Chapter 4: Exercise Metabolism

By studying this chapter, you should be able to do the following:

1. Discuss the relationship between exercise intensity/duration and the bioenergetic pathways that are most responsible for the production of ATP during various types of exercise.

2. Describe graphically the change in oxygen uptake during the transition from rest to steady-state exercise and then recovery from exercise. Identify the oxygen deficit, oxygen requirement, and oxygen debt (excess post-exercise oxygen uptake).

3. Describe graphically the changes in oxygen uptake during an incremental (graded) exercise test and identify the maximal oxygen uptake $(V˙O2 max)$.

4. Describe the various criteria for having achieved $(V˙O2 max)$.

5. Describe graphically the changes in the blood lactate concentration during an incremental (graded) exercise test and identify the lactate threshold.

6. Discuss several possible explanations for the sudden rise in blood-lactate concentration during incremental exercise.

7. List the factors that regulate fuel selection during exercise.

8. Describe the changes in the respiratory exchange ratio (R) with increasing intensities of exercise and during prolonged exercise of moderate intensity.

9. Describe the types of carbohydrates and fats used during increasing intensities of exercise and during prolonged exercise of moderate intensity.

10. Describe the lactate shuttle, with examples of how it is used during exercise.

• Energy Requirements at Rest 69

• Rest-to-Exercise Transitions 69

• Recovery from Exercise: Metabolic Responses 71

• Metabolic Responses to Exercise: Influence of Duration and Intensity 75

  • Short-Term, Intense Exercise 75

  • Prolonged Exercise 75

  • Incremental Exercise 76

• Estimation of Fuel Utilization during Exercise 80

• Factors Governing Fuel Selection 81

  • Exercise Intensity and Fuel Selection 81

  • Exercise Duration and Fuel Selection 82

  • Interaction of Fat/Carbohydrate Metabolism 84

  • Body Fuel Sources 84

anaerobic threshold

Cori cycle

excess post-exercise oxygen consumption (EPOC)

free fatty acids (FFAs)

gluconeogenesis

graded (or incremental) exercise test

incremental exercise test

lactate threshold

lipase

lipolysis

maximal oxygen uptake $(V˙O2 max)$

oxygen debt

oxygen deficit

respiratory exchange ratio (R)

Exercise poses a serious challenge to the bioenergetic pathways in the working muscle. For example, during heavy exercise, the body’s total energy expenditure may increase 15 to 25 times above expenditure at rest. Most of this increase in energy production is used to provide ATP for contracting skeletal muscles, which may increase their energy utilization 200 times over utilization at rest (1). Clearly, skeletal muscles have a great capacity to produce and use large quantities of ATP during exercise. This chapter describes (a) the metabolic responses at the beginning of exercise and during recovery from exercise; (b) the metabolic responses to high-intensity, incremental, and prolonged exercise; (c) the selection of fuels used to produce ATP; and (d) how exercise metabolism is regulated.

We begin with an overview of the energy requirements of the body at rest, followed by a discussion of which bioenergetic pathways are activated at the onset of exercise.

Recall that homeostasis is defined as a steady and an unchanging internal environment (see Chap. 2). During resting conditions, the healthy human body is in homeostasis, and therefore the body’s energy requirement is also constant. At rest, almost 100% of the energy (i.e., ATP) required to sustain bodily functions is produced by aerobic metabolism. It follows that resting blood lactate levels are also steady and low (e.g., 1.0 millimole per liter).

Because the measurement of oxygen (O₂) consumption (oxygen consumed by the body) is an index of aerobic ATP production, measurement of O₂ consumption during rest provides an estimate of the body’s “baseline” energy requirement. At rest, the total energy requirement of an individual is relatively low. For example, a 70-kilogram young adult would consume approximately 0.25 liter of oxygen each minute; this translates to a relative O₂ consumption of 3.5 ml of O₂ per kilogram (body weight) per minute. As mentioned earlier, muscular exercise can greatly increase the body’s need for energy. Let’s begin our discussion of exercise metabolism by considering which bioenergetic pathways are active during the transition from rest to exercise.

Assume you are standing alongside a treadmill with its belt moving at 7 mph, and you jump onto the belt and start running. Within one step, you go from zero to 7 mph, and in that one step your muscles increase their rate of ATP production from that required for standing to that required for running at 7 mph (see Fig. 4.1(a) and (b)). If ATP production did not increase instantaneously, you would have fallen off the back of the treadmill! What metabolic changes must occur in skeletal muscle at the beginning of exercise to provide the necessary energy to continue movement? Similar to the measurement of O₂ consumption during rest, the measurement of O₂ consumption during exercise can provide information about aerobic metabolism during exercise. For example, in the transition from rest to light or moderate exercise, O₂ consumption increases rapidly and reaches a steady state within one to four minutes (12, 22, 99) (Fig. 4.1(c)).

The fact that O₂ consumption does not increase instantaneously to a steady-state value means that anaerobic energy sources contribute to the overall production of ATP at the beginning of exercise. Indeed, much evidence suggests that at the onset of exercise, the ATP-PC system is the first active bioenergetic pathway, followed by glycolysis and, finally, aerobic energy production (4, 17, 41, 73, 104). This is shown in Figure 4.2(a), in which the PC concentration in muscle falls dramatically during a three-minute bout of exercise. Figure 4.2(b) shows that the production of ATP from PC was the highest in the first minute of exercise and fell off after that, due in part to the systematic reduction in the PC store. Figure 4.2(c) shows that glycolysis was already contributing ATP during the first minute of exercise and increased during the second minute (10). The effectiveness of these two anaerobic systems in the first minutes of exercise is such that ATP levels in muscle are virtually unchanged, even though ATP is being used at a much higher rate (120). However, as the steady-state O₂ consumption is reached, the body’s ATP requirement is met via aerobic metabolism, indicating that ATP is being produced aerobically as quickly as it is being used. The major point to be emphasized concerning the bioenergetics of rest-to-work transitions is that several energy systems are involved. In other words, the energy needed for exercise is not provided by simply turning on a single bioenergetic pathway, but rather by a mixture of several metabolic systems operating with considerable overlap.

The term oxygen deficit applies to the lag in oxygen uptake at the beginning of exercise. Specifically, the oxygen deficit is defined as the difference between oxygen uptake in the first few minutes of exercise and an equal time period after steady state has been obtained (90, 97). During this time, much of the ATP is supplied anaerobically (ATP-PC system and glycolysis) since aerobic ATP production is insufficient until the oxygen uptake reaches steady state. This is represented as the shaded area in the left portion of Figure 4.1(c). What causes this lag in oxygen uptake at the onset of exercise? Is it due to inadequate oxygen delivery to the muscle, or is it a failure of oxidative phosphorylation to increase immediately when exercise begins (82)? Dr. Bruce Gladden answers those questions in Ask the Expert 4.1.

Trained adults (64, 99) and adolescents (88) reach the steady-state $V˙O2$ faster than untrained subjects, resulting in a smaller oxygen deficit. What is the explanation for this difference? It seems likely that the trained subjects have a better developed aerobic bioenergetic capacity, resulting from either cardiovascular or muscular adaptations induced by endurance training (33, 64, 97, 99). Practically speaking, this means that aerobic ATP production is active earlier at the beginning of exercise and results in less production of lactate and H⁺ in the trained individual when compared to the untrained individual. Chapter 13 provides a detailed analysis of this adaptation to training.

If a subject is running on the treadmill at a speed that can be maintained comfortably for 20 or 30 minutes, and then jumps off to the side, the metabolic rate $(V˙O2)$ does not fall instantaneously from the steady-state value measured during the exercise to the resting $V˙O2$ value associated with standing by the treadmill. The metabolic rate remains elevated for several minutes immediately following exercise. This is shown in Figure 4.3(a), with a steady-state $V˙O2$ being achieved by minute 3 of submaximal exercise, and the oxygen uptake returning to resting levels by five minutes after exercise. This means that, for several minutes after exercise, the oxygen uptake is above the level needed to meet the demands of standing on the treadmill. In contrast, Figure 4.3(b) shows the subject doing nonsteady-state exercise that can be maintained for only six minutes before exhaustion occurs. This test is set at an intensity that exceeds the highest $V˙O2$ the subject can attain $(V˙O2 max)$. In this case, the subject could not meet the oxygen requirement for the task as shown by the much larger oxygen deficit, and the subject’s $V˙O2$ is still not back to the resting level by 14 minutes after exercise. Clearly, the magnitude and duration of this elevated post-exercise metabolic rate are influenced by the intensity of the exercise (6, 53, 97). The reason(s) for this observation will be discussed shortly.

Historically, the term oxygen debt has been applied to the elevated oxygen uptake (above resting levels) following exercise. The prominent British physiologist A. V. Hill (65) first used the term O₂ debt and reasoned that the excess oxygen consumed (above rest) following exercise was repayment for the O₂ deficit incurred at the onset of exercise (see A Look Back—Important People in Science). Evidence collected in the 1920s and 1930s by Hill and other researchers in Europe and the United States suggested that the oxygen debt could be divided into two portions: the rapid portion immediately following exercise (i.e., approximately two to three minutes post-exercise) and the slow portion, which persisted for greater than 30 minutes after some types of exercise. The rapid portion is represented by the steep decline in oxygen uptake following exercise, and the slow portion is represented by the slow decline in O₂ across time following exercise (Fig. 4.3(a) and (b)). The rationale for the two divisions of the O₂ debt was based on the belief that the rapid portion of the O₂ debt represented the oxygen that was required to resynthesize stored ATP and PC and replace tissue stores of O₂ (~20% of the O₂ debt), while the slow portion of the debt was due to the oxidative conversion of lactate to glucose in the liver (~80% of the O₂ debt).

Contradicting previous beliefs, current evidence shows that only about 20% of the oxygen debt is used to convert the lactate produced during exercise to glucose (the process of glucose synthesis from noncarbohydrate sources is called gluconeogenesis) (14, 17). Several investigators have argued that the term oxygen debt be eliminated from the literature because the elevated oxygen consumption following exercise does not appear to be entirely due to the “borrowing” of oxygen from the body’s oxygen stores (14, 15, 17, 46). In recent years, several replacement terms have been suggested. One such term is EPOC, which stands for “excess post-exercise oxygen consumption” (15, 46).

If the EPOC is not exclusively used to convert lactate to glucose, why does oxygen consumption remain elevated post-exercise? Several possibilities exist. First, at least part of the O₂ consumed immediately following exercise is used to restore PC in muscle and O₂ stores in blood and tissues (12, 46).

Restoration of both PC and oxygen stores in muscle is completed within two to three minutes of recovery (59). This is consistent with the classic view of the rapid portion of the oxygen debt. Further, heart rate and breathing remain elevated above resting levels for several minutes following exercise; therefore, both of these activities require additional O₂ above resting levels. Other factors that may result in the EPOC are an elevated body temperature and specific circulating hormones. Increases in body temperature result in an increased metabolic rate (called the Q₁₀ effect) (19, 57, 101). Further, it has been argued that high levels of epinephrine or norepinephrine result in increased oxygen consumption after exercise (48). However, both of these hormones are rapidly removed from the blood following exercise and therefore may not exist long enough to have a significant impact on the EPOC.

Compared to moderate-intensity exercise, the EPOC is greater during high-intensity exercise because (53)

• Heat production and body temperature are higher

• PC is depleted to a greater extent and more O₂ is required for its resynthesis

• Higher blood lactate levels mean more O₂ is required for lactate conversion to glucose in gluconeogenesis

• Epinephrine and norepinephrine levels are much higher.

All these factors may contribute to the EPOC being greater following high-intensity exercise than following moderate-intensity exercise. This observation has been used to make claims that high intensity exercise is better for weight loss because of the prolonged “after-burn.” However, it isn’t as important for weight loss as people might hope. It has been shown that when subjects are tested at the same absolute work rate following an endurance training program, the majority of these factors are reduced in magnitude, and with it, the EPOC (110). Figure 4.5 contains a summary of factors thought to contribute to the excess post-exercise oxygen consumption. Further, see A Closer Look 4.1 for more details on removal of lactate following exercise.

The point was made in Chap. 3 that short-term, high-intensity exercise lasting less than ten seconds utilizes primarily anaerobic metabolic pathways to produce ATP. In contrast, an event like the marathon makes primary use of aerobic ATP production to provide the needed ATP for work. However, events lasting longer than 10 to 20 seconds and less than 10 minutes generally produce the needed ATP for muscular contraction via a combination of both anaerobic and aerobic pathways. In fact, most sports use a combination of anaerobic and aerobic pathways to produce the ATP needed for muscular contraction. The next three sections consider which bioenergetic pathways are involved in energy production in specific types of exercise.

Short-Term, Intense Exercise

The energy to perform short-term exercise of high intensity comes primarily from anaerobic metabolic pathways. Whether the ATP production is dominated by the ATP-PC system or glycolysis depends primarily on the length of the activity (1, 4, 73, 80). For example, the energy to run a 50-meter dash or to complete a single play in a football game comes principally from the ATP-PC system. In contrast, the energy to complete the 400-meter dash (i.e., 55 seconds) comes from a combination of the ATP-PC system, glycolysis, and aerobic metabolism, with glycolysis producing most of the ATP. In general, the ATP-PC system can supply almost all the needed ATP for work for events lasting one to five seconds; intense exercise lasting longer than five seconds begins to utilize the ATP-producing capability of glycolysis. It should be emphasized that the transition from the ATP-PC system to an increased dependence upon glycolysis during exercise is not an abrupt change but rather a gradual shift from one pathway to another.

Events lasting longer than 45 seconds use a combination of all three energy systems (i.e., ATP-PC, glycolysis, and aerobic systems). This point was emphasized in Figure 3.23 in Chap. 3. In general, intense exercise lasting approximately 60 seconds utilizes 70%/30% (anaerobic/aerobic) energy production, whereas competitive events lasting 2 to 3 minutes utilize anaerobic and aerobic bioenergetic pathways almost equally to supply the needed ATP (see Fig. 3.23). Clearly, the contribution of aerobic energy production to the total energy requirement increases with the duration of the competition.

Prolonged Exercise

The energy to perform long-term exercise (i.e., more than ten minutes) comes primarily from aerobic metabolism. A steady-state oxygen uptake can generally be maintained during submaximal, moderate-intensity exercise. However, two exceptions to this rule exist. First, prolonged exercise in a hot/humid environment results in a “drift” upward of oxygen uptake; therefore, a steady state is not maintained in this type of exercise even though the work rate is constant (101) (see Fig. 4.6(a)). Second, continuous exercise at a high relative work rate (i.e., >75% $V˙O2 max$) results in a slow rise in oxygen uptake across time (57) (Fig. 4.6(b)). In each of these two types of exercise, the drift upward in $V˙O2$ is due principally to the effects of increasing body temperature and to rising blood levels of the hormones epinephrine and norepinephrine (19, 46, 48, 57, 78). Both of these variables tend to increase the metabolic rate, resulting in increased oxygen uptake across time. Use of a drug that blocks the receptors that epinephrine and norepinephrine bind to (to block their effects) results in an elimination of the drift in $V˙O2$, confirming the link between the two (78). In contrast, even though an eight-week endurance training program was shown to reduce the drift in $V˙O2$ during heavy exercise, it was not linked to a lower body temperature (21). Could lower epinephrine and norepinephrine levels be the cause, as was shown for the lower EPOC following endurance training (110)? Clearly, additional research is needed to explain the causes of this drift in $V˙O2$ in heavy exercise.

Incremental Exercise

Incremental exercise tests (also called graded exercise tests) are often employed by physicians to examine patients for possible heart disease and by exercise scientists to determine a subject’s cardiovascular fitness. These tests are usually conducted on a treadmill or a cycle ergometer. However, an arm crank ergometer can be employed for testing individuals who have lost use of their legs or athletes whose sport involves arm work (e.g., swimmers). The test generally begins with the subject performing a brief warm-up, followed by an increase in the work rate every one to three minutes until the subject cannot maintain the desired power output. This increase in work rate can be achieved on the treadmill by increasing either the speed of the treadmill or the incline. On the cycle or arm ergometer, the increase in power output is obtained by increasing the resistance against the flywheel.

Maximal Oxygen Uptake

The maximal capacity to transport and utilize oxygen during exercise (maximal oxygen uptake, or $V˙O2 max$) is considered by many exercise scientists to be the most valid measurement of cardiovascular fitness.

Figure 4.7 illustrates the change in oxygen uptake during a typical incremental exercise test on a cycle ergometer. Oxygen uptake increases systematically with work rate until $V˙O2 max$ is reached. When $V˙O2 max$ is reached, an increase in power output does not result in an increase in oxygen uptake; thus, $V˙O2 max$ represents a “physiological ceiling” for the ability of the oxygen transport system to deliver O₂ to contracting muscles. In the classic presentation of this test, the $V˙O2$ levels off or exhibits a “plateau” when the subject completes one stage further in the test (66, 117); Figure 4.7 shows this as a dashed line. The reason for using a dashed line is that many subjects do not demonstrate this plateau at the end of an incremental test; they simply cannot do one more stage beyond the one at which the highest $V˙O2$ was achieved. However, there are ways to demonstrate that the highest value reached is $V˙O2 max$ (3, 32, 71, 72, 76, 106) (see A Closer Look 4.2 for more on this). The physiological factors that influence $V˙O2 max$ include the following: (a) the maximum ability of the cardiorespiratory system to deliver oxygen to the contracting muscle and (b) the muscle’s ability to take up the oxygen and produce ATP aerobically. Both genetics and exercise training are known to influence $V˙O2 max$; this will be discussed in Chap. 13. Chapter 15 describes tests to measure or estimate $V˙O2 max$.

Lactate Threshold

During light and moderate intensity exercise, most of the ATP production used to provide energy for muscular contraction comes from aerobic sources (86, 98, 111). However, as the exercise intensity increases during an incremental exercise test, blood levels of lactate begin to rise in an exponential fashion (Fig. 4.8). This appears in untrained subjects around 50% to 60% of $V˙O2 max$, whereas it occurs at higher work rates in trained subjects (i.e., 65% to 80% $V˙O2 max$) (51). Early on, a common term used to describe the point of a systematic rise in blood lactate during incremental exercise was the anaerobic threshold (16, 31, 40, 67, 77, 100, 123, 125, 129) because of the obvious link between anaerobic metabolism and the appearance of lactate. However, because of arguments over terminology (discussed next), a more neutral term, the lactate threshold, has been widely adopted (30, 34, 116).

Another commonly used term that is related to the systematic rise in the blood lactate concentration is the onset of blood lactate accumulation (abbreviated as OBLA). This term, OBLA, differs from the lactate threshold in one important way. Rather than describing the blood lactate inflection point, the OBLA is defined as the exercise intensity (or oxygen consumption) at which a specific blood lactate concentration is reached (e.g., 4 millimoles per liter) (15, 61, 116). To avoid confusion, we will refer to the sudden rise in blood lactate levels during incremental exercise as the lactate threshold.

Some investigators believed that this sudden rise in the blood lactate concentration during incremental exercise represented a point of increasing reliance on anaerobic metabolism (i.e., glycolysis) (29, 121–125). Consequently, the term anaerobic threshold was adopted. The basic argument against the term anaerobic threshold centers around the question of whether the rise in blood lactate during incremental exercise is due to a lack of oxygen (hypoxia) in the working muscle or occurs for other reasons. Historically, rising blood lactate levels were considered an indication of increased anaerobic metabolism within the contracting muscle because of low levels of O₂ in the individual muscle cells (123, 125). However, whether the end product of glycolysis is pyruvate or lactate depends on a variety of factors. First, if the rate of glycolysis is rapid, NADH production may exceed the transport capacity of the shuttle mechanisms that move hydrogens from the sarcoplasm into the mitochondria (113, 115, 128). Indeed, blood levels of epinephrine begin to rise at 50% to 65% of $V˙O2 max$ during incremental exercise and have been shown to stimulate the glycolytic rate; this increase in glycolysis increases the rate of NADH production (115). Failure of the shuttle system to keep up with the rate of NADH production by glycolysis would result in pyruvate accepting some “unshuttled” hydrogens, and the formation of lactate could occur independent of whether the muscle cell had sufficient oxygen for aerobic ATP production (Fig. 4.9).

A second explanation for the formation of lactate in exercising muscle is related to the enzyme that catalyzes the conversion of pyruvate to lactate. The enzyme responsible for this reaction is lactate dehydrogenase (LDH), and it exists in several forms (different forms of the same enzyme are called isozymes). Recall that the reaction is as follows:

This reaction is reversible in that lactate can be converted back to pyruvate under the appropriate conditions. Human skeletal muscle can be classified into three fiber types (see Chap. 8). One of these is a “slow” fiber (sometimes called slow-twitch), whereas the remaining two are called “fast” fibers (sometimes called fast-twitch). As the names imply, fast fibers are recruited during intense, rapid exercise, whereas slow fibers are used primarily during low-intensity activity. The LDH isozyme found in fast fibers has a greater affinity for attaching to pyruvate, promoting the formation of lactate (69, 111). In contrast, slow fibers contain an LDH form that promotes the conversion of lactate to pyruvate. Therefore, lactate formation might occur in fast fibers during exercise simply because of the type of LDH present. Thus, lactate production would again be independent of oxygen availability in the muscle cell. Early in an incremental exercise test, it is likely that slow fibers are the first called into action. However, as the exercise intensity increases, the amount of muscular force produced must be increased. This increased muscular force is supplied by recruiting more and more fast fibers. Therefore, the involvement of more fast fibers may result in increased lactate production and thus may be responsible for the lactate threshold.

A final explanation for the lactate threshold may be related to the rate of removal of lactate from the blood during incremental exercise. When a researcher obtains a blood sample from a subject during an exercise test, the concentration of lactate in that sample is the difference between the rate at which lactate enters the blood and the rate at which lactate is removed from the blood. At any given time during exercise, some muscles are producing lactate and releasing it into the blood, and some tissues (e.g., liver, skeletal muscles, heart) are removing lactate. Therefore, the concentration of lactate in the blood at any given time can be expressed mathematically in the following way:

Thus, a rise in the blood lactate concentration can occur due to either an increase in lactate production or a decrease in lactate removal. Recent evidence suggests that the rise in blood lactate levels in animals during incremental exercise may be the result of both an increase in lactate production and a decrease in the rate of lactate removal (17, 37). See Chap. 13 for a discussion of how endurance training affects lactate production. Also, see The Winning Edge 4.1.

To summarize, controversy exists over both the terminology and the mechanism to explain the sudden rise in blood lactate concentration during incremental exercise. It is possible that any one or a combination of the explanations (including lack of O₂) might explain the lactate threshold. Figure 4.10 contains a summary of possible mechanisms to explain the lactate threshold. The search for definitive evidence to explain the mechanism(s) altering the blood lactate concentration during incremental exercise will continue for years to come.

Practical Use of the Lactate Threshold

Regardless of the physiological mechanism to explain the lactate threshold, it has important implications for predicting sports performance and perhaps in planning training programs for endurance athletes. For example, several studies have demonstrated that the lactate threshold, used in combination with other physiological measurements (e.g., $V˙O2 max$), is a useful predictor of success in distance running (43, 87). If $V˙O2 max$ is the “physiological ceiling” for aerobic ATP production during exercise, then the LT sets the upper limit for sustainable exercise intensity (e.g., $%V˙O2 max$ or running speed). Consequently, the lactate threshold might serve as a guideline for coaches and athletes in planning the level of exercise intensity needed to optimize training results (e.g., choose a training heart rate based on the LT). This is discussed in more detail in Chap. 16 and 21.

A noninvasive technique that is commonly used to estimate the percent contribution of carbohydrate or fat to energy metabolism during exercise is the ratio of the volume of carbon dioxide produced $(V˙CO2)$ to the volume of oxygen consumed $(V˙O2)$ (45, 127). This $V˙CO2/V˙O2$ ratio is called the respiratory exchange ratio (R). During steady-state conditions, the $V˙CO2/V˙O2$ ratio is often termed the respiratory quotient (RQ), as it is thought to reflect CO₂ production and O₂ consumption by the mitochondria of the active muscles. For simplicity, we will refer to the $V˙CO2/V˙O2$ ratio as the respiratory exchange ratio (R). How can the R be used to estimate whether fat or carbohydrate is being used as a fuel? The answer is related to the fact that fat and carbohydrate differ in the amount of O₂ used and CO₂ produced during oxidation. When using R as a predictor of fuel utilization during exercise, the role that protein contributes to ATP production during exercise is ignored. This is reasonable because protein generally plays a small role as a substrate during physical activity. Therefore, the R during exercise is often termed a nonprotein R.

Let’s consider the R for fat first. When fat is oxidized, O₂ combines with carbon to form CO₂ and joins with hydrogen to form water. The chemical relationship is as follows:

For R to be used as an estimate of substrate utilization during exercise, the subject must have reached a steady state. This is important because only during steady-state exercise are the $V˙CO2$ and $V˙O2$ reflective O₂ uptake and CO₂ production in the tissues. For example, if a person is hyperventilating due to the buildup of hydrogen ions in heavy work, excessive CO₂ loss from the body’s CO₂ stores (see Chap. 10 and 11) could bias the ratio of $V˙CO2$ to $V˙O2$ and invalidate the use of R to estimate which fuel is being consumed. That said, the elevated R measured at the end of a maximal incremental exercise test has been used as a secondary criterion for having achieved $V˙O2 max$ (see previous section on $V˙O2 max$).

Carbohydrate oxidation also results in a predictable ratio of the volume of CO₂ produced to the volume of O₂ consumed. The oxidation of carbohydrate results in an R of 1.0:

Fat oxidation requires more O₂ than carbohydrate oxidation because carbohydrate contains more O₂ than fat (116). The amount of energy released when one liter of oxygen is used (the caloric equivalent) is approximately 4.70 kcal when fats alone are used, and approximately 5.0 kcal when carbohydrates alone are used. Consequently, about 6% more energy (ATP) per liter of oxygen is obtained when using carbohydrate, compared to fat, as the sole fuel for exercise.

It is unlikely that either fat or carbohydrate would be the only substrate used during most types of submaximal exercise. Therefore, the R would likely be somewhere between 1.0 and 0.70. Table 4.1 lists a range of R values and the percentage of fat or carbohydrate metabolism they represent. Note that a nonprotein R of 0.85 represents a condition wherein fat and carbohydrate contribute equally as energy substrates. Further, notice that the higher the R, the greater the role of carbohydrate as an energy source, and the lower the R, the greater the contribution of fat. Table 4.1 shows how the caloric equivalent of oxygen changes with the mixture of fuel used (79).

Proteins contribute less than 2% of the substrate used during exercise of less than one hour’s duration. However, the role of proteins as a fuel source may increase slightly during prolonged exercise (i.e., three to five hours’ duration). During this type of exercise, the total contribution of protein to the fuel supply may reach 5% to 10% during the final minutes of work (11, 15, 70, 83, 84, 103, 126). Therefore, proteins play only a minor role as a substrate during most types of exercise, with fat and carbohydrate serving as the major sources of energy in healthy individuals consuming a balanced diet. Whether fat or carbohydrate is the primary substrate during work is determined by several factors, including (a) diet, (b) the intensity and duration of exercise, and (c) whether the subject is endurance trained. For example, consuming a high-fat/low-carbohydrate diet promotes a high rate of fat metabolism. In regard to exercise intensity, low-intensity exercise relies primarily on fat as fuel, whereas carbohydrate is the primary energy source during high-intensity exercise. Fuel selection is also influenced by the duration of exercise. During low-intensity, prolonged exercise, there is a progressive increase in the amount of fat oxidized by the working muscles. Endurance-trained subjects use more fat and less carbohydrate than less-fit subjects during prolonged exercise at the same intensity. In the next two sections, we discuss in detail the influence of exercise intensity and duration on fuel selection. The role of endurance training is discussed in detail in Chap. 13, and diet and performance is covered in Chap. 23.

Exercise Intensity and Fuel Selection

Again, fats are a primary fuel source for muscle during low-intensity exercise (i.e., 30% $V˙O2 max$), whereas carbohydrate is the dominant substrate during high-intensity exercise (i.e., 70% $V˙O2 max$) (20, 25, 94, 109). Consequently, the R increases as exercise intensity increases. The influence of exercise intensity on muscle fuel selection is illustrated in Figure 4.11. Note that as the exercise intensity increases, there is a progressive increase in carbohydrate metabolism and a decrease in fat metabolism. Also notice that as the exercise intensity increases, there is an exercise intensity at which the energy derived from carbohydrate exceeds that of fat; this work rate has been labeled the crossover point (20). That is, as the exercise intensity increases above the crossover point, a progressive shift occurs from fat to carbohydrate metabolism.

What causes this shift from fat to carbohydrate metabolism as the exercise intensity increases? Two primary factors are involved: (1) recruitment of fast fibers and (2) increasing blood levels of epinephrine. As the exercise intensity increases, more and more fast muscle fibers are recruited (50). These fibers have an abundance of glycolytic enzymes but few mitochondrial and lipolytic enzymes (enzymes responsible for fat breakdown). In short, this means that fast fibers are better equipped to metabolize carbohydrates than fats. Therefore, the increased recruitment of fast fibers results in greater carbohydrate metabolism and less fat metabolism (20).

A second factor that regulates carbohydrate metabolism during exercise is epinephrine. As exercise intensity increases, there is a progressive rise in blood levels of epinephrine. High levels of epinephrine increase phosphorylase activity, which causes an increase in muscle glycogen breakdown; this results in an increased rate of glycolysis and lactate production (20). Interestingly, there are some individuals who lack phosphorylase and cannot produce lactate (see Clinical Applications 4.1). This increased production of lactate inhibits fat metabolism by reducing the availability of fat as a substrate (119). The lack of fat as a substrate for working muscles under these conditions dictates that carbohydrate will be the primary fuel (see Chap. 5 for more details on how this occurs).

Many individuals use exercise as a means of keeping body weight and body fat in check, and you are probably familiar with pieces of exercise equipment having a selection for a “fat burning” workout. In such a workout, the emphasis is on low intensity and long duration. But is that really the best way to burn fat? See A Closer Look 4.3 for the answer.

Exercise Duration and Fuel Selection

During prolonged (i.e., greater than 30 minutes), moderate-intensity (40% to 59% $V˙O2 max$) exercise the R decreases over time, indicating a gradual shift from carbohydrate metabolism toward an increasing reliance on fat as a substrate (5, 49, 68, 81, 94, 102). Figure 4.12 demonstrates this point.

What factors control the rate of fat metabolism during prolonged exercise? Fat metabolism is regulated by those variables that control the rate of fat breakdown (a process called lipolysis). Triglycerides are broken down into free fatty acids (FFAs) and glycerol by enzymes called lipases. These lipases are generally inactive until stimulated by the hormones epinephrine, norepinephrine, and glucagon (68). For example, during low-intensity, prolonged exercise, blood levels of epinephrine rise, which increases lipase activity and thus promotes lipolysis. This increase in lipolysis results in an increase in blood and muscle levels of FFA and promotes fat metabolism. In general, lipolysis is a slow process, and an increase in fat metabolism occurs only after several minutes of exercise. This point is illustrated in Figure 4.12 by the slow increase in fat metabolism across time during prolonged submaximal exercise.

The mobilization of FFA into the blood is inhibited by the hormone insulin and high blood levels of lactate. Insulin inhibits lipolysis by the direct inhibition of lipase activity. Normally, blood insulin levels decline during prolonged exercise (see Chap. 5). However, if a high-carbohydrate meal or drink is consumed 30 to 60 minutes prior to exercise, blood glucose levels rise and more insulin is released from the pancreas. This elevation in blood insulin may result in diminished lipolysis and a reduction in fat metabolism, leading to a greater use of carbohydrate as a fuel (see Chap. 23 for more on this).

Interaction of Fat/Carbohydrate Metabolism

During short-term exercise, it is unlikely that muscle stores of glycogen or blood glucose levels would be depleted. However, during prolonged exercise (e.g., greater than two hours) muscle and liver stores of glycogen can reach very low levels (15, 26, 50, 55, 62). This is important because depletion of muscle and blood carbohydrate stores results in muscular fatigue (55). Why do low muscle glycogen levels produce fatigue? Evidence suggests the following answer. Depletion of available carbohydrate reduces the rate of glycolysis, and therefore the concentration of pyruvate in the muscle is also reduced (55). This lowers the rate of aerobic production of ATP by reducing the number of Krebs-cycle compounds (intermediates). In human muscle with adequate glycogen stores, submaximal exercise (i.e., 70% $V˙O2 max$) results in a ninefold increase (above resting values) in the number of Krebs-cycle intermediates (108). This elevated pool of Krebs-cycle intermediates is required for the Krebs cycle to “speed up” in an effort to meet the high ATP demands during exercise. Pyruvate (produced via glycolysis) is important in providing this increase in Krebs-cycle intermediates. For example, pyruvate is a precursor of several Kreb-scycle intermediates (e.g., oxaloacetate, malate). When the rate of glycolysis is reduced due to the unavailability of glucose or glycogen, pyruvate levels in the sarcoplasm decline, and the levels of Krebs-cycle intermediates decrease as well. This decline in Krebs-cycle intermediates slows the rate of Krebs-cycle activity, with the end result being a reduction in the rate of aerobic ATP production. This reduced rate of muscle ATP production limits muscular performance and may result in fatigue.

It is important to appreciate that a reduction in Krebs-cycle intermediates (due to glycogen depletion) results in a diminished rate of ATP production from fat metabolism because fat can be metabolized only via Krebs-cycle oxidation. Hence, when carbohydrate stores are depleted in the body, the rate at which fat is metabolized is also reduced (108). Therefore, “fats burn in the flame of carbohydrates” (115). The role that depletion of body carbohydrate stores may play in limiting performance during prolonged exercise is introduced in The Winning Edge 4.2 and is further discussed in both Chaps. 19 and 23.

Body Fuel Sources

In this section, we outline the storage sites in the body for carbohydrates, fats, and proteins. Further, we define the role that each of these fuel storage sites plays in providing energy during exercise. Finally, we discuss the use of lactate as a fuel source during work.

Sources of Carbohydrate During Exercise

Carbohydrate is stored as glycogen in both the muscle and the liver (see Table 4.2). Muscle glycogen stores provide a direct source of carbohydrate for muscle energy metabolism, whereas liver glycogen stores serve as a means of replacing blood glucose. For example, when blood glucose levels decline during prolonged exercise, liver glycogenolysis is stimulated and glucose is released into the blood. This glucose can then be transported to the contracting muscle and used as fuel.

Carbohydrate used as a substrate during exercise comes from both glycogen stores in muscle and from blood glucose (23, 27, 50, 74, 114). The relative contribution of muscle glycogen and blood glucose to energy metabolism during exercise varies as a function of the exercise intensity and duration. Blood glucose plays the greater role during low-intensity exercise, whereas muscle glycogen is the primary source of carbohydrate during high-intensity exercise (see Fig. 4.14). As mentioned earlier, the increased glycogen usage during high-intensity exercise can be explained by the increased rate of glycogenolysis that occurs due to recruitment of fast-twitch fibers and elevated blood epinephrine levels.

During the first hour of submaximal (i.e., 65% to 75% $V˙O2 max$) prolonged exercise, much of the carbohydrate metabolized by muscle comes from muscle glycogen. However, as muscle glycogen levels decline across time, blood glucose becomes an increasingly important source of fuel (see Fig. 4.15).

Sources of Fat During Exercise

When an individual consumes more energy (i.e., food) than he or she expends, this additional energy is stored in the form of fat. A gain of 3500 kcal of energy results in the storage of 1 pound of fat. Most fat is stored in the form of triglycerides in adipocytes (fat cells), but some is stored in muscle cells as well (see Table 4.2). As mentioned earlier, the major factor that determines the role of fat as a substrate during exercise is its availability to the muscle cell. To be metabolized, triglycerides must be degraded to FFA (three molecules) and glycerol (one molecule). The FFA can be converted into acetyl-CoA and enter the Krebs cycle.

Which fat stores are used as a fuel source varies as a function of the exercise intensity and duration. For example, plasma FFAs (i.e., FFA from adipocytes) are the primary source of fat during low-intensity exercise. At higher work rates, metabolism of muscle triglycerides increases (see Fig. 4.14). At exercise intensities between 65% and 85% $V˙O2 max$, the contribution of fat as a muscle fuel source is approximately equal between plasma FFA and muscle triglycerides (25, 58, 105).

The contribution of plasma FFA and muscle triglycerides to exercise metabolism during prolonged exercise is summarized in Figure 4.15. Note that at the beginning of exercise, the contribution of plasma FFA and muscle triglycerides is equal. However, as the duration of exercise increases, there is a progressive rise in the role of plasma FFA as a fuel source.

Sources of Protein During Exercise

To be used as a fuel source, proteins must first be degraded into amino acids. Amino acids can be supplied to muscle from the blood or from the amino acid pool in the fiber itself. Again, the role that protein plays as a substrate during exercise is small and is principally dependent on the availability of branch-chained amino acids and the amino acid alanine (8, 54). Skeletal muscle can directly metabolize branched-chain amino acids (e.g., valine, leucine, isoleucine) to produce ATP (52, 70). Further, in the liver, alanine can be converted to glucose and returned via the blood to skeletal muscle to be utilized as a substrate.

Any factor that increases the amino acid pool (amount of available amino acids) in the liver or in skeletal muscle can theoretically enhance protein metabolism (70, 85). One such factor is prolonged exercise (i.e., more than two hours). Numerous investigators have demonstrated that enzymes capable of degrading muscle proteins (proteases) are activated during long-term exercise (2, 35, 36, 95). The mechanism responsible for activation of these proteases during prolonged exercise appears to be exercise-induced increases in calcium levels within muscle fibers (2, 91). Indeed, several families of proteases are activated by increases in cellular levels of calcium (2, 91). As a result of this activation, amino acids are liberated from their parent proteins and increase the use of amino acids as fuel during exercise (94). The use of protein as a fuel during exercise is also related to carbohydrate availability (see Chap. 23).

Lactate as a Fuel Source During Exercise

For many years, lactate was considered to be a waste product of glycolysis with limited metabolic use. However, evidence has shown that lactate plays a beneficial role during exercise by serving as both a substrate for the liver to synthesize glucose (see A Closer Look 4.4) and as a direct fuel source for skeletal muscle and the heart (13, 17, 58). That is, in slow skeletal muscle fibers and the heart, lactate removed from the blood can be converted to pyruvate, which can then be transformed to acetyl-CoA. This acetyl-CoA can then enter the Krebs cycle and contribute to oxidative metabolism. The concept that lactate can be produced in one tissue and then transported to another to be used as an energy source has been termed the lactate shuttle (13, 14, 16–18). This has implications well beyond lactate being used as a fuel or participating in gluconeogenesis. Lactate shuttles have been implicated in the growth of cancer cells (38, 75, 112).

1. Identify the predominant energy systems used to produce ATP during the following types of exercise:

   1. Short-term, intense exercise (i.e., less than ten seconds’ duration)

   2. 400-meter dash

   3. 20-kilometer race (i.e., 12.4 miles)

2. Graph the change in oxygen uptake during the transition from rest to steady-state, submaximal exercise. Label the oxygen deficit. Where does the ATP come from during the transition period from rest to steady state?

3. Graph the change in oxygen uptake during recovery from exercise. Label the excess post-exercise oxygen consumption (EPOC) (i.e., oxygen debt).

4. Graph the change in oxygen uptake and blood lactate concentration during incremental exercise. Label the point on the graph that might be considered the lactate threshold.

5. Discuss several possible reasons why blood lactate begins to rise rapidly during incremental exercise.

6. Briefly explain how the respiratory exchange ratio is used to estimate which substrate is being utilized during exercise. What is meant by the term nonprotein R?

7. List the factors that play a role in the regulation of carbohydrate metabolism during exercise.

8. Discuss the influence of exercise intensity on muscle fuel selection.

9. How does the duration of exercise influence muscle fuel selection?

10. List those variables that regulate fat metabolism during exercise.

11. What is the “lactate shuttle”?