, indicating a higher car- bohydrate to fat ratio at higher work rates. The slow decline in R likely results from a slow depletion of the muscle carbohydrate stores. 009-061_Wasserman_29774_Chapter_02.indd 15 9/24/11 12:22:20 AM  16 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION Extramuscular lipid sources are also used during syndrome). The alanine formed by transamination in exercise. These derive from adipose tissue where trig- muscle is transported in the blood to the liver, where it lycerides undergo hydrolysis to glycerol and free fatty serves as a precursor for gluconeogenesis. Thus, an al- acids (mainly palmitic, stearic, oleic, and linoleic acids). anine–glucose cycle is established between muscle and The fatty acids are transported in the blood, bound liver, with the carbon skeleton of alanine supporting he- predominantly to albumin. The store of extramuscular patic glucose synthesis. lipid is large. In a 70-kg man, fat accounts for approxi- mately 15 kg of triglycerides, which is equivalent to about 135,000 Kcal of energy. OXYGEN COST OF WORK The sympathetic nervous system, along with cate- The oxygen cost of performing work depends on the work cholamines from the adrenal medulla, regulate adipose rate. Figure 2.6 shows the time course of oxygen uptake tissue lipolysis. Epinephrine and norepinephrine increase (V̇O2) from unloaded cycling for various levels of cycle the local concentration of cyclic 3′,5′-AMP through ac- ergometer exercise in a normal individual. Note that, in tivation of adenyl cyclase. This leads to increased rates this individual, a steady state is reached by 3 minutes of hydrolysis of the stored adipose tissue triglycerides. up to a work rate of 150 W. At higher work rates, V̇O2 Other factors reduce the rate of adipose tissue lipolysis continued to increase above the 3-minute value, and the during exercise, including increased blood lactate and subject was unable to continue the exercise task.162,166 exogenous glucose loads. The maximum V̇O2 for each work rate above 200 W was The free fatty acids account for only a small propor- the same, thereby identifying the subject’s V̇O2max. Note tion (usually less than 5%) of the total plasma fatty acid that the earlier the V̇O2max is reached, the higher the pool; the remainder are triglycerides. Resting plasma free work rate, thus signifying that the subject reached the fatty acid concentrations are approximately 0.5 mmol/L, level of fatigue earlier (i.e., characterizing the subject’s increasing during exercise to approximately 2 mmol/L. power–duration relationship at this work intensity). The The turnover rate of the plasma free fatty acid pool is subject cannot sustain exercise at V̇O2max. The V̇O2 ki- high, with a half-time of 2 to 3 minutes at rest and less netic profiles shown in Figure 2.6 are typical of all sub- during exercise. As a consequence, the flux of free fatty jects, but the work rate at which the non–steady-state acids to the exercising muscle (i.e., plasma flow × plasma pattern of V̇O2 is seen differs depending on the subject’s free fatty acid concentration) is an important determinant fitness for aerobic work. of skeletal muscle uptake. The plasma concentration of free fatty acids does not increase—and may even decrease slightly—with physi- cal training. Therefore, the increased proportional contri- 4 200 400 bution of free fatty acid oxidation to exercise energetics, when measured at a specific work rate after training, may reflect increased utilization from intramuscular sources. 0 Adipose tissue lipolysis does not appear to be enhanced 4 150 350 by training. V˙ O2 (L / min) 0 Amino Acids 4 100 300 During exercise, the rate of release of intramuscular ala- nine increases appreciably, but with little or no change in 0 other amino acids.106 The arterial alanine concentration 4 50 250 increases as much as twofold during severe exercise.134 The source of the alanine released from muscle is pre- dominantly from the transamination of pyruvate (derived 0 from increased rates of carbohydrate metabolism). The 10 min 10 min amino groups are derived from the deamination of inos- FIGURE 2.6. Breath-by-breath time course of oxygen uptake for eight ine monophosphate during purine nucleotide metabolism levels of constant work rate cycle ergometer exercise, starting from and the branch-chain amino acids (valine, leucine, and unloaded cycling, for a normal male subject. The work rate (watts) for isoleucine). each study is shown in the respective panel. The bar on the x-axis indi- A highly linear relationship exists between the cates the period of the imposed work rate. The V̇O2 asymptote (steady plasma concentrations of alanine and pyruvate at rest state) is significantly delayed for work above the anaerobic threshold. and during exercise. A decreased muscle release of ala- (From Whipp BJ, Mahler M. Dynamics of pulmonary gas exchange dur- nine, associated with the decreased output of pyruvate,135 ing exercise. In: West JB, ed. Pulmonary Gas Exchange. New York, NY: is observed in phosphorylase-deficient muscle (McArdle Academic Press, 1980:33–96, with permission.) 009-061_Wasserman_29774_Chapter_02.indd 16 9/24/11 12:22:21 AM  CHAPTER 2: PHYSIOLOGY OF EXERCISE 17 required to perform the work (ΔV̇O2) varies only slightly from one individual to another.6 Trained and untrained individuals, regardless of age and sex, all have similar work efficiencies. This similarity reflects the basic bio- chemical energy-yielding reactions needed for muscle contraction. However, it is important to recognize that the V̇O2 of the “unloaded” ergometer can vary consider- ably from one subject to another because of differences in subject size and the actual work rate of the “unloaded” cycling. Thus, ΔV̇O2 /ΔWR is much more uniform among subjects than V̇O2 /WR. Care must be taken not to confuse changes in skill or motor efficiency due to practice with the assessment of work efficiency. To measure work efficiency, relatively simple tasks must be employed that do not depend on technique and for which the work output can be mea- sured (e.g., cycling). To calculate muscle work efficiency, the caloric equivalent of the steady-state V̇O2 (4.98 Cal/L FIGURE 2.7. The effect of work rate on steady-state oxygen consump- V̇O2 at RQ = 0.95, see Fig. 2.3) and the external power tion during cycle ergometer exercise. The oxygen consumption response (0.014 Cal/min/W) for at least two measured work rates in normal subjects is quite predictable for cycle ergometer work regard- must be known. For lower-extremity cycle ergometer less of age, gender, or training. The predicting equation is given in the work, normal subjects have an efficiency of approxi- figure. In obese subjects, the oxygen requirement to perform work is mately 28%.150,165 displaced upward, with the displacement dependent on body weight. (From Wasserman K, Whipp BJ. Exercise physiology in health and dis- ease. Am Rev Respir Dis. 1975;112:219–249, with permission.) V̇O2 Non–Steady State The continued slow increase in V̇O2 observed after 3 min- When plotting the steady-state V̇O2 values for those utes during constant work rate exercise in healthy young cycle ergometer work rates in which a steady state subjects is only seen for work rates that are accompanied is achieved, such as shown for 50, 100, and 150 W in by a lactic acidosis.114,162,166 The rate of increase in V̇O2 in Figure 2.6, a linear relationship between V̇O2 and work response to constant work rate exercise for 3 to 6 minutes rate is obtained (Fig. 2.7). The slope of this relation- correlates with the increase in blood lactate,76,114,166,176 as ship is approximately the same for all normal people discussed in “Gas Exchange Kinetics” later in this chap- (approximately 10 mL/min/W), although it appears to be ter. At least six mechanisms may contribute to the slow slightly steeper (approximately 11 mL/min/kg) in highly increase in V̇O2 after 3 minutes of exercise: fit cyclists.110 Therefore, work efficiency in humans is rel- atively fixed for a given work task. Although the slope of 1. Increase in V̇O2 needed to satisfy the increased work of the relationship between steady-state V̇O2 and work rate is the muscles of respiration and the heart at high venti- not perceptibly affected by age or sex, the position of the latory and cardiac output responses relationship depends on body weight. 2. Calling into play additional groups of muscles (such as On the cycle ergometer, obese subjects exhibit an more forceful pulling on the handlebars) upward displacement of approximately 5.8 mL/min/kg of 3. Acidemia facilitating O2 unloading from hemoglobin body weight,150 which reflects the added work rate gen- by shifting the oxyhemoglobin dissociation curve erated as a result of moving the heavier lower extremi- downward and rightward for a given PO2 ties. The effect of body weight on V̇O2 is more pronounced 4. Progressive vasodilation to the local muscle units by on the treadmill because an even greater work rate must metabolic vasodilators (e.g., ↑[H+], ↑PCO2, ↓PO2, sheer be done to support the movement of the entire body stress), thereby increasing O2 flow and O2 consump- through space. tion at the O2-deficient sites 5. The O2 cost of converting lactate to glycogen in the liver as the lactate concentration rises, which must Work Efficiency and Steady-State V̇O2 also contribute to the increase in V̇O2, but its magni- Cycle ergometer work rate and the steady-state V̇O2 mea- tude is quite small compared to the rate of V̇O2 increase surement are commonly used interchangeably when de- during the slow phase168 scribing the level of exercise being performed, because 6. And predominantly, reduced muscular efficiency dur- work efficiency or the increase in work rate (ΔWR) as ing heavy work by recruiting more low-efficiency fast- related to the energy equivalent of the increase in V̇O2 twitch muscle fibers. 009-061_Wasserman_29774_Chapter_02.indd 17 9/24/11 12:22:21 AM  18 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION Power-Duration Curve and Critical Power subject’s aerobic capacity and which increases with en- The power-duration curve describes the time for which durance training in concert with the lactate threshold high-intensity, constant-load exercise may be sustained and V̇O2max. The curvature constant of the hyperbola, to the limit of tolerance (t LIM). This relationship has W ′, is a parameter of exercise tolerance that is math- been demonstrated to be hyperbolic for work rates that ematically equivalent to a constant amount of work (i.e., result in V̇O2max being attained (Fig. 2.8A). This pro- the product of P and t LIM) that can be performed above vides a power asymptote at what is termed the critical CP.97,104 When P is plotted as a function of the recipro- power (CP)—a parameter that correlates highly with the cal of time (1/t LIM), the relationship is highly linear (Fig. 2.8B) with a slope indicative of W ′. CP presumably par- titions the supralactate threshold exercise intensity into its heavy and very heavy intensity domains.159 Exercise A training that increases the endurance time for the work rate domain above the CP would affect W ′ and the CP; it 400 can be used to evaluate the benefit of exercise training curvature constant: W ' or therapy. POWER (Watts) LACTATE INCREASE 300 Lactate Increase as Related to Work Rate CP Figure 2.9 shows the arterial blood lactate concentra- tion as related to V̇O2 in three groups of subjects per- 200 forming progressively increasing cycle ergometer work: normal subjects who are relatively active, sedentary r 1 3 5 7 9 TIME (min) B 400 CP POWER (Watts) 300 slope: W ' 200 r 0 0.1 0.3 0.5 0.7 0.9 –1 1/t (min ) FIGURE 2.9. Pattern of increase in arterial lactate in active and sed- FIGURE 2.8. A: The hyperbolic relationship between power and its entary healthy subjects and patients with heart disease as related to tolerable duration for very heavy intensity exercise. The power asymp- increasing exercise oxygen uptake V̇O2. Lactate (LAC) concentration tote (horizontal line) provides an estimation of the subject’s critical rises from approximately the same resting value to approximately the power (CP), with a curvature constant termed W′. B: The linearized same concentration at maximal exercise in each of the three groups. relationship between power and the inverse of its tolerable duration. The fitter the subject for aerobic work, the higher the V̇O2 before lac- The subject’s CP is determined from the linear extrapolation, as shown. tate starts to increase significantly above resting levels. (Modified W′ provided by the slope of this relationship. (Modified from Fukuba Y, from Wasserman K. Coupling of external to cellular respiration during Whipp, BJ. A metabolic limit on the ability to make up for lost time in exercise: the wisdom of the body revisited. Am J Physiol. 1994;266: endurance events. J Appl Physiol. 1999;87:853–861.) E519–E539.) 009-061_Wasserman_29774_Chapter_02.indd 18 9/24/11 12:22:22 AM  CHAPTER 2: PHYSIOLOGY OF EXERCISE 19 normal subjects, and patients with heart disease. All Lactate Increase as Related to Time show similar resting and low-level exercise lactate con- Work rate or power output is an absolute quantity of centrations. The pattern of lactate increase is the same work performed per unit of time. Although a given work for each group, but the V̇O2 at which the lactate starts rate may be stressful for one individual and thus cause to increase differs. Lactate does not start to increase in early fatigue, it may not be a significant physical stress subjects who are relatively young and physically active for a more fit individual. Therefore, adjectives such as until V̇O2 is increased to as much as 10 times the rest- moderate, heavy, and very heavy are used to describe the ing metabolic rate. In contrast, the V̇O2 at which lactate degree of physical stress based on the pattern of arte- starts to increase in sedentary subjects is about four rial lactate change.148 The magnitude and pattern of times the resting level (equivalent to the V̇O2 required arterial lactate increase for a given work rate closely re- for adults to walk at a normal pace). In cardiac patients flect the fitness of an individual for endurance (aerobic) with a low, symptom-limited maximum V̇O2, arterial exercise.140 lactate increases at exceedingly low exercise levels, per- For constant-load cycle ergometer exercise, three pat- haps less than twice that of the resting metabolic rate, terns of arterial blood lactate concentration increase are as shown in Figure 2.9. observed (Fig. 2.10).148 The first pattern is one in which The V̇O2 at which lactate starts to increase in nor- either no increase in lactate is observed or lactate tran- mal subjects is, on average, about 50% to 60% of their siently rises and then returns to its resting value as V̇O2 V̇O2max, but with a range extending from 40% to more reaches a steady state. This is defined as moderate work than 80%. It is higher in aerobically fit subjects. The lac- intensity and implies that the work is not uncomfortable tate threshold (LT) and V̇O2max increase with endurance and hence can be sustained in a true steady state. training. As a person ages, the V̇O2 at the LT becomes a Heavy-intensity exercise is defined as a sustained but higher fraction of V̇O2max because V̇O2max decreases at a constant increase in arterial lactate resulting from a bal- proportionately faster rate than the LT. ance between increased rate of production by the exercis- ing muscle and increased rate of utilization by the liver and other actively metabolizing organs, such as the heart. This work can only be sustained for a limited duration (Figs. 2.10 and 2.11) because a true metabolic steady state does not occur. The acid–base balance at this work inten- sity reflects a sustained metabolic acidosis.152 FIGURE 2.11. The endurance time as related to the increase in arte- rial lactate (above the preexercise resting value) during the last min- ute of constant work rate cycle ergometer exercise. Data are from 30 FIGURE 2.10. Arterial lactate increase and bicarbonate decrease with experiments on 10 male subjects, each studied at three work rates. time for moderate, heavy, and very heavy exercise intensities for a nor- The target exercise time for each work rate was 50 minutes. The mal subject. Bicarbonate changes in an opposite direction to lactate, in target endurance time is reduced when lactate is increased. (From a quantitatively similar manner. Although the target exercise duration Wasserman K. The anaerobic threshold measurement to evaluate was 50 minutes for each work rate, the endurance time was reduced exercise performance. Am Rev Respir Dis. 1984;129:S35–S40, with for the heavy and very heavy work rates. permission.) 009-061_Wasserman_29774_Chapter_02.indd 19 9/24/11 12:22:22 AM  20 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION When arterial lactate continues to increase through- out the exercise to the point of fatigue (see Fig. 2.10), this is termed very heavy exercise. At these work rates, arterial lactate concentration in normal subjects typically continues to increase to levels as great as 10 mmol/L or more. Higher lactate causes earlier fatigue, whether arte- rial lactate is in the heavy or very heavy work intensity range (see Fig. 2.11). Lactate Increase in Response to Increasing Work Rate As illustrated in Figure 2.9, arterial lactate does not ap- preciably increase above resting values until a V̇O2 is reached above which lactate increases at a progressively steeper rate. To determine the best-fit mathematical model describing the V̇O2 at which lactate starts to in- crease, both continuous-exponential and threshold mod- els were tested.11,143 The purpose of this model testing was to better understand the physiological events that accompany the development of the highly reproducible FIGURE 2.12. The threshold behavior of arterial lactate increase as lactic acidosis engendered by heavy exercise. To obtain related to V̇O2 in response to exercise. Data are arterial lactate mea- a better picture of the systematic pattern of the change surements from 17 active healthy subjects (shown in Fig. 2.9). Points in arterial lactate with increasing V̇O2, the arterial blood are plotted only up to a lactate level of 4.5 mmol/L (the region of inter- lactate was plotted against the simultaneously measured est in evaluating threshold versus a continuous exponential model). V̇O2 after the V̇O2 scale was normalized to demonstrate a The vertical solid line shows the average threshold for the 17 sub- significant increase in arterial lactate for the 17 physically jects. The points for the individual subjects are plotted in the same active, healthy young male subjects shown in Figure 2.12. relation to the threshold V̇O2 as existed in their individual plots. In the In this plot, the data points are distributed with the same upper panel, the solid curve describes the continuous exponential deviation relative to the average curve as they were dis- model. Lactate values fall above the exponential model curve at the tributed in the individual curves for each subject. Because lowest V̇O2, whereas the lactate values are below the model curve in lactate increases steeply with little increase in V̇O2 as the region of the threshold. In contrast, the threshold model (solid V̇O2max is approached, the data were examined to address lines, lower panel) is a better fit to the actual lactate measurements. the question of model behavior for lactate increase dur- (Details of the mathematical analysis for a smaller number of subjects ing exercise (threshold or exponential), the analysis was are presented in Wasserman K, Beaver WL, Whipp BJ. Gas exchange restricted to the region of interest, from resting lactate to theory and the lactic acidosis (anaerobic) threshold. Circulation. 1990; arterial lactate of 4.5 mmol/L. 81(suppl 1):II14–II30) As illustrated in Figure 2.12 (upper panel), a mono- exponential model of lactate increase from rest as a func- lactate begins to increase in arterial blood coincides with tion of V̇O2 does not describe the lactate data well. Lactate that of the muscle.75 points fall above the model curve at the low V̇O2 values, whereas in the region of V̇O2 just below that at which lactate starts to rise (identified as the threshold in the Mechanisms of Lactate Increase threshold model), the points fall below the model curve. Several mechanisms have the potential to yield increases In contrast, the points distribute evenly around the two in lactate production as V̇O2 increases during exercise, as components of the threshold model (Fig. 2.12, lower described in the following sections. panel). This threshold denotes the LT. Neither the threshold nor the monoexponential mod- els is a perfect fit for the lactate–V̇O2 relationship at all Overload of the Tricarboxylic Acid Cycle work levels. However, the data in the region of interest Lactate can accumulate in the muscle and blood during (i.e., below 4.5 mmol/L) clearly fit the threshold model exercise if glycolysis proceeds at a rate faster than pyru- better than the exponential model. Supporting the thresh- vate can be utilized by the mitochondrial tricarboxylic old model are numerous muscle biopsy studies that show acid cycle (see Fig. 2.1). This mechanism should cause that muscle lactate does not increase at work rates within lactate to increase as a result of and in proportion to pyru- the moderate-intensity domain.31,65,72,75 The V̇O2 at which vate increase—that is, a mass action effect. 009-061_Wasserman_29774_Chapter_02.indd 20 9/24/11 12:22:23 AM  CHAPTER 2: PHYSIOLOGY OF EXERCISE 21 Sequential Recruitment of Fiber Types Another mechanism proposed for the increase in lactate during exercise is the increased recruitment of type IIx muscle fibers above the LT.62 These fibers contain high levels of glycogen. However, it has not been demonstrated that these fibers are activated at the LT. Furthermore, it would be necessary to demonstrate that type IIx fibers have a redox state with a higher NADH + H+ to NAD+ ratio and, therefore, higher lactate-to-pyruvate (L/P) ratio than types I or IIa fibers. Additionally, there is no evi- dence that activation of type IIx fiber types is influenced FIGURE 2.13. Log lactate (La−), log pyruvate (Pyr−), and log lactate- by changes in oxygenation, as is the case for arterial lac- to-pyruvate (L/P) ratio plotted against log V̇O2. The log–log transform of tate concentration. the lactate-V̇O2 and pyruvate-V̇O2 relationships allows easy detection of the lactate and pyruvate inflection points. The pyruvate inflection point Change in Cytosolic Redox State due is at a higher V̇O2 than the lactate inflection point. Because the pre- to Hypoxia Limiting the Mitochondrial threshold pyruvate slope is the same as the lactate slope, the L/P ratio Membrane Proton Shuttle does not increase until the lactate inflection point. (From Wasserman K, In the process of glycolysis (see Fig. 2.1), the oxidized Beaver WL, Davis JA, et al. Lactate, pyruvate, and lactate to pyruvate form of cytosolic NAD + is converted into the reduced ratio during exercise and recovery. J Appl Physiol. 1985;59:935–940, form (NADH + H+). It is subsequently reoxidized back with permission.) to NAD + by the mitochondrial membrane proton shuttle (see pathway A of Fig. 2.1). If, because of inadequate O2 availability in the mitochondria to reoxidize cytosolic vate as a result of change in the NADH + H+ /NAD + ratio NADH + H+ by the proton shuttle, the [NADH + H+]/ (cytosolic redox state) (see Fig. 2.1). The conversion of NAD + ratio increases (pathway B of Fig. 2.1). With this pyruvate to lactate results in the reoxidation of cytoso- change in redox state of the muscle, reoxidation of cy- lic NADH + H+, providing NAD + for continued glyco- tosolic [NADH + H+] can take place by pathway B of lysis even under anaerobic conditions. Because no O2 Figure 2.1 (pyruvate + [NADH + H+] → lactate + NAD +). is used in the reoxidation of pathway B (see Fig. 2.1), This mechanism is operative when the oxygen required this glycolysis is anaerobic. Simultaneously, reoxidation by the exercising muscles cannot be supplied at a suffi- of cytosolic NADH + H+ can take place aerobically, in ciently rapid rate to regenerate cytosolic NAD + by path- better oxygenated contracting muscle cells, by pathway way A. Thus, the cell redox state is lowered (increased A; this is aerobic glycolysis (see Fig. 2.1). A reversal of [NADH + H+]/NAD +), forcing an increase in the L/P the exercise-induced increase in arterial L/P is seen ratio (Fig. 2.13). at the start of recovery (Fig. 2.14), which provides an Figure 2.13 shows a plot of the log–log transfor- important clue to the mechanism(s) of the lactic aci- mation of arterial lactate, pyruvate, and L/P ratio as dosis during the exercise. The exercise-induced rise in a function of V̇O2 in one normal subject who was rep- arterial lactate may continue into the recovery phase resentative of the average response of 10 healthy sub- at a slowed rate for several minutes before it starts to jects.142 Below the LT, lactate increased by a few tenths decrease. Pyruvate concentration, on the other hand, of a mmol/L as pyruvate increased, but the L/P ratio did actually increases more rapidly at the start of recovery not increase until the LT was reached. Pyruvate also in- (see Fig. 2.14, middle panel). Thus, as soon as exercise creased steeply, but not until a V̇O2 was reached that was stops (and the O2 requirement decreases), the L/P ratio well above that of the LT. Also, the rate of increase in reverses, supporting the evidence obtained during ex- pyruvate was always slower than lactate. Consequently, ercise that the exercise-induced lactate increase is not the L/P ratio increased at the LT and continued to in- simply a mass action effect consequent to pyruvate in- crease until V̇O2max. A similar phenomenon has been crease. A reversal in L/P ratio, with lactate decreasing observed in the muscle cells of humans.22 The increase and pyruvate increasing, takes place in the muscle at the in muscle L/P was accompanied by a reduction in the start of recovery.142 muscle energy charge, indicated by an increase in the In summary, it is difficult to attribute the increase in ADP/ATP ratio.22 lactate with an increase in L/P ratio, as seen with heavy The increase in lactate with an increase in L/P ratio exercise, solely to accelerated glycolysis, inadequate tri- indicates that the increase in lactate during exercise is carboxylic acid cycle enzymes, or changes in contract- not simply a mass action phenomenon resulting from ing muscle fiber type. Rather, the experimental studies increased glycolysis. Rather, the lactate increase results support the concept that the major mechanism account- from a shift in equilibrium between lactate and pyru- ing for the lactate increase at the LT is the lowering of 009-061_Wasserman_29774_Chapter_02.indd 21 9/24/11 12:22:23 AM  22 PRINCIPLES OF EXERCISE TESTING AND INTERPRETATION FIGURE 2.14. Lactate (Lact ), pyruvate (Pyr ), and lactate-to-pyruvate (L/P) ratio during last 5 minutes (highest three work rates) of exercise and first 5 minutes of recovery. Studies show that lactate either increases or decreases slightly by 2 minutes of recovery. All subjects show a decrease by 5 minutes of recovery. In contrast, pyruvate continues to rise through the first 5 minutes of recovery. As a consequence, L/P ratio decreases by 2 minutes and continues to decrease by 5 minutes of recovery toward control value. (From Wasserman K, Beaver WL, Davis JA, et al. Lactate, pyruvate, and lactate-to-pyruvate ratio during exercise and recovery. J Appl Physiol. 1985;59:935–940, with permission.) cytosolic redox state induced by a net increase in an- saturation in the dog gracilis muscle during a moderate aerobic glycolysis. level of exercise, Gayeski and Honig estimated the PO2 in the sarcoplasm to be about 5 mm Hg.47 The P50 for oxy- myoglobin in humans is 3 to 6 mm Hg.46 Because it would Oxygen Supply, Critical Capillary PO2, and be less than one-half saturated, oxymyoglobin can serve Lactate Increase as an O2 store to support only very short bursts of heavy O2 is consumed by the contracting muscles for the aerobic exercise. However, it may play a role in facilitating O2 dif- regeneration of ATP (see Fig. 2.1). Therefore, under the fusion in muscle fibers containing myoglobin. partial pressure gradient, O2 is extracted from the capil- To obtain a PO2 of 15 mm Hg at the end capillary, a lary blood by the actively contracting muscles. Although muscle blood flow of at least 6 L would be needed for a isolated mitochondria can respire and rephosphorylate muscle O2 consumption of 1 L/min, assuming a hemoglo- ADP to ATP at a PO2 of 1 mm Hg or less,170 the capillary bin concentration of 15 g/dL and an alveolar PO2 adequate PO2 must be appreciably greater than 1 mm Hg to provide to saturate the arterial oxyhemoglobin to at least 95%. Thus, the O2 pressure to diffuse from the red cell to the sarco- approximately one-sixth of the O2 inflow into the capillary plasm to sustain muscle mitochondrial respiration dur- bed would remain at the venous end of the capillary. ing exercise. Wittenberg and Wittenberg estimated this Figure 2.15 illustrates the change in PO2 along a mus- pressure to be 15 to 20 mm Hg.170 It was termed the criti- cle capillary for various blood flow–metabolic rate ratios cal capillary PO2 because it represents the lowest capillary (Q̇m/V̇O2m) thought to be physiologic. This model allows PO2 that allows the muscle mitochondria to receive the O2 for the Bohr effect resulting from aerobic metabolism required to perform exercise aerobically. The major fac- (decreasing pH in the capillary from aerobic CO2 produc- tors determining the PO2 difference between red cell and tion) but not for anaerobic metabolism (lactic acidosis). sarcoplasm are the resistances to O2 diffusion by the red A blood flow–O2 consumption ratio of 5:1 would cause cell membrane, plasma, capillary endothelium, interstitial obligatory anaerobiosis and lactic acidosis because the space, and sarcolemma.47 By measuring oxymyoglobin muscle capillary PO2 would fall below the critical level 009-061_Wasserman_29774_Chapter_02.indd 22 9/24/11 12:22:23 AM  CHAPTER 2: PHYSIOLOGY OF EXERCISE 23 femoral vein PO2 and lactate closely approximate the av- erage end-capillary values of contracting muscle. Because the blood enters the muscle with a PO2 of 90 mm Hg (in a normal subject at sea level) and leaves the capillary bed at a PO2 that is approximately equal to that of the femoral vein PO2, the PO2 in the muscle fiber depends on the anatomical relation between the arterial and the venous end of the muscle capillary bed, and the Q̇m/V̇O2m ratio of the muscle unit (see Fig. 2.15). The critical capillary PO2 would be the lowest PO2 to which the end-capillary PO2 could fall. The capillary PO2 can- not decrease below the critical capillary PO2 because the mitochondrial PO2 would be too low to consume O2. That the critical capillary PO2 was reached would be evidenced by the failure of end-capillary or femoral vein PO2 to de- crease further despite increasing work rate. The model shown in Figure 2.15 is instructive in sev- eral respects. First, it illustrates that the capillary PO2 is heterogeneous, ranging from high values at the arterial end to low values at the venous end of the capillary bed, FIGURE 2.15. Model of muscle capillary bed O2 partial pressure (PO2) even when the muscle Q̇m/V̇O2m ratios for individual as blood travels from artery to vein. The model assumes hemoglobin capillary beds in the muscle are homogeneous. It also concentration of 15 g/dL, arterial PO2 of 90 mm Hg, and a linear O2 con- shows that estimates of mean muscle PO2, calculated from sumption along the capillary. The rate of fall of capillary PO2 depends femoral vein PO2, are erroneous unless it is certain that on the muscle blood flow (Q̇m)/muscle V̇O2 (V̇O2m) ratio. The curves there is no heterogeneity in Q̇m/V̇O2m ratios and that the include a Bohr effect due to a respiratory CO2 production. The capillary Q̇m/V̇O2m ratio is at least 6 (i.e., lactate is not increased). PO2 is heterogeneous along the capillary bed even with a homogenous Rather than the mean capillary PO2, the question must be Q̇m/muscle V̇O2. The end capillary PO2 cannot decrease below the criti- asked whether the muscle blood flow and therefore capil- cal capillary PO2. Any muscle unit with a theoretical Q̇m/V̇O2m less lary PO2 are sufficiently high to prevent a muscle lactic than 6 will have increased anaerobic metabolism and lactate produc- acidosis. When exercise is performed above the LT, both tion. See text for application of model. (From Wasserman K. Coupling aerobic and anaerobic metabolism take place. O2 is con-