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R.R. Wolfe*
* Metabolism Unit, Shriners Burns Institute, 610 Texas Avenue, Galveston, TX 77550, U.S.A.
Abstract
1. Energy metabolism in exercise
2. Are protein requirements affected by exercise when energy requirements are met?
3. Muscle protein breakdown and amino acid oxidation
4. Substrate metabolism in exercise
5. Effect of exercise on protein synthesis
6. Summary and dietary recommendations
Acknowledgements
References
Endurance exercise
causes an increase in energy expenditure that directly translates
to an increased caloric requirement for intake to maintain energy
balance. If energy balance is not maintained, exercise causes an
increased excretion of N. On the other hand, in subjects
maintained on adequate caloric intake, exercise does not increase
N excretion. Although data are not consistent, it also appears
that exercise causes little, if any, effect on the rate of muscle
protein breakdown. The oxidation of leucine, and possibly other
amino acids, is increased in exercise. This response is minimized
by a rapid mobilization and extensive oxidation of fatty acids.
Muscle glycogen may also play a role in sparing amino acid
oxidation at intensive levels of exercise. Despite increased
amino acid oxidation in exercise, muscle protein synthesis is
maintained. It is proposed this occurs by a redistribution of gut
amino acids to peripheral muscle via incorporation into rapidly
turning-over proteins. In recovery, amino acid oxidation is
inhibited, and the muscle protein synthesis in the exercising
muscle is stimulated. It is concluded that, provided energy
intake is adequate, endurance exercise does not increase protein
requirements.
Exercise causes an
immediate and dramatic change in energy expenditure associated
primarily with the process of muscle contraction. The effects of
this response on energy requirements can be calculated rather
well, given the large data base documenting the energy cost of
various activities. Alternatively, the energy cost of physical
activity can be more directly assessed with a combination of
indirect calorimetry and the doubly-labelled water technique.
These estimations, or direct measurements, of energy expenditure
can be translated directly into dietary energy requirements. For
example, SCHULTZ et al. (1991) have recently determined by
indirect calorimetry the daily energy expenditure of elite female
runners who lived in a metabolic chamber for 24 hours, and
subtracted this value from the rate of free-living (including
training) total energy expenditure determined by the
doubly-labelled water technique. This study revealed that heavy
exercise training had no effect on any component of energy
expenditure other than the activity factor.
The extent to which the composition of caloric intake (i.e., percent fat vs carbohydrate) affects the ability of that intake to support net protein synthesis in exercising individuals is not clear. Whereas glycogen depletion will cause a more marked increase in ammonia during exercise (WAGENMAKERS et al., 1991), it is not clear that this reflects an increased amino acid catabolism (see below). On the other hand, it is evident that failure to meet the caloric requirements will increase amino acid oxidation (and thus protein requirements) in exercising individuals. This can be seen by comparing the results of a study reported by GONTZEA, SUTZESCU and DIMITRACHE (1975) and work done in our own laboratory (CARRARO et al., 1990).
GONTZEA et
al. (1975) maintained resting men on an energy intake 10%
greater than their measured resting energy expenditure. Without
increasing the energy intake, energy expenditure was increased by
beginning a daily exercise training schedule. Over the first
several days of exercise the N balance became markedly negative,
although it eventually came back to the baseline equilibrium.
Conversely, in our study, in which two levels of protein intake
were given (0.9 and 2.5 g/kg/d) along with an adequate energy
intake (42 kcal/kg/d) for 5 days prior to performing 4 hours of
treadmill exercise, no change in N balance was observed as
compared to the resting situation. The divergent results of these
two studies underscore the importance of assessing the effect of
exercise on protein metabolism in the context of adequate energy
intake.
There are several variables
to consider in formulating an answer to this question. The type
of exercise is likely to be important. This can easily be
appreciated by considering the difference in muscle mass between
a weight-lifter and a marathon runner. There are obvious
differences in the exercise regimens that these athletes follow,
but even more specific differences, such as the type of movements
involved, must also be considered. For example, eccentric
exercise appears to cause muscle damage in a unique manner
(NEWHAM et al., 1983). Because almost all data pertinent
to the issue of the effect of exercise on protein requirements
have been obtained during endurance exercise (cycling or
treadmill walking), this discussion will be limited to that
circumstance.
There is no consensus as to whether exercise affects protein requirements. Whereas the results cited above from our own study indicate that endurance exercise does not affect N excretion, and therefore protein requirements, there are ample data to the contrary. For example, TARNOPOLSKY, MacDOUGALL and ATKINSON (1988) studied endurance athletes and sedentary individuals given two levels of protein intake, and found that whereas increasing the protein intake in both groups had about the same positive effect on N balance, at a given level of protein intake the sedentary subjects had better N balance than the athletes in training. From these results they concluded that endurance athletes require greater daily protein intakes than either body builders (also studied) or sedentary individuals. Contrary to their conclusion, however, hydrostatic weighing of their subjects failed to reveal any effect of protein intake on body composition of endurance athletes.
The
detailed studies of BUTTERFIELD and CALLOWAY (1984) provide
results that are in disagreement with the results reported by
TARNOPOLSKY et al (1988). They determined N balance in
subjects exercising daily who were given different amounts of
energy intake with a constant protein intake of 0.57 g/kg/d. Two
levels of exercise intensity were tested. Regardless of whether
the subjects were in energy balance or energy intake exceeded
expenditure (positive energy balance), increasing exercise
intensity improved N balance for a given level of energy intake.
From these results it was concluded that physical activity
improves protein utilization. In contrast to the Tarnopolsky
study, body composition analysis by total body potassium counting
and hydrostatic weighing were consistent with the conclusion of
BUTTERFIELD and CALLOWAY (1984).
The rate of skeletal muscle
breakdown during exercise has been estimated by a number of
investigators using the measurement of 3-methylhistidine
excretion. The varied results probably reflect the difficulty of
measurement, changes in renal blood flow and urine excretion
during exercise. Nonetheless, there appears to be evidence to
indicate that muscle protein breakdown is either not increased in
endurance exercise or increased very little. For example, RENNIE et
al. (1981) showed no stimulatory effect of exercise on
3-methylhistidine excretion and a decrease in its intracellular
concentration in muscle. Our own work (CARRARO et al., 1990)
similarly found no significant effect of exercise on
3-methylhistidine excretion, although there was a significant
increase in excretion during recovery.
Whereas N-balance studies in which energy intake was both controlled and adequate or surfeit are consistent in their failure to identify either an increase in protein requirement with exercise or a consistent increase in protein breakdown, as assessed by 3-methylhistidine excretion, it is nonetheless appropriate to examine whether or not exercise stimulates amino acid oxidation. This is because a number of papers support the notion that it does. For example, it is well established that leucine oxidation is increased in exercise (e.g., WOLFE et al., 1982) and that leucine N is released from the muscle in alanine at an increased rate (WOLFE et al., 1984). Furthermore, the increased N release from muscle in the form of alanine comes in part from the increased metabolism of amino acids other than leucine (WOLFE et al., 1984).
Taken by
itself, this increased catabolism of leucine, and other amino
acids, should lead to the conclusion that endurance exercise has
a net catabolic effect on muscle protein. However, there are
important considerations that limit the certainty with which one
can extrapolate from the leucine data to conclusions about muscle
protein. In contrast to leucine, lysine oxidation is minimally
affected. Also, whereas alanine release is increased in all types
of endurance exercise, glutamine release is increased only in
strenuous exercise. Furthermore, the contribution of leucine
oxidation to overall energy expenditure in exercise falls,
despite the increase in absolute rate. Thus, although there is
some variance in amino acid oxidation in exercise, there is
little doubt that changes in substrate energy metabolism minimize
the extent to which amino acids serve as a fuel for exercising
muscle. The question therefore arises as to why amino acid
oxidation is spared in exercise.
At moderate levels of
exercise intensity, there is a rapid increase in plasma fatty
acid availability via a stimulation of lipolysis (WOLFE et
al., 1990). Furthermore, fatty acid oxidation is increased in
exercise because of a greater clearance of FFA from the plasma.
At rest, about 70% of fatty acids released into the blood from
adipocytes are not oxidized, but rather cleared by the liver and
re-esterified into triglyceride and recycled back to the
adipocyte for storage. In exercise, the percentage of plasma FFA
recycled back to triglyceride drops precipitously. At 40% VO2
max. 75% of released fatty acids are oxidized, and only 25 % are
re-esterified.
At this level of exercise, about half of the increase in fat oxidation that occurs is due to a greater extraction of plasma FFA by working muscles and about half is due to the stimulation of lipolysis (WOLFE, WEBER and KLEIN, 1990). Consequently, the combined effect of a stimulation of lipolysis and greater efficiency of extraction and oxidation enables fat to be effectively used as an energy substrate in endurance exercise. The ability to mobilize and utilize fat as an energy substrate is amplified in trained individuals. When we compared the response in untrained subjects (VO2 max = 51 ± 3 mL/kg/min) vs trained runners (VO2 max = 72 ± 3 mL/kg/min), the rate of fat oxidation was significantly higher in the trained subjects. This was due to both a greater lipolytic response and to more effective clearance and oxidation of plasma FFA.
The response of energy substrate metabolism depends on the level of intensity. Whereas the role of plasma FFA predominates at lower intensities, the rate of lipolysis does not increase markedly at higher intensities. In fact, we have recently found that at 85% VO2 max in trained subjects lipolysis (as reflected by glycerol appearance) actually falls below its peak rate. Rather, muscle glycogen and muscle triglyceride become important sources of energy at more intensive exercise. Muscle glycogen utilization can be estimated from the difference between plasma glucose uptake and glucose oxidation, as determined by indirect calorimetry. This approach reveals a steady increase in the relative contribution of muscle glycogen as the exercise intensity increases. A roughly analogous approach enables calculation of intramuscular triglyceride oxidation. As with muscle glycogen breakdown, increased exercise intensity causes increased reliance on the breakdown of intramuscular triglyceride and direct oxidation of the fatty acids, with the glycerol being released into plasma to reflect the lipolytic process.
Increased availability and thus oxidation of fatty acids could spare amino acid oxidation by competition for entry into the TCA cycle via acetyl CoA. In addition, fatty acids could play a regulatory role in the control of protein breakdown. TESSARI et al. (1986) showed that in resting dogs the rate of leucine appearance and oxidation were inversely proportional to FFA availability, implying a direct effect of FFA not only on amino acid oxidation but also on protein breakdown. Whatever the mechanism, it is clear that whereas amino acid oxidation is increased to some extent in exercise, the mobilization and oxidation of fatty acids play an important role in minimizing the extent to which amino acids are oxidized in exercise.
It is
logical to presume that the oxidation of intramuscular glycogen
spares amino acid oxidation in the same manner as fatty acid
oxidation. This notion is supported by the observation that
glycogen-depleted subjects have a more rapid accumulation of
ammonia than normal ones during strenuous exercise (WAGENMAKERS
et al., 1991). This response was attributed to increased
amino acid oxidation, since exercise caused a 3.6-fold increase
in the proportion of active branched-chain 2-oxoacid
dehydrogenase in muscle of glycogen-depleted subjects, whereas no
activation occurred in exercise in control subjects. However,
this evidence of increased amino acid oxidation is indirect, and
does not rule out an alternative explanation. That is, in the
absence of glycogen, pyruvate availability for transamination to
alanine could be depressed (as indicated by lower alanine levels
in glycogen-depleted subjects). If there is a limitation in the
extent to which glutamate can be transaminated to glutamine, then
ammonia could accumulate solely because of decreased
transamination, rather than increased production. This latter
possibility is supported by the fact that urea production is not
significantly increased even at 70% VO2 max (CARRARO
and WOLFE, 1991).
In order to directly assess
the response of muscle protein synthesis in exercise we performed
a study in which 1, 2-13C-leucine was continuously
infused into volunteers on two separate days. On the control day,
the subjects rested throughout. On the experimental day, the
subjects walked for 4 hours on a treadmill at 40% VO2
max. The results showed that during exercise the rate of muscle
protein synthesis was slightly (but not significantly) decreased;
in the 4 hours of recovery from exercise muscle protein synthesis
was significantly increased (CARRARO et al., 1991). From
this direct observation, at least two important questions
immediately arise: (1) how is muscle protein synthesis maintained
during exercise even though amino acid (including leucine)
oxidation is at least moderately increased, and (2) how is muscle
protein synthesis increased in recovery despite the absence of
amino acid intake?
The proposed mechanism responsible for the maintenance of muscle synthesis during exercise is speculative to at least some extent. We propose that N released from muscle at an increased rate in exercise is cleared by the liver, transaminated to different amino acids, and incorporated into rapidly turning-over proteins rather than being incorporated into urea and excreted in urine. Other amino acids necessary to enable complete synthesis of these proteins are derived from an increased net catabolism of gut protein, stemming from a restriction of gut blood flow in exercise. These hepatic proteins are then excreted into the plasma at an increased rate and subsequently cleared and catabolized to some extent in the muscle, thereby providing a mechanism to transfer amino nitrogen from the gut to the muscle during exercise.
There are several lines of evidence to support this speculation: (1) urea production is not increased in exercise (WOLFE et al., 1982; CARRARO and WOLFE, 1991), (2) rapidly turning-over plasma proteins are synthesized at an increased rate in response to exercise (CARRARO et al., 1990, (3) plasma proteins can contribute to the muscle amino acid pool (KOMJATT and WALDHAUSL, 1989), and (4) net release of amino N from the gut is increased in exercising dogs (WASSERMAN et al., 1991). The question of how this overall process can proceed without a balanced supply of amino acids (due to increased oxidation of essential amino acids) remains unanswered, but it must be considered that exercise has a finite duration, and the existence of a physiological non-steady state in the amino acid pools during exercise is certainly a possibility.
The
increased muscle protein synthesis in recovery can be explained
largely by a decrease below the normal rate of amino acid
oxidation in recovery. DEVLIN et al. (1990) showed that leucine
oxidation was decreased in recovery. Furthermore, from A-V
difference data across the arm, they deduced that synthesis was
decreased in the non-exercised arm, thereby making more amino
acids available for synthesis in the exercised muscle despite the
absence of exogenous amino acid intake.
1. Energy expenditure (and
caloric requirements) are directly related to physical activity.
2. Amino acid oxidation is increased in exercise but falls dramatically in its relative role in energy metabolism due to increased availability and oxidation of fatty acids. In strenuous exercise, muscle glycogen oxidation also appears to play a role in sparing amino acid oxidation.
3. Increased muscle protein synthesis in recovery balances any deficit that occurs during exercise.
4.
Nutritional implications: if energy intake is adequate to
maintain energy balance, exercise does not increase protein
requirements.
This work has been
supported by NIH grant DK 38010 and a grant from the Shriners
Hospital.
BUTTERFIELD, G. CALLOWAY,
D.H.: Physical activity improves protein utilization in young
men. Br. J. Nutr., 51, 171-184 (1984).
CARRARO, E, HARTL, W.H., STUART, C.A., LAYMAN, D.K., JAHOOR, F., WOLFE, R.R.: Whole-body and plasma protein synthesis in exercise and recovery in human subjects. Am. J. Physiol., 258 (Endocrinol. Metab., 21), E821-E831 (1990).
CARRARO, E, STUART, C.A., HARTL, W.H., ROSENBLATT, J., WOLFE, R.R.: Effect of exercise and recovery on muscle protein synthesis in human subjects. Am. J. Physiol., 259 (Endocrinol. Metab., 22), E470-E476 (1991).
CARRARO, E, WOLFE, R.R.: Urea production and urea nitrogen recycling during two levels of exercise intensity. Submitted for publication (1992).
DEVLIN, T.J., BRODSKY, I., SCRIMGEOUR, A., FULLER, S., BIER, D.M.: Amino acid metabolism after intense exercise. Am. J. Physiol., 258, E249-E255 (1990).
GONTZEA, 1., SUTZESCU, R., DIMITRACHE, S.: The influence of adaptation to physical effort on nitrogen balance in man. Nutr. Rep. Int., 11, 231-236 (1975).
KOMJATI, M., WALDHAUSL, N.: Contribution of plasma protein to muscular de novo synthesis of glutamine. Metabolism, 38, 52-55 (1989).
NEWHAM, D. J., McPHAIL, D. J., MILLS, G., EDWARDS, R.H.T.: Ultrastructural changes after concentric and eccentric contractions of human muscle. J. Neurol. Sci., 61,, 109-122 (1983).
RENNIE, M.J., EDWARDS, R.H.T., KRYWAWYCH, S., DAVIES, D.T.M., HALLIDAY, D., WATERLOW, J.C., MILLWARD, D.J.: Effect of exercise on protein turnover in man. Clin. Sci., 61, 627-639 (1981).
SCHULTZ, L.O., ALGER, S., HARPER, I., WITMORE, J.H., RAVUSSIN, E.: Energy expenditure of elite female runners measured by respiratory chamber and doubly-labeled water. J. Appl. Physiol. (1991).
TARNOPOLSKY, M.-A., MacDOUGALL, J.D., ATKINSON, S.A.: Influence of protein intake and training status on nitrogen balance and lean body mass. J. Appl. Physiol., 64, 187-193 (1988).
TESSARI, P., NISSAN, S.L., MILES, J.M., HAYWARD, M.W.: Inverse relationship of leucine flux and oxidation to free fatty acid availability in vivo. J. Clin. Invest., 77, 575-583 (1986).
WAGENMAKERS, A.J.M., BECHERS, E.J., BROWNS, E, KEIPERS, H., SOCTERS, P.B., VAN DER VUSSE, G. J., SARIS, W.H.M.: Carbohydrate supplementation, glycogen depletion, and amino acid metabolism during exercise. Am. J. Physiol., 260, E883-E890 (1991).
WASSERMAN, D.H., GEER, R.J., WILLIAMS, P.E. BECKER, T., LACY, B.D., ABUMRAD, N.: Interaction of gut and liver in nitrogen metabolism in exercise. Metabolism, 40, 307-314 (1991).
WOLFE, R.R., GOODENOUGH, R.D., WOLFE, M.H., ROYLE, G.T., NADEL, E.R.: Isotopic analysis of leucine and urea metabolism in exercising humans. J. Appl. Physiol., 52, 458-466 (1982).
WOLFE, R. R., WOLFE, M.H., NADEL, E. R., SHAW, J.H.F.: Isotopic determination of amino acid-urea interactions in exercise in humans. J. Appl. Physiol., 56, 221-229 (1984)
WOLFE, R.R., WEBER, J.M., KLEIN, S., CARRARO, E: Rate of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exercise. Am. J. Physiol., 258, E382-E389, (1990).