Physical activity as a metabolic stressor13

Edward F Coyle

ABSTRACT Both physical activity and diet stimulate very specific and varied adaptations according to the type, inten-
processes that, over time, alter the morphologic composition and sity, and duration of exercise performed.
biochemical function of the body. Physical activity provides
stimuli that promote very specific and varied adaptations accord-
ing to the type, intensity, and duration of exercise performed. STRESS OF PHYSICAL ACTIVITY
There is further interest in the extent to which diet or supple- A conceptual scheme of the stress, stimuli, and adaptation
mentation can enhance the positive stimuli. Prolonged walking derived from physical activity in skeletal muscle is shown in Fig-

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at low intensity presents little metabolic, hormonal, or cardio- ure 1. Carbohydrate, fat, and protein, obtained either directly
vascular stress, and the greatest perturbation from rest appears to from daily meals or from endogenous stores in the body, provide
be from increased fat oxidation and plasma free fatty acid mobi- the substrates that fuel the chemical reactions that in turn are cat-
lization resulting from a combination of increased lipolysis and alyzed by enzymes and cofactors. In the process of these reac-
decreased reesterification. More intense jogging or running tions, the chemical energy in substrates is converted to the type
largely stimulates increased oxidation of glycogen and triacyl- of chemical energy that cells can harness, namely ATP. ATP can
glycerol, both of which are stored directly within the muscle be resynthesized anaerobically by dissolving glucose or glyco-
fibers. Furthermore, these intramuscular stores of carbohydrate gen (glycolysis) in the cytoplasm of cells, or it can be resynthe-
and fat appear to be the primary substrates for the enhanced sized aerobically by chemical reactions within the mitochondria
oxidative and performance ability derived from endurance train- that consume oxygen. These metabolic reactions proceed at the
inginduced increases in muscle mitochondrial density. Weight- rates required to maintain ATP concentrations in the cells. Thus,
lifting that produces fatigue in brief periods (ie, in 1590 s and increasing exercise intensity increases metabolic rate as reflected
after 15 repetitive contractions) elicits a high degree of motor by increasing rates of chemical reactions, oxygen consumption,
unit recruitment and muscle fiber stimulation. This is a remark- and substrate depletion. The resynthesis of ATP during exercise
ably potent stimulus for altering protein synthesis in muscle and signals a disturbance in metabolic homeostasis and provides
increasing neuromuscular function. The metabolic stress of powerful stimuli to the cell that eventually cause it to adapt to
physical activity can be measured by substrate turnover and aerobic exercise training, generally by altering the balance
depletion, cardiovascular response, hormonal perturbation, between select protein synthesis and protein degradation (Fig-
accumulation of metabolites, or even the extent to which the ure 1). Increases in mitochondrial protein within skeletal muscle
synthesis and degradation of specific proteins are altered, either as a result of aerobic endurance training are generally thought to
acutely or by chronic exercise training. Am J Clin Nutr be stimulated by some aspect of ATP resynthesis (2).
2000;72(suppl):512S20S. In muscle, the chemical energy released by ATP hydrolysis dur-
ing contraction is converted to either heat or muscle force. Muscle
KEY WORDS Exercise, physical activity, exertion, nutrition, force develops from the tension generated by the interaction of the
carbohydrate, triacylglycerol, protein synthesis, hormone, muscle actin-myosin filaments and produces a mechanical loading on the
muscle fibers that also provides stimuli for muscle adaptation. In
this case, however, mechanical force on muscle fibers stimulates
INTRODUCTION an increase in the actin-myosin mass within the muscle fiber, again
It is becoming increasingly clear that a persons health and by altering the balance between synthesis and degradation of these
well-being are improved by physical activity as well as by a specific proteins (3). This process describes the hypertrophy that
nutritious diet (1). Both physical activity and diet stimulate occurs with weightlifting, as discussed below.
processes that, over time, alter the morphologic composition and
biochemical function of the body. Physical activity and diet are 1
From the Human Performance Laboratory, Department of Kinesiology
interrelated in that optimal adaptation to the stress of exercise
and Health Education and Division of Nutritional Sciences, University of
training usually requires a diet that is not lacking in various Texas at Austin.
nutrients. The optimal amount of dietary nutrients for effective 2
Presented at the workshop Role of Dietary Supplements for Physically
adaptation is a theme of this journal supplement. Physical activ- Active People, held in Bethesda, MD, June 34, 1996.
ity should therefore be viewed as providing stimuli that stress 3
Address reprint requests to EF Coyle, University of Texas at Austin,
various systems of the body to various degrees and thus promote Room 222, Bellmont Hall, Austin, TX 78712.

512S Am J Clin Nutr 2000;72(suppl):512S20S. Printed in USA. 2000 American Society for Clinical Nutrition
 PHYSICAL ACTIVITY AS A METABOLIC STRESSOR 513S

plasma norepinephrine concentration all increase linearly with

increasing intensity of aerobic exercise (13). Ventilation, muscle
glycogenolysis, and plasma epinephrine concentration also
increase with intensity of aerobic exercise but at a nonlinear rate
as the metabolic stress becomes progressively more severe (13).
Examples of many other types of responses could be given. The
salient point is that each marker of the various systems is
responding to a unique stress that its end organ is experiencing
during physical activity.

Determinants of metabolic stress of physical activity

Within a given individual, the metabolic stress during physi-
cal activity is generally determined by the type and intensity of
exercise, state of physical fitness, nutritional status, and environ-
FIGURE 1. Theoretical scheme of the metabolic and mechanical mental factors. To some extent, these determinants of metabolic
stress on skeletal muscle during and after physical activity.
stress can be controlled. Other factors that influence the meta-
bolic stress an individual experiences during physical activity
include genetic disposition, age, and sex.
Attempt to maximize positive stress while minimizing
negative stress Intensity and type of exercise

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The metabolic and mechanical stresses of physical activity This paper compares the metabolic stress encountered while
stimulate many healthful adaptations in numerous tissues and walking, running, and lifting heavy weights. Physical activity
organs in a dose-response manner (4). In this context, the stress of can be quite varied, but these 3 common activities provide good
physical activity can elicit an overall positive outcome, reflected examples of the influence of increasing the intensity of pro-
by a reduced risk of heart disease on the one hand and increased longed aerobic exercise from walking to running and of repeat-
physical performance on the other (5). However, physical activity edly generating high muscle forces for short durations (ie,
can also place various tissues under acute stress. An underlying weightlifting). For example, presented in Table 1 are the
question for this journal supplement is the extent to which diet or responses of a typical adult who engages in regular exercise and
supplementation can enhance the positive stimuli of physical is of above-average fitness with a maximal oxygen uptake

activity and reduce the negative stimuli so as to optimize the (VO2max) of 45 mL kg1 min1 relative to body weight (ie,
healthful adaptations and improvements in physical performance. 3 L/min in absolute terms). Walking at 4.8 km/h (3 miles/h)

would elicit  33% of VO2max in this person, which corresponds
Measures of the metabolic stress of physical activity to a rate of energy expenditure of 1.25 MJ/h (300 kcal/h).
In a general sense, the metabolic stress of physical activity can Healthy persons can walk for many hours at this rate. This typical

be gauged by fluxes generated within the exercising muscles in person could run comfortably at 65% of VO2max (ie, 2.5 MJ/h, or
any or all of the reactions illustrated in Figure 1. It is most com- 600 kcal/h) and cover 10 km in 1 h. This would be classified as
mon to quantify ATP turnover during continuous aerobic, steady moderate- to high-intensity exercise.
state exercise by measuring whole-body oxygen consumption. Lifting heavy weights while performing actions such as leg
When a person lifts weights, typically for a short duration (eg, squats, bench presses, or arm curls causes fatigue after relatively
1030 s), ATP resynthesis is derived largely from anaerobic gly- few repetitions. The intensity of weightlifting is quantified as a
colysis, and the stress of exercise is commonly gauged from the percentage of a persons one-repetition maximum (1RM; ie, the
muscle force developed. Muscle force is proportional to the heaviest weight an individual can lift just one time) (14). As indi-
amount weightlifted through a given range of motion. Other less cated in Table 2, a person can usually lift 65% of his or her 1RM
practical and more specific ways of quantifying the various for 15 repetitions and for 1 min before fatiguing. Also shown
aspects of metabolic stress during physical activity include meas- in Table 2 is the extent to which the number of repetitions, until
urement of substrate turnover (ie, flux or kinetics) (6), substrate fatigue, declines with increases in the percentage of 1RM. For
depletion (7, 8), enzymatic activity in muscle (9), heat production general skeletal-muscular fitness, the recommended minimum is
(10), or accumulation of metabolites (eg, lactate, hydrogen ion, 1 set of 812 repetitions of 810 exercises that condition the
ammonia, and hexose monophosphates) (11). It is even possible major muscle groups 2 d/wk. People can comfortably progress
to use molecular techniques to probe the extent to which the syn- to completing 3 sets of each exercise 34 times/wk.
thesis and degradation of specific proteins are altered by acute
physical activity or chronic exercise training (2, 3).
Increased metabolism in the active skeletal musculature must NEUROMUSCULAR RECRUITMENT
be supported, and sometimes initiated, by other systems of the Movement is initiated by the central nervous system. It begins
body, especially the nervous, cardiovascular, endocrine, and res- with activation of the motor cortex in the brain and depolariza-
piratory systems (12). The metabolic stress of physical activity tion of the corticospinal neurons that innervate the  motor neu-
can also be gauged generally by the extent to which each of these rons in the spine. These neurons lead to the muscle fibers that
systems is activated to respond. However, each of these unique power activity. As the intensity of exercise increases, the higher
systems differs somewhat in its threshold and sensitivity to the muscle forces and power outputs are generated by both recruit-
various components of metabolic stress. For example, heart rate, ing more motor units (ie, the motor neuron and its muscle fibers)
cardiac output, systolic blood pressure, muscle blood flow, and per contraction and increasing the firing frequency with which a
514S COYLE

TABLE 1 energy (100 000 kcal), which is enough to fuel  1600 km

Aerobic metabolic stress for a typically active 30-y-old when walking and (1000 miles) of walking (assuming  0.3 MJ/km or 100 kcal/mile).
jogging1 Triacylglycerol is also stored directly within individual muscle
Percentage Energy fibers [intramuscular triacylglycerol (IMTG)]. The amount of
these IMTG stores is less well studied but is assumed to contain
Activity of VO2max VO2 expenditure METs
% L /min MJ/h (kcal/min)
1220 MJ energy (19). For triacylglycerol to be oxidized in
skeletal muscle during exercise, it must first be hydrolyzed by the
Walking (4.8 km) 33 1.0 1.25 (300) 34 process of lipolysis to free fatty acids and transported to the meta-
Jogging (9.7 km) 65 2.0 2.50 (600) 68
bolically active inner mitochondria (20). The fatty acids gener-
1
This example applies to a person with a maximal oxygen consumption ated from adipocyte triacylglycerol are either reesterified or

(VO2max) of 3 L/min (ie, 45 mL kg1 min1) and a body weight of 66 kg. released from the cell for potential binding to plasma albumin,
METs, metabolic equivalent relative to rest (the number of times that oxy-
the major protein carrier in the bloodstream (20). These circulat-
gen consumption is elevated above resting metabolic rate).
ing plasma fatty acids are then available for uptake by tissue. The
active skeletal muscles oxidize 8090% of the fatty acids disap-
given motor unit is recruited (15). A theoretical example of the pearing from the circulation (21) and the remainder are presum-
pattern with which fibers in the vastus lateralis muscle are ably reesterified. Transport of fatty acids from IMTG to the outer
recruited during cycling and running of increasing exercise mitochondrial membrane is less complicated.
intensity is depicted in Figure 2. Walking or cycling at low All fatty acids must be transported across the mitochondrial
intensity is believed to recruit mostly the type I motor units that membrane for oxidation, and this may be a rate-limiting step.
innervate the slow-twitch muscle fibers because they have a low For example, the common long-chain fatty acid palmitate is

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threshold for recruitment (15). On average among a population, transported via the carnitine O-palmitoyltransferase reaction,
approximately one-half of the fibers in the vastus lateralis are which is greatly inhibited by malonyl-CoA (22). This metabo-
slow-twitch fibers, yet values can range from 20% to 80% (16). lite has been proposed as a fuel sensor (23) because it increases

Running or cycling at 65% of VO2max recruits both type I and when either carbohydrate or fat is available and declines during
some type IIa motor units (fast-twitch A fibers). The type IIb exercise in the fasting state (24). Indeed, our laboratory
motor units innervating the fast-twitch B muscle fibers are not observed that plasma palmitate oxidation during exercise is
recruited to contract until the exercise intensity is high. actively reduced when blood glucose uptake and glycolytic flux
As indicated in Figure 2, an exercise intensity that elicits are increased (21). Furthermore, this phenomenon seems to

100% of VO2max, which can be maintained for 38 min before involve reduction in mitochondrial transport, on the basis of the
fatiguing, requires a muscular force that is only 3060% of 1RM observation that oxidation of a medium-chain fatty acid (ie,
or maximal power. It appears that in the vastus lateralis muscle, octanoate) is neither limited nor reduced by increased glycolytic
force production >3060% of 1RM is generated not so much by flux. It is our hypothesis that fatty acid oxidation may be lim-
recruiting more muscle fibers but by increasing the frequency of ited to some extent by carbohydrate availability, which reduces
fiber recruitment per contraction to attain the greater instan- fatty acid transport into mitochondria (21). This hypothesis
taneous actin-myosin interaction. Various muscles throughout implies that when carbohydrate and fatty acids are both readily
the body differ markedly in the pattern with which they increase available to muscle during exercise, carbohydrate seems to be
the number of fibers recruited compared with the frequency of preferred. However, people do not normally have the ability to

recruitment to generate higher forces as acute exercise intensity run at 65% of VO2max while oxidizing mostly fatty acids (ie,
increases. Thus, only one example is shown in Figure 2. This > 70% of energy). For this reason, when carbohydrate availabil-
understanding also indicates that the improvement in 1RM that ity is very low, such as during the muscle glycogen depletion
people typically experience after a chronic (eg, several weeks) and hypoglycemia that is typically experienced after 23 h of
training program of weightlifting is due partly to neurologic exercise, people normally are not able to exercise more

adaptations that are thought to increase the number and fre- intensely than 4060% of VO2max (25).
quency of motor unit recruitment (15).
Muscle fibers that are very rarely recruited to contract are
obviously under little metabolic stress and thus receive minimal TABLE 2
stimuli. An important point of Figure 2 and the preceding dis- Classification of the intensity of weightlifting for physically active people
cussion is that many of our skeletal muscle fibers, especially the Estimated number of
higher-threshold, fast-twitch ones, would not be expected to be Intensity Percentage of 1RM1 repetitions possible2
sufficiently active when a person does not engage in periodic, %
high-intensity, aerobic exercise or weight training. It is impres-
sive that only 10 contractions per training session, lasting only Very heavy 95100 12
Heavy 9095 26
40 s, appear to be a powerful stimulus for some aspects of mus-
Moderately heavy 8590 38
cle adaptation (17, 18). Moderate 8085 510
Substrate storage and maximal rates of utilization Moderately light 7580 712
Light 7075 1015
The major substrates for ATP resynthesis in active muscle are Very light 6570 15
fat and carbohydrate; protein plays a minor role except in extreme 1
1RM, one-repetition maximum (the maximal weight that can be lifted
conditions analogous to starvation (19). Fat is stored as triacyl- through one full range of motion).
glycerol, mostly in adipocytes throughout the body. For example, 2
The estimated number of repetitions possible will depend on the per-
in a 66-kg person with 18% body fat, this amounts to > 480 MJ sons strength-to-endurance ratio (14).
 PHYSICAL ACTIVITY AS A METABOLIC STRESSOR 515S

during prolonged exercise with hyperinsulinemia and hypergly-

cemia, blood glucose uptake can reach 2.5 g/min (38).

METABOLIC STRESS OF LOW-INTENSITY AEROBIC

EXERCISE

In the fasting state

Shown in Figure 3 is the substrate oxidation observed in well-
trained cyclists at rest and after 30 min of exercise after an
overnight fast (6). At rest, oxidative needs can be met by plasma

fatty acids and blood glucose. During exercise at 25% of VO2max,
metabolic rate is increased 3- to 4-fold above rest, a requirement
met primarily by an increase in mobilization, uptake, and oxida-
tion of plasma fatty acids (6). Blood glucose uptake increases
only slightly. Low-intensity exercise markedly increases mobi-
lization of plasma fatty acids (ie, rate of appearance of fatty acids
into plasma), partly because exercise stimulates increased lipoly-
sis and largely because the rate of reesterification of fatty acids
FIGURE 2. Theoretical relation between exercise intensity and the
percentage of active muscle fibers in the vastus lateralis during cycling. within the adipocytes diminishes remarkably, from  80% at rest

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Exercise intensity is expressed as a percentage of maximal oxygen con- to 20% during exercise (39). Lipolysis in adipose tissue is
increased during exercise primarily because epinephrine stimu-
sumption (% of VO2max) as well as a percentage of the one-repetition
lates -adrenergic receptors (40) and because plasma insulin, a
maximum (1RM). Note that 100% of VO2max corresponds to  3060%
of 1RM. The muscle fiber (slow and fast twitch) and motor neuron types potent inhibitor of lipolysis, decreases (32, 41). Metabolic stress
(type I, IIa, or IIb) that are progressively recruited are indicated (15). during low-intensity exercise is not great and thus responses
remain relatively stable, not differing substantially after 30 min
from those observed after 24 h (6). Blood glucose kinetics, and
Other possible explanations for a limit in the rate of oxida- thus concentration, appear stable, as do plasma fatty acid kinetics
tion that can be supported solely by fatty acids during exercise and total fat oxidation (6). Accordingly, the hormonal responses
may involve an anaplerotic loss of tricarboxylic acid cycle that are indicative of metabolic stress are also not substantially
intermediates that requires replenishment from carbohydrate altered. For example, plasma epinephrine and norepinephrine are
(2628). Although definitive answers are lacking, it is clear only slightly increased above resting values (6). Plasma cortisol
that availability of carnitine for mitochondrial transport of actually declines throughout prolonged low-intensity exercise,
fatty acids during exercise is not limiting and that carnitine probably as a result of increased clearance (42). These responses
supplementation is not beneficial in normal individuals and are consistent with the observation that people can walk for many
athletes (29, 30). Triacylglycerol in blood, another substrate, hours without much metabolic stress (43).
appears to be only slowly converted to fatty acids and thus is
not thought to be a major substrate during exercise (31), After eating a meal
although it is probably important for replenishment of IMTG Fatty acid mobilization and oxidation are markedly reduced
stores after exercise. when a meal containing carbohydrate is eaten during the hours
Carbohydrate is stored in the body as glycogen, a starch com- before exercise, or even when carbohydrate is eaten during low-
prising glucose molecules that can be readily hydrolyzed. Glyco- intensity exercise (33, 44, 45). Of course, carbohydrate ingestion
gen is stored directly in the muscle fiber and is the major source at rest or during very low-intensity exercise with minimal
of carbohydrate during most types of exercise. The amount of increases in catecholamines will stimulate insulin secretion.
glycogen stored in skeletal muscle can vary with diet and train- Insulin is a potent inhibitor of lipolysis and plasma fatty acid
ing, but it is generally in the range of 610 MJ (15002500 kcal) mobilization and is a potent stimulator of muscle glucose uptake
(19). A most important aspect of muscle glycogen hydrolysis is (41, 46). With both of these effects of insulin, substrate oxidation
that it can be quickly activated to resynthesize ATP at high shifts from plasma fatty acids to blood glucose (21, 44, 46). The

ratesup to 1.52-fold of VO2max. These high-intensity sprints source of the increased carbohydrate oxidation appears to be
cannot be maintained for > 3060 s because lactic acid largely blood glucose from the ingested carbohydrate (46).
accumulates in muscle and eventually inhibits excitation-con- Therefore, eating before or during low-intensity exercise does
traction coupling. Glycogen stores in the liver amount to  1 MJ not seem to present much metabolic stress because it does not
(240 kcal) when fed and serve primarily to maintain blood glu- appreciably increase endogenous glucose utilization. In fact, if
cose concentration. As exercise intensity increases, the working the amount of carbohydrate in the meal is larger than the increase
muscles increase glucose uptake from blood, and to maintain in carbohydrate oxidation that it stimulates, glycogen and glu-
blood glucose concentration, liver glucose output must increase cose stores in the body will increase (47).
(32). In addition to liver glycogen, blood glucose can be gener-
ated from liver glycogenolysis or from the entry of ingested glu- State of physical fitness
cose into the splanchnic circulation (33). Blood glucose uptake Endurance training is well known for increasing fat oxidation
during exercise can increase to  1 g/min during prolonged exer- during exercise, partly because of increases in mitochondria,
cise, which normally elicits low plasma insulin (3437). However, which contain the necessary oxidative enzymes (5). For example,
516S COYLE

when walking at the same speed that elicits an absolute oxygen

consumption of 20 mL kg1 min1, endurance-trained persons
displayed a rate of fat oxidation that was 32% higher than that of

untrained subjects (48). This speed elicited 28% of VO2max in

the trained subjects and 43% of VO2max in the untrained sub-
jects. Interestingly, rates of lipolysis and plasma fatty acid mobi-
lization were not significantly different, and even the rates of
plasma fatty acid disappearance from the circulation were simi-
lar in untrained and endurance-trained subjects. In untrained
subjects, the rates of plasma fatty acid mobilization were in
excess of total fat oxidation during exercise. Thus, the limiting
factor for fat oxidation does not appear to be the availability of
fatty acids. It is assumed that the muscles intrinsic ability to
oxidize fat limits its oxidation, possibly owing to suboptimal
mitochondrial density (5).
During low-intensity exercise, the endurance-trained sub-
jects, who probably had an increase in mitochondrial density
of 2-fold (5), showed a close matching between plasma fatty
acid disappearance and total fat oxidation (6, 48). Thus, the
major effect of endurance training for increasing fat oxidation FIGURE 3. Contribution of the 4 major substrates to energy expen-

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during low-intensity exercise does not appear to be an increase diture at rest and after 30 min of exercise at 25% and 65% of maximal
in lipolysis or plasma fatty acid mobilization; rather, endurance
oxygen consumption ( VO2max) in well-trained men when fasted. FFA,
training increases the matching between plasma fatty acid disap- free fatty acids. To convert kcal to kJ, multiply by 4.184. Adapted from
pearance and total fatty acid oxidation, probably owing to Romijn et al (6).
increased mitochondrial density.
Because fat oxidation is increased in endurance-trained sub-
jects, carbohydrate oxidation must be reduced. It is interesting fatty acid mobilization and uptake during exercise does not

that this reduction in carbohydrate oxidation is partly due to a increase as the intensity increases from 25% to 65% of VO2max,
reduction in muscle glucose uptake (49). This is despite the fact despite large increases in plasma catecholamines. It seems that
that skeletal muscle in endurance-trained subjects is more sensi- plasma fatty acid mobilization during exercise is quite respon-
tive to insulin and also possesses more of the proteins (ie, protein sive to the low amount of hormonal activation typical of low-
glucose transporter measured in the total muscle) responsible for intensity exercise. However, total fat oxidation is markedly

transporting glucose into the muscle (50). Thus, the disparity higher during exercise at 65% of VO2max than at 25% of VO2max,
between the isolated biochemical properties of the muscle, apparently because of the marked oxidation of fatty acid from
which would seem to favor increased glucose uptake during IMTG. Although little is known about the factors that stimulate
exercise, and the actual observation of reduced glucose uptake lipolysis of IMTG (52), it is suspected to be responsive to some
during whole-body exercise indicate that other factors are of the same factors that activate muscle glycogenolysis, at least
involved that are not clearly understood. during moderate- to high-intensity exercise (20).
There is practical interest in identifying the exercise intensity
that oxidizes (ie, burns) the most body fat. As indicated in Fig-

METABOLIC STRESS OF MODERATE- TO ure 3, during exercise at 25% of VO2max, a high percentage

HIGH-INTENSITY AEROBIC EXERCISE ( 6085% of VO2max) of energy is derived from fat, whereas

during exercise at 65% of VO2max, 50% of the energy is
In the fasting state derived from fat. However, because the total energy expenditure

The sources for substrate oxidation after 30 min of moderate- is 2- to 3-fold higher at 65% of VO2max than at 25% of VO2max,

to high-intensity exercise at 65% of VO2max in endurance- the actual absolute rate of fat oxidation (MJ kg h1 or
1

trained subjects who fasted overnight are shown in Figure 3. The kcal kg1 min1) is much higher at the higher intensity, largely
increase in oxygen consumption and thus mitochondrial respira- owing to oxidation of IMTG. In terms of using exercise that can
tion for increased ATP resynthesis is generated by the greater be performed for only a limited amount of time (eg, 1 h/d) to

disturbance of metabolic homeostasis in the muscle fiber during lower body fat stores, it seems that exercise at 65% of VO2max

more intense exercise (5). These metabolic disturbances [ie, would be more effective than exercising at 25% of VO2max,
increased ADP, AMP, and inorganic phosphate concentrations because absolute fat loss from the body would be higher.
(51)] also serve to accelerate muscle glycogenolysis, thus con-
tributing to the large increase in total oxidation in general and Prolonged exercise
carbohydrate oxidation in particular. Blood glucose uptake by Shown in Figure 4 are the alterations in substrate mix that

muscle also increases with increasing intensity of exercise. How- occurred throughout several hours of exercise at 6575% of VO2max
ever, its contribution to total energy is not yet very high after in endurance-trained men after an overnight fast (6, 19, 53). The
only 30 min of exercise (Figure 3). Heavy reliance on muscle relative contribution of fat and carbohydrate changes only
glycogen is necessary because fat, for the reasons discussed slightly: fat oxidation increases and carbohydrate oxidation
above, cannot be oxidized at sufficiently high rates during mod- declines slightly. The most dramatic shift in substrate oxidation
erate- to high-intensity exercise. Interestingly, the rate of plasma occurs in the source of carbohydrate energy. With increasing
 PHYSICAL ACTIVITY AS A METABOLIC STRESSOR 517S

hypothalamic-pituitary-adrenal axis (58). These hormonal mark-

ers of metabolic stress influence numerous physiologic systems,
and some of the responses do not appear to be productive. For
example, elevation of cortisol is believed to acutely reduce
immune function (59). This is thought to be a possible cause of the
observation that chronically stressed individuals, especially those
who are performing exhaustive exercise on a daily basis, appear to
be more susceptible to upper respiratory tract infections (59, 60).

After eating a meal

Total fat oxidation during the first 100 min of exercise is
markedly suppressed and carbohydrate oxidation is obviously
increased when carbohydrate is ingested during the 6 h before
moderate- to high-intensity exercise (44, 61). The observation
that fat oxidation increases as exercise duration increases is
largely due to the reversal of this suppression of fat oxidation
FIGURE 4. Percentage of energy derived from the 4 major substrates
resulting from the last meal. This effect is related to the insulin
during prolonged exercise at 6575% of maximal oxygen uptake. Initially,
effect of the meal, which appears to persist long after plasma
approximately one-half of the energy is derived each from carbohydrate
and fat. As muscle glycogen concentration declines, blood glucose insulin has returned to fasting values (44, 61). This observation
becomes an increasingly important source of carbohydrate energy for is supported by the finding that increases in plasma glycerol con-

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muscle. *After 2 h of exercise, carbohydrate ingestion is needed to main- centration during exercise, an index of lipolysis, were blunted
tain blood glucose concentration and carbohydrate oxidation. FFA, free for 12 h after ingestion of carbohydrate (44). Preexercise car-
fatty acids. Reproduced from reference 19 with permission. Copyright bohydrate ingestion reduced oxidation of both plasma fatty acid
American Society for Clinical Nutrition. and IMTG (21). There is much practical interest as to whether
preexercise carbohydrate feedings that raise insulin sufficiently,
as do almost all carbohydrate feedings, should be avoided. These
duration of exercise, the contribution of muscle glycogen feedings also produce a phenomenon in which blood glucose
declines as its stores are lowered, and the contribution of blood concentration declines during the first 30 min of exercise (44,
glucose increases to remarkably high amounts. This shift from 62), most likely because of increased blood glucose uptake by
muscle glycogen to blood glucose is necessary to maintain the muscle (46). It seems that the determinant of whether metabolic
total carbohydrate oxidation that is required of exercise at this stress is increased depends on whether the reduction in fat oxi-
intensity because of the limitations in fat oxidation. This pro- dation is met by a sufficient increase in blood glucose oxidation.
gressive and heavy reliance on blood glucose oxidation forms If not, muscle glycogen oxidation might be increased (62), an
the basis for carbohydrate ingestion during prolonged exercise effect that could be interpreted as increased metabolic stress.
(53). After 12 h of exercise at these intensities, blood glucose With the idea that preexercise carbohydrate feedings should be
concentration begins to decline because of an imbalance, sufficiently large to stimulate a sufficiently high muscle glucose
whereby glucose disappearance from blood becomes greater uptake to offset reduced fat oxidation, persons are practically
than glucose appearance into blood (36, 53). Reductions in liver advised to ingest 1 g carbohydrate, rather than smaller
glycogen stores contribute to the inability to maintain blood glu- amounts, per kilogram body weight before exercise (19).
cose concentration. As a result, people exercising in the fasted
state usually become hypoglycemic (ie, blood glucose < 3 mmol) State of physical fitness
during the third hour and then become fatigued (25, 53). Fatigue The increased fat oxidation during moderate-intensity exer-
is preceded by a decline in carbohydrate oxidation and is related cise that is characteristic of endurance training appears to be due
to the depletion of muscle glycogen with concomitant hypogly- solely to increased oxidation of IMTG. In a 2-study series, exer-
cemia. The metabolic stress of substrate depletion in the exercis- cise metabolism was measured before and after training at the

ing muscles at the point of fatigue suggests an energy production same absolute intensity that elicited 64% of pretraining VO2max
imbalance (eg, ATP flux), as reflected by increased ammonia (63, 64). Of interest was the observation that total fat oxidation
concentrations (28). Carbohydrate ingestion throughout exercise increased during exercise despite a significant reduction in
maintains blood glucose concentration and carbohydrate oxida- plasma fatty acid mobilization and oxidation (64). Direct meas-
tion, which delays fatigue (54). ures of IMTG use in muscle confirmed that its use increased
The stress of moderate- to high-intensity exercise is reflected in dramatically with endurance training, and calculations sug-
hormonal responses, which, among other functions, serve to gested that it could account for the entire increase in fat oxida-
regulate substrate utilization and cardiovascular responses. After tion (63). Conversely, muscle glycogen use was reduced (63),

30 min of exercise at 65% of VO2max, plasma epinephrine and and blood glucose uptake was also found to be reduced (49). It
norepinephrine are elevated 4- to 6-fold above resting values (6, appears that the increase in both mitochondrial density and
55). Hypoglycemia markedly stimulates epinephrine release, IMTG use are functionally related, which is interesting because
probably in an attempt to attenuate reductions in blood glucose these IMTG droplets are often in physical contact with the mito-
concentration by increasing liver glucose output and/or reducing chondria (65). The mitochondria provide the cellular organelles
glucose uptake (56, 57). The fatigue experienced from hypogly- for oxidation with less disturbance of homeostasis, and thus less
cemia and muscle glycogen depletion is also associated with glycogenolysis, and the IMTG provides the substrate for the
marked elevations in plasma cortisol, indicating activation of the shift from carbohydrate to fat oxidation.
518S COYLE

CARDIOVASCULAR STRESS OF AEROBIC PHYSICAL endurance training is an increased stroke volume during exer-
ACTIVITY cise (67). This allows cardiac output and muscle blood flow to
The cardiovascular system supports physical activity primar- be achieved with a reduced heart rate during submaximal exer-
ily by ensuring adequate delivery of blood carrying oxygen, sub- cise at a given absolute intensity. Furthermore, the biochemical
strates, and hormones to the exercising muscles. The removal of adaptations in muscle that reduce disturbance of metabolic
metabolic waste products from muscle, as well as the dissipation homeostasis also seem to be important for reducing the heart
of heat from the body, are other important cardiovascular func- rates response to exercise by causing less stimulation of affer-
tions during physical activity. The most functional cardiovascu- ent nerves in muscle (66).
lar responses involve generation of the appropriate arterial blood Typically, the fatigue experienced in exercising muscles limits
pressure and blood flow to various organs (14, 66, 67). The cen- a persons tolerance for aerobic exercise and thus the cardiovas-
tral nervous system responds immediately to physical activity by cular system generally does not display signs of dysfunction, at
increasing the efferent activity of the sympathetic nervous sys- least in persons free of ischemic heart disease or other diseases.
tem to the heart and blood vessels while withdrawing parasym- However, the extent of cardiovascular stress during aerobic exer-
pathetic activity (60, 67). cise can be greatly increased by hyperthermia and dehydration.
Sensory (ie, afferent) nerves monitor the metabolic status of Dehydration and hyperthermia can each individually reduce
exercising muscles, as well as blood pressure and other factors (eg, stroke volume during exercise (70). Furthermore, when these 2
oxygen content, pH, and temperature) in several areas of the circu- phenomena occur together, as is typical of dehydration-induced
lation, thus providing feedback to the central nervous system hyperthermia, the reductions in stroke volume are more than
regarding the adequacy of cardiovascular responses (66). Aerobic additive, and as a result, cardiac output also declines significantly
exercise stimulates a metabolite-induced local vasodilatation in the (7072). Other indications of compromised cardiovascular func-

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arterioles of the contracting muscles, thus dramatically increasing tion include reduced blood pressure and skin blood flow. Further-
blood flow, provided that blood pressure is maintained or more, the plasma norepinephrine response to dehydration-
increased. The nervous system responds to this challenge by induced hyperthermia is very large and is indicative of stress (73).
increasing activity in the sympathetic nerves that release norepi-
nephrine in the heart, thereby increasing the heart rate. Norepi-
nephrine released in the kidneys, liver, and resting muscle increases METABOLIC, CARDIOVASCULAR, AND NEUROLOGIC
vascular resistance to these organs (67). Therefore, the basic pat- STRESS OF WEIGHTLIFTING
tern of response is an increase in heart rate and cardiac output with When persons lift weights corresponding to 6575% of their
increased exercise intensity and an even more dramatic increase in 1RM, they generally can perform 1015 repetitions before
muscle blood flow as an increasingly greater percentage of cardiac becoming fatigued and unable to perform another full repetition
output is directed to the exercising muscles (67). (Table 2). The first few repetitions of such a set are not sensed as
Blood flow to muscle during several minutes of dynamic exer- being difficult, but thereafter each repetition of the given weight
cise with a small muscle mass (eg, using just the knee extensors) becomes progressively more difficult as the neuromuscular sys-
can increase blood flow per kilogram of active muscle to values tem becomes fatigued. The motor unit activation seems to paral-
as high as 3 L min1 kg1 (68). These concentrations could be lel the perceived effort, and the last repetition seems to elicit
considered to be hyperperfusion, owing to the relatively high maximal recruitment of motor unit number and frequency, at
content of oxygen in venous blood (67). This innate muscle least under those specific conditions (15). For this reason, lifting
capacity for high blood flow can present a severe challenge to weights to the point of fatigue and failure to complete another
the cardiovascular system during exercise that recruits a large contraction is believed to be a powerful stimulus to neurologic
muscle mass (eg, running or cycling), because the ability of this recruitment, especially of the high-threshold type II motor units
large mass to accept blood flow can easily exceed maximal car- that may not be frequently stimulated in inactive people.
diac output (12, 68). Therefore, during intense aerobic exercise The fatigue experienced with repetitive weightlifting could
with a large muscle mass, blood flow per kilogram muscle is typ- result from impairment of any number of factors, including
ically reduced to 12 L/min by increased sympathetic nerve recruitment, excitation-contraction coupling, ATP production,
activity that superimposes vasoconstriction on metabolite- and cross-bridge cycling (74). Repetitive contractions lasting
induced vasodilatation. This balanced response maintains the 3090 s promote rapid muscle glycogenolysis and accumulation
appropriate arterial blood pressure and minimizes overperfusion in muscle of hexose monophosphates and lactate, with a con-
of the exercising muscle (68). comitant lowering of creatine phosphate (11). Muscle blood flow
Heart rate provides a generally reasonable and practical meas- is impeded during intense contraction, which in combination
ure of the degree of cardiovascular stress during physical activity. with high rates of energy expenditure, makes the exercising mus-
Thus, intensity is typically rated as a percentage of maximal heart cles hypoxic (74). During recovery from contraction, the muscle
rate (4). However, the highest heart rate a person can achieve experiences a postcontraction hyperemia and fluid shifts into the
during exercise is proportional to the amount of muscle mass acti- interstitial and intracellular compartments (12). The metabolic
vated (69). For example, during exercise with just the arms, a per- stress in the muscle contributes to the contraction-induced eleva-
son may not be able to elevate the heart rate above 130 beats/min, tion of heart rate and arterial blood pressure, and interestingly,
even if the exercise is performed to the point of extreme fatigue. blood pressure remains elevated if blood flow to the fatigued
However, during intense running that involves large leg muscles, muscle is occluded, thus preventing metabolic recovery (66).
a typical 30-y-old can raise the heart rate to 180190 beats/min. Weightlifting elicits a sympathoadrenal-medullary response, as
The metabolic stress encountered in exercising muscles indicated by elevations in plasma catecholamines postcontrac-
influences the cardiovascular responses of heart rate and blood tion (75, 76). Furthermore, weightlifting seems to influence var-
pressure. The most important cardiovascular adaptation to ious anabolic hormonal and growth factor responses (74, 77).
 PHYSICAL ACTIVITY AS A METABOLIC STRESSOR 519S

SUMMARY 14. Wathen D. Load assignment. In: Bacchle T, ed. Essentials of strength
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43547.
promote specific and varied adaptations depending on the type,
15. Sale DG. Influence of exercise and training on motor unit activation.
intensity, and duration of exercise performed. It is clear that Exerc Sport Sci Rev 1987;15:95151.
chronic adaptations to the acute stress of physical activity pro- 16. Johnson MA, Polgar J, Weightman JD, Appleton D. Data on the dis-
mote health (78). Prolonged walking at low intensity presents lit- tribution of fiber types in thirty-six human muscles. J Neurol Sci
tle metabolic, hormonal, or cardiovascular stress, and the great- 1973;18:11129.
est perturbation from rest appears to be that fat oxidation and 17. Caiozzo VJ, Haddad F, Baker MJ, Baldwin KM. Influence of
plasma fatty acid mobilization are increased by a combination of mechanical loading on myosin heavy-chain protein and mRNA iso-
increased lipolysis and decreased reesterification, at least when form expression. J Appl Physiol 1996;80:150312.
subjects are fasted. More intense jogging or running largely 18. Caiozzo VJ, Haddad F, Baker MJ, Herrick RE, Prietto N, Baldwin
stimulates increased oxidation of glycogen and triacylglycerol, KM. Microgravity-induced transformations of myosin isoforms and
contractile properties of skeletal muscle. J Appl Physiol 1996;81:
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12332.
thermore, these intramuscular stores of carbohydrate and fat 19. Coyle EF. Substrate utilization during exercise in active people. Am
appear to be the primary substrates for enhanced oxidative and J Clin Nutr 1995;61(suppl):S96879.
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