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Acta Physiol Scand 1998, 162, 377387

Exercise-induced changes in protein metabolism

K . D . T I P T O N and R . R . W O L F E
Departments of Surgery, and Anesthesiology, The University of Texas Medical Branch and the Metabolism Unit,
Shriner's Burns Institute, Galveston, Texas, USA

Exercise has a profound acute effect on protein metabolism. Whereas reports on whole body
responses to exercise have varied results, it is generally agreed leucine oxidation is increased during
exercise, thus indicating increased net protein breakdown. Following endurance exercise, whole
body protein breakdown is generally reduced from resting levels, while following eccentric exercise,
both whole body protein breakdown and leucine oxidation are increased. Whole body protein
synthesis, on the other hand, is either increased or unchanged. Much of the disagreement in the
results of studies on the response of whole body protein metabolism to exercise may be attributed to
the limitations of the available methods. Even if the methodology accurately reflects whole body
metabolism, this may not reflect changes in the protein metabolism of muscle. Although endurance
exercise has not been studied, muscle protein breakdown is increased following resistance exercise.
There is a concomitant, and qualitatively greater, increase in muscle protein synthesis following
resistance exercise, which may last for as long as 48 h. Increased muscle protein synthesis is linked
to increased intramuscular availability of amino acids, and thus, to increased blood flow and increased
amino acid delivery to the muscle, as well as increased amino acid transport. Administration of
exogenous amino acids after exercise increases protein synthesis while ameliorating protein
breakdown, thus improving net muscle protein balance. While it is clear that muscle protein synthesis
and protein breakdown increase in a qualitatively similar manner following exercise, the mechanisms
of stimulation have yet to be determined. However, we propose that the intracellular availability of
amino acids is the link between these processes.

Keywords muscle, protein breakdown, protein synthesis, stable Isotopes.

Received 2 March 1997, accepted 26 July 1997

Exercise has a profound acute effect on protein me- increases muscle size and ability to produce force.
tabolism. The available information on protein metab- Unfortunately, with regard to acute responses to en-
olism is not without some controversy. Much of the durance and resistance exercise, there are few instances
disagreement in the literature may be linked to the in which the response of protein metabolism to both
disparate methodology used in the studies. In this re- endurance and resistance exercise has been character-
view we will summarize the results of studies on the ized. As will be seen, in these situations, the responses
acute response of in vivo protein metabolism in human are similar. Therefore, in our discussion we will gen-
subjects, primarily those using stable isotopic tracers, erally not differentiate between endurance and resis-
during and following exercise. We will then attempt to tance exercise.
propose a scheme, based on this information, that
might help explain how the metabolic processes in the
various tissues are linked and how they operate in re-
sponse to exercise. The responses of protein synthesis and protein break-
The general nature of exercise can be classied as down have been reported to last from several minutes
either resistance or endurance exercise. It is easy to to as long as several days after exercise (Fielding et al.
separate these, as the responses to training in each are 1991). Since exercise generally lasts only a relatively
different. Endurance training results in increased aer- short time (a few minutes to 34 h), it can be argued
obic capacity of muscle, whereas resistance training that the post-exercise responses may be fundamentally

Correspondence: Robert Wolfe Ph D, Shriners Burns Institute, 815 Market St., Galveston, Texas, USA 77550.

1998 Scandinavian Physiological Society 377

Protein metabolism following exercise  K D Tipton and R R Wolfe Acta Physiol Scand 1998, 162, 377387

more important to the overall state of protein metab- following resistance exercise whole body protein syn-
olism than changes that occur during exercise. Whereas thesis was unchanged (Tarnopolsky et al. 1991).
the primary focus of this paper is on the responses of
protein metabolism following exercise, we will also
briey discuss the responses during exercise in order to Leucine oxidation
better understand the starting point for recovery. Although results of studies on protein breakdown, as
indicated by whole body amino acid appearance, are
not clear, it seems clear that leucine oxidation is in-
During exercise creased, thus indicating an increase in net protein
breakdown that may result from a need for amino acids
There does not seem to be good agreement between
to be oxidized for energy in the working muscles. Al-
studies that have examined whole body responses of
ternatively, increased protein breakdown may provide a
protein metabolism during and after exercise. Most of
source of amino N for later use for protein synthesis
the information on this topic comes from whole body
following exercise. While protein breakdown is in-
studies during endurance exercise, usually cycling or
creased in response to exercise, urea production does
walking. The rate of leucine appearance in the plasma
not appear to be elevated from rest either during
pool, as determined by the infusion of isotopically la-
(Wolfe et al. 1982, 1984, Carraro et al. 1993) or fol-
belled leucine can be used as an indicator of whole
lowing exercise (Carraro et al. 1993). This would seem
body protein breakdown. Several studies have deter-
to be a contradiction, since urea production is generally
mined that whole body protein breakdown, as reected
considered to be a reection of protein breakdown.
by leucine appearance, is increased during endurance
An increased rate of amino acid oxidation during
exercise in humans (Rennie et al. 1981, Wolfe et al. 1982,
exercise should increase the transfer of N to other
Phillips et al. 1993, Carraro et al. 1994) and dogs (Wil-
amino acids, particularly alanine and glutamine. Since
liams et al. 1996). On the other hand, others found
urea is the end product for the disposal of N, it might
protein breakdown to be unchanged (Stein et al. 1989,
be expected that urea production would increase during
Carraro et al. 1990a). However, in all cases, leucine
or following exercise. Thus, the infusion of alanine into
oxidation has been shown to increase during exercise
resting volunteers causes an immediate increase in urea
(Rennie et al. 1981, Hagg et al. 1982, Wolfe et al. 1982),
production (Wolfe et al. 1987). However, this does not
so there is apparently a net negative balance of leucine,
seem to be the case in exercise. The rate of appearance
which should correspond to increased net protein
of alanine into plasma has been shown to increase
breakdown. The increase in whole body protein
during exercise (Williams et al. 1997), but as stated
breakdown arises primarily from gut (Williams et al.
above, urea production is unaffected at low (Wolfe et al.
1996) and, perhaps, the muscle (Rennie et al. 1981).
1982, 1984, Carraro et al. 1993) or high (Carraro et al.
1993) exercise intensities, both during and following
exercise. It might be argued that the total N available to
the liver during exercise might be diminished if gluta-
Following endurance exercise, whole body techniques mine production is reduced in favor of alanine syn-
indicate that protein breakdown is either unchanged thesis. Thus, urea production would not have to be
(Devlin et al. 1990, Tipton et al. 1996b), or decreased increased. However, work in our laboratory (Williams
(Rennie et al. 1981), from rest. Following resistance et al. 1998) has demonstrated that the rate of appear-
exercise (Tarnopolsky et al. 1991, Biolo et al. 1995c, ance of glutamine is unchanged during moderate aer-
Tipton et al. 1996b), or the combination of endurance obic exercise and, combined with a 2.5-fold increase in
and resistance exercise (Tipton et al. 1996b), whole alanine rate of appearance, the total rate of appearance
body protein breakdown is unchanged from rest. Fol- of N is increased.
lowing cycling exercise, the rate of leucine oxidation A possible, partial explanation for the apparent
was reported to be less than the rate at rest (Devlin et al. discrepancy between increased protein breakdown and
1990). However, Fielding et al. (1991) reported that lack of change in urea production is that acute phase
whole body protein breakdown and leucine oxidation plasma protein synthesis is increased both during and
were increased for up to 10 days following a bout of following endurance exercise (Carraro et al. 1990a). The
eccentric cycling exercise. Whole body protein synthesis increased alanine, and thus N, ux seen during exercise
has been reported to be decreased (Rennie et al. 1981, may be accounted for, in part, by incorporation into
Wolfe et al. 1982) or unchanged (Carraro et al. 1990a, these acute phase proteins (Carraro et al. 1990a), rather
Phillips et al. 1993) during endurance exercise. Follow- than urea (Wolfe et al. 1982, 1984, Carraro et al. 1993).
ing endurance exercise, increased protein synthesis was Also, in another study, the recycling of urea N back into
reported (Rennie et al. 1981, Devlin et al. 1990), whereas protein was shown to be accelerated both during and

378 1998 Scandinavian Physiological Society

Acta Physiol Scand 1998, 162, 377387 K D Tipton and R R Wolfe  Protein metabolism following exercise

following exercise (Carraro et al. 1993), thus providing The results from our A-V balance technique illus-
another source of N for these acute phase proteins. trate the limitations in whole body kinetic data when
Therefore, N from protein breakdown seems to be evaluating the responses to exercise. We measured leg
channelled to the acute phase proteins, rather than urea protein breakdown following an intense resistance ex-
(Carraro et al. 1993). The acute phase proteins would ercise bout in six untrained male volunteers, while si-
then be available as an amino acid N source for protein multaneously measuring whole body protein
synthesis following exercise. The disproportionate in- breakdown (Biolo et al. 1995c). Leg protein breakdown
crease in leucine oxidation may simply reect the fact was increased by 50% after exercise, but only a slight
that there is relatively more leucine in skeletal muscle (non-signicant) increase in whole body protein
than in acute phase proteins (Reeds et al. 1994). breakdown was noted (Fig. 1).
The poor agreement between studies on the re- The results shown in Figure 1 were the rst direct
sponse of whole body protein metabolism to exercise evidence that there is an increase in muscle protein
probably reects the limitations of the methodology. breakdown after exercise. Although some previous
Whole body methods were designed for studying studies had derived this conclusion from an increase in
steady-state circumstances and may be inaccurate and/ the rate of excretion of 3-methylhistidine (Rennie et al.
or too insensitive in the non-steady-state of exercise 1981, Dohm et al. 1982, 1985), others found no change
and recovery. Even if the methodology accurately re- (Plante & Houston 1984a,b, Carraro et al. 1990a), or
ects whole body metabolism, this may not reect decreased (Radha & Bessman 1983, Dohm et al. 1985,
changes in the protein metabolism of muscle. For ex- Mussini et al. 1985) excretion of 3-methylhistidine in
ample, whereas muscle protein makes up about 50% of response to exercise. Thus, using whole body and
the protein in the body, it accounts for only about 25% 3-methylhistidine techniques to measure protein
of total protein synthesis at rest (Nair et al. 1988, breakdown gives a less than clear picture of the re-
Bennett et al. 1989). Therefore, an increase of 50% in sponse of protein breakdown to exercise.
muscle protein synthesis theoretically would result in an
increase of 12.5% in whole body protein synthesis.
Since only exercised muscles are likely to respond to the
exercise (Devlin et al. 1990), much less than the theo-
retical 12.5% increase in whole body protein synthesis
is likely. Further, responses in various tissues of the
body other than muscle, e.g. splanchnic bed (Williams
et al. 1996), may obscure changes in muscle when only
whole body data are considered.

Arteriovenous model. Due to limitations of the whole
body approach, we developed a new approach to
quantifying muscle protein and amino acid kinetics. The
approach is a modication of the traditional arteriove-
nous (A-V) model that also includes data obtained by
tissue biopsy (Biolo et al. 1992). Stable isotopic tracers
of various amino acids are infused intravenously, and
steady-state enrichments and concentrations are deter-
mined in the femoral artery, femoral vein, and in the
intramuscular uid. From these measurements, the
model allows calculation of muscle protein synthesis,
breakdown and also the rates of transmembrane amino Figure 1 Comparison of the response of (a) whole body
acid transport. Because of the specicity of analysis of phenylalanine rate of appearance (Ra), a measure of whole body
enrichment by gas chromatography-mass spectrometry, protein breakdown and (b) muscle protein synthesis (PS), muscle
multiple amino acid tracers can be infused simulta- protein breakdown (PB) and net protein balance (NB) measured by
the A-V/biopsy model. Both were determined at rest and 34 h
neously. This is the rst model developed to quantify, following a heavy resistance exercise routine in untrained male
in vivo, either muscle protein breakdown or the trans- volunteers. Values are mean SE. *, signicant difference (P < 0.05)
membrane transport of naturally occurring amino acids. from corresponding resting value. (Adapted from Biolo et al. 1995c.)

1998 Scandinavian Physiological Society 379

Protein metabolism following exercise  K D Tipton and R R Wolfe Acta Physiol Scand 1998, 162, 377387

Figure 2 Relationship of A-V/biopsy model-derived values of

muscle protein breakdown and muscle protein synthesis in healthy Figure 3 Relationship between fractional synthetic rate (FSR)
human volunteers. (Adapted from Biolo et al. 1997.) determined by the direct incorporation of phenylalanine into muscle
and FSR derived from the A-V/biopsy model. To express the A-V
biopsy model data as FSR, it was necessary to account for the
Quantication of the rate of muscle protein break- phenylalanine content of muscle protein, the protein content of
muscle and the assumption that muscle accounts for 60% of leg
down is an important step forward in the understanding volume in normal human volunteers. (Adapted from Biolo et al.
of the response to exercise, since any net change in 1995a.)
muscle mass caused by exercise is the result of changes
in not only protein synthesis, but also protein break-
protein synthesis determined by the A-V/biopsy model
down. Further, in a variety of studies we have per-
revealed a signicant (P 0:0006) correlation
formed using this model (Biolo et al. 1992, 1995c,
(r 0:88) (Fig. 3), signifying good agreement between
Ferrando et al. 1996), we have consistently found a close
the model derived values and the direct approach
relationship between muscle protein synthesis and
(Biolo et al. 1995a). Additionally, we found that changes
breakdown (Fig. 2), and we propose (see below) a
in both FSR and the model-derived value of protein
mechanistic link between the two processes. Conse-
synthesis were similar following resistance exercise
quently, assessment of protein metabolism after exer-
(Biolo et al. 1995c), as well as during hyperaminoac-
cise is incomplete if both protein synthesis and
idaemia at rest and following resistance exercise (Biolo
breakdown are not quantied. We have also repeatedly
et al. 1997). Since different assumptions underlie each
noted a relationship between amino acid delivery to the
approach, the correspondence of the values derived
muscle, blood ow, amino acid transport into the
from the two methods supports the validity of each
muscle and protein synthesis (Biolo et al. 1995a, c). All
these factors appear to be linked, although it is yet
unclear as to any cause and effect relationships between Fractional breakdown rate. The A-V/biopsy model has
these aspects of muscle protein metabolism. some potential limitations and, therefore, may not be
Whereas our A-V model was the rst approach appropriate in all situations. For example, it might be
described to quantify muscle protein breakdown, the valuable to examine protein breakdown and protein
approach has some potential limitations. Most promi- synthesis in particular muscles, including those that
nently, it is often not feasible to place the necessary cannot be isolated by A-V sampling, e.g. deltoid muscle.
catheters, especially in healthy and/or exercising vol- Therefore, we have developed an alternative method of
unteers. Additionally, the method requires the mea- quantifying muscle protein breakdown (Zhang et al.
surement of blood ow, and changes in blood ow may 1996). This approach measures the fractional break-
predominate in the calculation of changes in synthesis down rate (FBR) of muscle protein and is analogous to
and breakdown. Finally, the leg balance is not deter- the FSR, which is the traditional approach for deter-
mined entirely by muscle, but also reects contributions mining synthesis. The general principle of the FBR is
from skin and bone, and we must assume that the bi- that the rate of entry of an essential amino acid into the
opsy data are representative of the muscle of the entire muscle intracellular compartment is a function of
leg. These assumptions have been previously discussed the FBR and the rate of entry of that amino acid from
in detail (Biolo et al. 1992). Despite these potential the blood. The FBR is calculated by rst infusing a
limitations, results from the A-V/biopsy model agree tracer of an amino acid that is not produced de novo in
well with the more widely used direct incorporation the muscle, e.g. phenylalanine, until an isotopic equi-
method of measuring protein synthesis using the frac- librium is achieved in the intramuscular pool. When the
tional synthetic rate (FSR). A comparison of FSR to tracer infusion is then stopped, the intracellular en-

380 1998 Scandinavian Physiological Society

Acta Physiol Scand 1998, 162, 377387 K D Tipton and R R Wolfe  Protein metabolism following exercise

richment will decay as a function of the rate of entry of

unlabelled and labelled phenylalanine from blood, and
unlabelled phenylalanine from muscle protein break-
down. The derivation of the equation for this mea-
surement is presented in Zhang et al. (1996). Thus the
FBR can be determined at the same time and in the
same tissue as the FSR, provided uniquely identiable
tracers of phenylalanine are used to calculate FSR and
FBR, respectively. Since the direct approach of FSR
and FBR and the A-V/biopsy model operate using
different assumptions, both may be utilized simulta-
neously to measure protein synthesis and protein
breakdown. We have compared the FBR, and FSR,
with the A-V/biopsy model results and found good
agreement between the two approaches (Zhang et al.

Post-exercise muscle protein kinetics

Using our new tracer decay technique to directly
measure muscle FBR, we again demonstrated increased
muscle protein degradation following resistance exer-
cise (Phillips et al. 1997). We have also found that
muscle protein synthesis was increased, using both the
A-V model (Biolo et al. 1995c) and amino acid incor-
poration method (FSR) (Biolo et al. 1995c, Phillips et al.
1997). Using both approaches, the increase in protein
synthesis was always greater than the increase in pro-
tein breakdown following exercise (Fig. 1); (Biolo et al.
Figure 4 Relationship between (a) muscle protein synthesis and
1995c, 1997, Phillips et al. 1997). Similar ndings, with
amino acid transport into the muscle cell, and (b) muscle protein
regard to protein synthesis, have been reported by synthesis and intracellular amino acid availability in human muscle. All
other investigators using the tracer incorporation values were determined by the A-V/biopsy model.
technique (Chesley et al. 1992, Yarasheski et al. 1993,
MacDougall et al. 1995). To date, protein breakdown
has not been measured in exercised skeletal muscle protein synthesis (Fig. 4; Biolo et al. 1995b, c, 1997). We
during or following an endurance exercise bout in have repeatedly found that the changes in muscle
human subjects and only a few studies have measured protein synthesis and muscle protein are correlated
protein synthesis directly. However, we have demon- (Fig. 2), but that protein synthesis shows a consistently
strated that muscle protein synthesis was increased greater increase in response to resistance exercise than
following both long-term endurance exercise in un- does protein breakdown (Fig. 1; Biolo et al. 1995b, c,
trained volunteers (Carraro et al. 1990b) and, more re- 1997, Phillips et al. 1997). We can only speculate as to
cently, a combination of endurance and resistance whether protein synthesis or protein breakdown is
exercise in trained female swimmers (Tipton et al. initially stimulated by exercise and if changes in the
1996b). On the other hand, there was no increase in other follow.
FSR in the deltoid muscles of trained female swimmers
following resistance exercise or swimming only (Tipton
Practical implications
et al. 1996b).
Similarly, using the A-V model, we have shown that There are practical implications regarding the link be-
amino acid transport into the muscle and muscle blood tween the intracellular availability of amino acids in
ow are increased following resistance exercise (Biolo muscle and the rate of protein synthesis. In one sce-
et al. 1995c). The increased blood ow is linked to the nario, the availability of amino acids inside the muscle
increased transport of amino acids into the muscle by cell would be the limiting factor for protein synthesis.
increasing delivery of amino acids to the muscle. It The exercise-induced stimulation of protein synthesis
follows that intracellular appearance of amino acids would cause a concomitant, transient decrease in the
increases the amino acid availability and thus muscle intracellular amino acid pool. Without an increase in

1998 Scandinavian Physiological Society 381

Protein metabolism following exercise  K D Tipton and R R Wolfe Acta Physiol Scand 1998, 162, 377387

protein breakdown and/or amino acid transport, this ing in improved (vs. rest) net protein balance for at least
pool would be depleted, thereby limiting protein syn- 48 h in our study (Phillips et al. 1997).
thesis. This suggests that the timing of protein intake
following exercise may be critical for post-exercise re-
covery, because if more amino acids were available to I N I T I A T I O N O F M U S CL E PR O T E I N
the muscle in the post-exercise state, the muscle might S Y N TH E S I S A N D BR E A K D O W N
be more responsive. Support for this notion is provided Muscle protein synthesis
by a recent study from our laboratory. Muscle protein
breakdown and synthesis were measured in six volun- Assuming the stimulation of protein synthesis precedes,
teers 34 h post-exercise (Biolo et al. 1997). An amino and thus causes, elevated protein breakdown, we can
acid infusion elevated plasma amino acid concentra- only speculate on the factors responsible for increased
tions, inward amino acid transport and muscle intra- protein synthesis following exercise. Mechanical fac-
cellular amino acid levels. The rate of protein synthesis tors, such as stretch, possibly mediated by prostaglan-
following exercise was elevated by amino acid infusion dins (Vandenburgh et al. 1990), may be important.
to a greater extent than when amino acids were infused While we are aware of no in vivo data in humans, stretch
at rest. Further, there was not a concomitant increase in has been demonstrated to initiate a twofold increase in
protein breakdown, as was seen without exogenous protein synthesis in wing muscles of domestic fowl
amino acids (Biolo et al. 1995c, Phillips et al. 1997). (Laurent et al. 1978). However, we do have indirect
Providing amino acids to the intracellular pool follow- evidence in humans to support this particular scheme.
ing exercise allows protein synthesis rates to increase We have demonstrated that the lack of mechanical ac-
without the necessity for increasing protein degrada- tivity decreases protein synthetic rates in human muscle.
tion. The amelioration of the increase in protein Two weeks of bed rest resulted in a 50% decrease in the
breakdown after exercise by providing exogenous FSR of muscle protein in human volunteers (Ferrando et
amino acids and increasing inward amino acid transport al. 1996). More recently, we noted that when mechanical
to the muscle (Biolo et al. 1997) would enable the high activity, in the form of light resistance exercise, was
rate of protein synthesis post-exercise to be maintained. added to the bed rest every other day, there was no
By maximizing protein synthesis and minimizing pro- decrease in FSR (Ferrando et al. 1997).
tein breakdown when both are at their peak in the rst Alternatively, increased blood ow from exercise
few hours following exercise, net protein balance, the may contribute to elevated protein synthesis following
difference between synthesis and breakdown that is exercise. Post-exercise increases in blood ow will in-
necessary for muscle hypertrophy and remodelling, crease amino acid delivery to the muscle (Biolo et al.
would then be optimized. We have demonstrated that 1995c). Increased amino acid delivery is associated with
providing exogenous amino acids, both through infu- increased transport of amino acids into muscle, thus
sion (Biolo et al. 1997) and orally (Tipton et al. 1996a), in increasing the intracellular availability of amino acids
the rst 4 h after resistance exercise maximizes protein necessary for protein synthesis (Biolo et al. 1995c, 1997)
synthesis and reduces protein breakdown, thus max- and possibly initiating the elevation of muscle protein
imizing net protein balance. This may be an important synthesis following exercise. Protein turnover in non-
addition to any strategy aimed at optimizing post-ex- exercised muscle is decreased following exercise (De-
ercise recovery or for stimulating an anabolic response vlin et al. 1990), perhaps due to decreased blood ow to
in muscle. those muscles. Additionally, the decreased protein
Resistance exercise exerts a prolonged effect on synthetic rate of non-exercised muscles would mean
muscle protein metabolism. Muscle protein synthesis that more amino acids would be available for protein
was reported to be increased for up to 24 h following synthesis in previously exercised muscles. On the other
resistance exercise (Chesley et al. 1992, MacDougall et al. hand, it has been demonstrated that an anabolic shift in
1995, Phillips et al. 1997). MacDougall et al. (1995) re- protein metabolism due to hormonal stimulation is not
ported that the elevation of muscle protein synthesis dependent on increasing blood ow (Fryburg et al. 1995,
lasts for 24 h in trained weight lifters, but returns to Fryburg 1996). Further, increased blood ow is transient
baseline by 36 h post-exercise. However, we recently and only lasts for a relatively short time post-exercise
found that the stimulation of muscle protein synthesis (Hussain et al. 1996), while protein synthesis may last for
lasted for 48 h (Phillips et al. 1997) in untrained sub- up to 48 h post-exercise (Phillips et al. 1997).
jects. It is possible that the training status of the sub-
jects played a role in the difference in duration of
Muscle protein breakdown
muscle protein synthesis stimulation between studies.
Muscle protein breakdown, on the other hand, had It is also possible that protein breakdown may be
returned to resting levels by 24 h post-exercise, result- stimulated during exercise and remain elevated post-

382 1998 Scandinavian Physiological Society

Acta Physiol Scand 1998, 162, 377387 K D Tipton and R R Wolfe  Protein metabolism following exercise

exercise, thus stimulating protein synthesis by increas- data do not support the idea that muscle damage is
ing the intracellular concentration of amino acids. necessary to induce muscle protein breakdown, and
Whereas it is somewhat uncertain if muscle protein thus protein synthesis, although muscle damage could
breakdown is increased during exercise, we have clearly amplify the responses. Alternatively, calcium-activated
demonstrated that skeletal muscle proteolysis is ele- proteases are stimulated by exercise and have been
vated post-exercise (Biolo et al. 1995c, Phillips et al. implicated in increasing post-exercise protein break-
1997). If protein breakdown precedes protein synthesis, down in vitro (Belcastro 1993).
then we would expect increased muscle amino acid The stimulus for increasing protein breakdown
concentrations immediately post-exercise. Unfortu- during exercise may be hormonally mediated. Endur-
nately, at present, the available data on intramuscular ance exercise causes a suppression in the release of
amino acid concentrations immediately following ex- insulin (Bloom et al. 1976, Galbo 1985) and an in-
ercise are conicting and do not help decipher this crease in the levels of glucocorticoids (Cumming et al.
puzzle. Cycling at 75% VO2 max has been reported to 1987, Davis et al. 1987, Kraemer et al. 1993). Several
both increase (MacLean et al. 1991) and decrease authors have shown that increased insulin levels
(Blomstrand et al. 1995) amino acid concentrations in caused a decrease in the rate of release of essential
the vastus lateralis immediately post-exercise, while 3 h amino acids across both the forearm (Gelfand &
of knee extension exercise did not change the amino Barrett 1987, Louard et al. 1992) and the leg (Denne et
acid concentrations (Graham et al. 1995). Moreover, al. 1991), thus concluding that muscle protein break-
muscle amino acid concentrations were not signicantly down was reduced. Hence, reduced insulin levels
changed from rest 4590 min following a 30 or during exercise may contribute to increasing muscle
42.2 km run (Blomstrand & Newsholme 1992). Thus protein breakdown. However, ndings from our lab-
the available data on post-exercise muscle amino acid oratory, using a tracer model that takes into account
concentrations do not help determine the temporal the re-utilization of amino acids from the intracellular
course of protein metabolism after exercise. pool, showed no decrease in muscle protein break-
If an increase in protein breakdown is the primary down with hyperinsulinaemia (Biolo et al. 1995b).
response of muscle protein to exercise, factors that may Further, Balon et al. (1990) demonstrated that there
be responsible for this response are not clear. Intense was no effect of insulin on protein degradation in
or prolonged exercise, especially eccentric exercise, may isolated rat hindquarters after exercise. Additionally,
result in increased skeletal muscle damage (Friden et al. resistance exercise does not result in suppressed in-
1983, Newham et al. 1983, Fielding et al. 1991). A direct sulin (Jurimae et al. 1990, Chandler et al. 1994), but
link between exercise-induced muscle damage and clearly results in increased protein breakdown (Biolo et
muscle protein breakdown has not been demonstrated. al. 1995b, Phillips et al. 1997).
Fielding et al. (1991) reported that whole body protein Glucocorticoids are known as potent stimulators of
breakdown was increased and Cannon et al. (1991) re- protein breakdown (Simmons et al. 1984, Louard et al.
ported increased urinary 3-methylhistidine excretion, an 1994, Garrel et al. 1995) and leucine oxidation (Garrel
indirect marker of myobrillar protein breakdown, et al. 1995). Therefore, increases in glucocorticoid levels
following eccentric exercise. These authors concluded from exercise (Cumming et al. 1987, Davis et al. 1987,
that the increased muscle damage was responsible for Kraemer et al. 1993) may contribute to stimulation of
elevated muscle protein breakdown (Cannon et al. 1991, amino acid oxidation and protein breakdown. Addi-
Fielding et al. 1991), possibly due to increased muscle tionally, it has been shown that insulin-mediated
levels of cytokines (Cannon et al. 1989, 1991, Fielding changes in protein metabolism are attenuated by glu-
et al. 1993). Whereas these data do not directly support cocorticoids (Louard et al. 1994). On the other hand,
the link between the immediate elevation in post- since leucine oxidation is not elevated following exer-
exercise muscle proteolysis (Biolo et al. 1995c) and cise (Devlin et al. 1990) and net muscle synthesis is
muscle damage, caution may be warranted in the in- improved (Biolo et al. 1995c, 1997), it is unlikely glu-
terpretation of urinary 3-methylhistidine excretion data cocorticoids play a dominant role in controlling muscle
(Rennie & Millward 1983). Furthermore, muscle pro- protein kinetics after exercise.
tein breakdown may be elevated after exercise in the
absence of any morphological change in muscle. In a
recent study, we found that, although muscle protein
breakdown was increased immediately and for up to Given the state of knowledge, we propose a working
24 h following a resistance exercise workout involving physiological scheme in which muscle protein synthesis
either eccentric or concentric exercise, there was no is directly stimulated by yet to be determined factors,
evidence of muscle damage immediately, or 24 and leading to decreasing levels of intracellular amino acids
48 h following the workout (Phillips et al. 1997). These (Fig. 5). We propose that the transient fall in intracel-

1998 Scandinavian Physiological Society 383

Protein metabolism following exercise  K D Tipton and R R Wolfe Acta Physiol Scand 1998, 162, 377387

Figure 5 Hypothetical
scheme of protein
metabolism in a muscle cell
following exercise. Starting
from upper left and
proceeding clockwise: (a) as
yet unknown factors
stimulate muscle protein
synthesis, which leads to (b)
decreasing intracellular
concentrations of amino
acids; (c) decreasing amino
acid levels stimulate
increased muscle protein
breakdown and/or inward
transport of amino acids; (d)
increased availability of
amino acids from protein
breakdown and/or increased
amino acid transport into the
cell further stimulates the
increase in muscle protein

lular amino acids, as a result of the increased protein synthesis? We have already shown that the infusion of
synthesis, leads to increases in both protein breakdown exogenous amino acids prevents the rise in protein
and/or inward amino acid transport to maintain the breakdown after exercise. Further, since the response
intracellular amino acid pool. If protein breakdown or of protein synthesis following exercise is always greater
inward amino acid transport, or both, were not in- in magnitude than the response of protein breakdown,
creased, then elevated levels of synthesis could not be it is difcult to envision how, if protein breakdown is
maintained in the presence of diminished intracellular driving protein synthesis, protein breakdown could
amino acid levels. Thus protein breakdown and amino provide the amino acids necessary for the greater in-
acid transport would be `pulled' by the original stimu- crease in protein synthesis.
lation of protein synthesis. If this were the case, then Although, most studies of protein metabolism after
synthetic mechanisms that were turned on by exercise exercise present data from a single point in time, it
would be limited by the intracellular availability of seems logical that the response to exercise is transient.
amino acids. This is supported by the fact that muscle We know that protein synthesis and protein breakdown
protein synthesis can be increased without a simulta- change on the order of days following resistance ex-
neous increase in protein breakdown as long as intra- ercise, but it is unknown how protein metabolism
cellular availability is maintained. changes on the order of minutes to hours post-exercise.
We recognize that, at this juncture, it is impossible Therefore, studying only a given time point following
to rule out other schemes. For example, it is possible exercise provides only a snapshot and hampers the
that protein breakdown is initially stimulated by exer- interpretation of the available information. It is neces-
cise, which in turn would drive an increase in protein sary to study the time course of the responses of pro-
synthesis. Alternatively, increased blood ow from ex- tein synthesis, protein breakdown, inward amino acid
ercise may cause an increased inward amino acid transport and the intracellular amino acid pool to allow
transport and subsequent stimulation of protein syn- a complete delineation of the order of events and the
thesis. We feel that the available data do not support precise nature of the controlling factors of post-exercise
these explanations as well as the scenario of an initial protein metabolism.
pull from protein synthesis. For example, it is difcult Finally we cannot rule out the possibility that all the
to imagine why a stimulation of protein breakdown central aspects of muscle protein metabolism (i.e. syn-
would coincide with an increase in inward amino acid thesis, breakdown and amino acid transport) are inde-
transport, since amino acid availability would already be pendently regulated and their coordinated response to
increased by the increased protein degradation. On the exercise occurs by coincidence. However, the close
other hand, why would protein breakdown be increased correspondence of, and apparent coordination of, the
if inward transport were providing the push for protein responses of these factors suggests that they are linked.

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Acta Physiol Scand 1998, 162, 377387 K D Tipton and R R Wolfe  Protein metabolism following exercise

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