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Effects of physical activity on protein-energy interactions: Metabolic and nutritional considerations

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


Abstract


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.

1. Energy metabolism in exercise


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.

2. Are protein requirements affected by exercise when energy requirements are met?


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).

3. Muscle protein breakdown and amino acid oxidation


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.

4. Substrate metabolism 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).

5. Effect of exercise on protein synthesis


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.

6. Summary and dietary recommendations


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.

Acknowledgements


This work has been supported by NIH grant DK 38010 and a grant from the Shriners Hospital.

References


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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).

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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).

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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).

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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).

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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).


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