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Exercise-Induced Muscle Damage and
Potential Mechanisms for the Repeated
Bout Effect
Malachy P. McHugh,
1,2
Declan A.J. Connolly,
3
Roger G. Eston
1
and Gilbert W. Gleim
2
1 School of Sport, Health and Physical Education Sciences, University of Wales, Bangor,
Gwynedd, Wales
2 Nicholas Institute of Sports Medicine and Athletic Trauma, Lenox Hill Hospital, New York,
New York, USA
3 Department of Physical Education, University of Vermont, Burlington, Vermont, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
1. Evidence for the Repeated Bout Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
2. Neural Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
2.1 Neural Control of Eccentric Contractions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
2.2 Potential Neural Adaptations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
2.3 Indirect Evidence for Neural Adaptations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
2.4 Evidence Against a Neural Adaptation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3. Connective Tissue Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
3.1 Mechanical Factors Associated with Muscle Damage . . . . . . . . . . . . . . . . . . . . . . 162
3.2 Role of the Intermediate Filaments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
3.3 Intramuscular Connective Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
3.4 Changes in Passive Muscle Stiffness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
4. Cellular Theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
4.1 Sarcomere Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
4.2 Potential Cellular Adaptations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
4.3 Direct Evidence for Cellular Adaptation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
5. Other Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6. Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Abstract
Unfamiliar, predominantly eccentric exercise, frequently results in muscle
damage. A repeated bout of similar eccentric exercise results in less damage and
is referred to as the ‘repeated bout effect’. Despite numerous studies that have
clearly demonstrated the repeated bout effect, there is little consensus as to the
actual mechanism. In general, the adaptation has been attributed to neural, con-
nective tissue or cellular adaptations. Other possible mechanisms include, adap-
tation in excitation-contraction coupling or adaptation in the inflammatory
response.
The ‘neural theory’ predicts that the initial damage is a result of high stress on
REVIEW ARTICLE
Sports Med 1999 Mar; 27 (3):157-170
0112-1642/99/0003-0157/$07.00/0
© Adis International Limited. All rights reserved.
a relatively small number of active fast-twitch fibres. For the repeated bout, an
increase in motor unit activation and/or a shift to slow-twitch fibre activation
distributes the contractile stress over a larger number of active fibres. Although
eccentric training results in marked increases in motor unit activation, specific
adaptations to a single bout of eccentric exercise have not been examined.
The ‘connective tissue theory’ predicts that muscle damage occurs when the
noncontractile connective tissue elements are disrupted and myofibrillar integrity
is lost. Indirect evidence suggests that remodelling of the intermediate filaments
and/or increased intramuscular connective tissue are responsible for the repeated
bout effect.
The ‘cellular theory’ predicts that muscle damage is the result of irreversible
sarcomere strain during eccentric contractions. Sarcomere lengths are thought to
be highly non-uniform during eccentric contractions, with some sarcomeres
stretched beyond myofilament overlap. Loss of contractile integrity results in
sarcomere strain and is seen as the initial stage of damage. Some data suggest
that an increase in the number of sarcomeres connected in series, following an
initial bout, reduces sarcomere strain during a repeated bout and limits the sub-
sequent damage.
It is unlikely that one theory can explain all of the various observations of the
repeated bout effect found in the literature. That the phenomenon occurs in elec-
trically stimulated contractions in an animal model precludes an exclusive neural
adaptation. Connective tissue and cellular adaptations are unlikely explanations
when the repeated bout effect is demonstrated prior to full recovery, and when
the fact that the initial bout does not have to cause appreciable damage in order
to provide a protective effect is considered. It is possible that the repeated bout
effect occurs through the interaction of various neural, connective tissue and
cellular factors that are dependent on the particulars of the eccentric exercise bout
and the specific muscle groups involved.
1. Evidence for the Repeated
Bout Effect
Unfamiliar eccentric exercise frequently results
in muscle damage, the symptoms of which include
strength loss, pain, muscle tenderness and elevated
creatine kinase activity. Following recovery, a re-
peated bout of the same exercise results in minimal
symptoms of muscle damage and has been referred
to as the ‘repeated bout effect’.
[1]
This protective
effect of prior exercise was first indicated by High-
man and Altland
[2]
and specifically attributed to ec-
centric contractions in later work.
[3]
The repeated
bout effect has subsequently been demonstrated in
humans and in animal models, with various types
of activities using different muscle groups (table
I).
[1,3-20]
Many theories have been proposed to ex-
plain the repeated bout effect but a specific mech-
anism has not been identified. In general, 3 catego-
ries of hypotheses have been proposed to explain
this phenomenon which are neural, mechanical and
cellular in origin. Other theories include adaptations
in excitation-contraction (E-C) coupling
[21,22]
and
reduced inflammatory response.
[17]
2. Neural Theory
2.1 Neural Control of Eccentric Contractions
The terms ‘eccentric contraction’, ‘pliometric
contraction’, ‘lengthening contraction’, ‘eccentric
activation’ and ‘eccentric action’ have been used
synonymously to describe what happens when the
force generated by a muscle is less than the oppos-
ing load. In agreement with the position adopted
by the American College of Sports Medicine,
[23]
158 McHugh et al.
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Table I. Studies demonstrating the repeated bout effect
Population Muscle group Exercise mode Delay between bouts Proposed mechanism Reference
12 men Elbow flexors Isotonic at 80% MVC 3 and 6 days Neural adaptation 1
84 rats Soleus, vastus
intermedius, triceps
medialis
Downhill running, level
running
3-8 days Strengthening of muscle
tissue
3
11 women, 5 men Lower extremity
muscles
Downhill walking 1-8 weeks No mechanism discussed 4
18 women, 6 men Knee extensors Maximal isokinetic 3 weeks Improved ability to repair
initial injury
5
11 women,
11 men
Lower extremity
muscles
Downhill running 3, 6 or 9 weeks Removal of weak fibres 6
8 women Elbow flexors Maximal isotonic 2 weeks Connective tissue
adaptation or removal of
weak fibres or
strengthening of cell
membrane
7
20 women Elbow flexors Maximal isotonic 5 or 14 days Strengthening of
connective tissue or cell
membrane
8
10 men Quadriceps Downhill running
following maximal
isokinetic quadriceps
exercise
2 weeks No mechanism discussed 9
9 women Quadriceps Cycling 8 weeks’ training Serial addition of
sarcomeres or
intermediate filament
remodelling
10
15 men Quadriceps Cycling 4 and 8 weeks’ training Reorganisation of
intermediate filament
11
24 men Quadriceps Isotonic at ≤85% MVC 3 weeks Neural adaptations 12
67 rats Vastus intermedius Downhill running 1-3 weeks Serial addition of
sarcomeres
13
22 men Quadriceps Maximal isotonic 4 and 13 days Removal of weak fibres
or connective tissue
adaptation or neural
adaptation
14
5 women, 3 men Elbow flexors Maximal isotonic 2 and 4 weeks Connective tissue
adaptation and/or
removal of weak fibres
15
9 men Lower extremity
muscles
Downhill running 4 days Increased tissue strength
or neural adaptation
16
10 men Elbow flexors Maximal isotonic 3 weeks Decreased inflammatory
response
17
Mice
a
Tibialis anterior Supramaximal nerve
stimulation
10, 21, 84 or 166 days Excludes possibility of
neural adaptation
18
3 women, 3 men Lower extremity
muscles
Downhill running 2 weeks Neural adaptation 19
4 women, 3 men Lower extremity
muscles
Downhill running 2 weeks No mechanism discussed 20
a number not stated.
MVC = maximal voluntary contraction.
Potential Mechanisms for the Repeated Bout Effect 159
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the term ‘eccentric contraction’ is used in this re-
view.
Exercise-induced muscle damage is associated
with exercise involving a predominance of eccen-
tric contractions.
[24-26]
Specific neural control of
eccentric contractions has been implicated in the
initiation of muscle damage
[27]
and the repeated
bout effect.
[1,12,14,16]
It is well established that for a
given force production, less motor unit activation
is required for eccentric compared with concentric
contractions.
[27-31]
Bigland and Lippold
[29]
showed
surface electromyograph (EMG) amplitudes for
eccentric contractions of the plantar flexors to be
approximately 50% of concentric contractions at
similar force levels. Similar results have been dem-
onstrated in the elbow flexors (eccentric EMG 56%
of concentric)
[31]
and the knee extensors (eccentric
EMG 49% of concentric).
[30]
Moritani et al.
[27]
pro-
posed that muscle damage was a result of high
stress on a small number of active fibres during
repeated eccentric contractions.
In addition to less motor unit activation, some
authors have suggested that high threshold motor
units are selectively recruited during submaximal
eccentric contractions.
[32-34]
Nardone et al.
[33]
identi-
fied motor units according to their recruitment
threshold during ramp isometric contractions of the
plantar flexors. Individuals then performed recip-
rocal low intensity [<20% maximal voluntary con-
traction (MVC)] eccentric and concentric contrac-
tions. Interestingly, some motor units were
activated during the eccentric portion that had been
silent during both the concentric portion and the
ramp isometric contractions. The amplitude of the
action potentials from these units were consistent
with high threshold motor units. Additionally, the
soleus (predominantly slow twitch) appeared to be
inhibited during the eccentric contractions with a
corresponding increase in gastrocnemius (predom-
inantly fast twitch) activation. These observations
were taken to represent selective recruitment of
high threshold motor units with a predominance of
fast twitch fibres for submaximal eccentric con-
tractions.
In contrast with the findings of Nardone and
Schieppati
[34]
and Nardone et al.
[33]
analysis of the
frequency content of the surface EMG signal dur-
ing submaximal eccentric contractions of the el-
bow flexors
[27,31]
or maximal eccentric contractions
of the quadriceps
[35]
failed to demonstrate evidence
for selective recruitment of high threshold motor
units. In fact, Nakazawa et al.
[36]
provided evidence
of de-recruitment of high threshold motor units
during submaximal eccentric contractions of the
elbow flexors. However, as suggested by Pot-
vin,
[31]
similar frequencies at lower activation lev-
els may indicate preferential high threshold motor
unit recruitment during eccentric contractions.
Selective recruitment of high threshold motor
units would be expected to increase the rate of fa-
tigue. However, maximum eccentric contractions
have been shown to be extremely fatigue resistant
despite high force production.
[35,37]
Hortobágyi et
al.
[37]
demonstrated force decrements of 41 and
32% following maximal isometric and concentric
contractions of the plantar flexors contrasted with
no change in force following eccentric contrac-
tions. Similarly Tesch et al.
[35]
demonstrated 34 to
47% fatigue following maximal concentric con-
tractions of the quadriceps with no fatigue follow-
ing the same number of maximal eccentric contrac-
tions. Concentric fatigue was associated with a
decrease in the mean power frequency (MPF) of
the EMG signal with no change in MPF during
eccentric contractions. These results are consistent
with fatigue in fast fatigable motor units with con-
centric contractions contrasting with sustained
function of fast fatigable motor units during eccen-
tric contractions.
Although it was suggested that the mechanism
of fatigue is fundamentally different for eccentric
compared with concentric contractions,
[35]
specific
mechanisms were not discussed. Lower energy de-
mand may explain the fatigue resistance for eccen-
tric contractions. Komi et al.
[30]
demonstrated
greater mechanical efficiency (ratio of output to
input energy) for eccentric (85%) compared with
concentric contractions (19%) of the knee exten-
sors.
160 McHugh et al.
Adis International Limited. All rights reserved. Sports Med 1999 Mar; 27 (3)
While the possibility of selective recruitment of
high threshold motor units remains uncertain, it
appears that fast twitch fibres are more susceptible
to damage during eccentric exercise.
[11,38-40]
Fridén
et al.
[38]
found myofibrillar disruption to be 3 times
more prevalent in fast compared with slow twitch
fibres 3 days after eccentric bicycle ergometer ex-
ercise. It is possible that selective recruitment of a
small number of high threshold motor units places
excessive stress on fast twitch fibres leading ulti-
mately to damage of these fibres. A neural recruit-
ment pattern combining less motor unit activation,
selective fast twitch fibre recruitment and fatigue
resistance may predispose the muscle to injury.
2.2 Potential Neural Adaptations
Several authors have discussed the possibility
that there is a change in motor unit recruitment
during the repeated bout, which limits the extent of
damage.
[1,12,14,16]
Specifically, Golden and Dud-
ley
[12]
suggested that less motor unit activation as-
sociated with eccentric contractions ‘may provide
the opportunity to ‘learn’ more efficient recruit-
ment’ for a repeated bout. Accordingly, Pierrynowski
et al.
[17]
suggested that ‘increased synchrony of mo-
tor unit firing’ may reduce myofibrillar stresses dur-
ing a repeated bout. Similarly, Nosaka and Clark-
son
[1]
suggested that the neural adaptation would
‘better distribute the workload among fibres’.
Several studies point to the potential for neural
adaptation. In strength training studies, greater in-
creases in integrated EMG activity (iEMG) have
been demonstrated with purely eccentric compared
with purely concentric training.
[41-43]
12 weeks of
eccentric strength training of the knee extensors (in
men) resulted in a 116% increase in strength with
a 188% increase in iEMG compared with a 53%
increase in strength and a 28% increase in iEMG
with concentric strength training.
[42]
A subsequent
study by Hortobágyi et al.
[41]
demonstrated similar
neural adaptations in women, with only 6 weeks
of training. With eccentric training, strength in-
creased by 42% while iEMG increased by 89%.
With concentric training, strength increased by
36% and iEMG increased by 39%.
Similarly, Komi and Buskirk
[43]
found that 7
weeks of eccentric strength training of the elbow
flexors in men resulted in a 16% increase in eccen-
tric strength associated with a 22% increase in
iEMG, while concentric strength training resulted
in a 12% increase in concentric strength associated
with a 10% decrease in iEMG. Interestingly, the
greatest increases in iEMG with eccentric training
occurred at weeks 2 and 3, the point at which the
authors noted that the muscle soreness associated
with the eccentric training had subsided. It was not
clear whether the increase in iEMG was caused by
the repeated bouts (6 maximum contractions, 4
days/week) or the initial bouts that resulted in mus-
cle soreness.
Despite strength improvements, force
:
iEMG
ratio was decreased in these studies
[41-43]
suggest-
ing that eccentric strength training results in a de-
crease in force per motor unit activation. The fact
that Komi and Buskirk
[43]
noted the largest in-
crease in iEMG at 3 weeks suggests the effect was
not due to hypertrophy. This may represent a neural
adaptation consistent with the theory of Nosaka
and Clarkson
[1]
whereby the workload for the re-
peated bouts is distributed over a greater number
of active fibres.
Eccentric strength training also resulted in
marked cross education to contralateral muscle
groups.
[44,45]
Hortobágyi et al.
[44]
demonstrated
that 12 weeks of unilateral eccentric quadriceps
training increased contralateral strength by 77%
and iEMG by 54%. Concentric training increased
contralateral strength by 30% and iEMG by 28%.
Similarly, Weir et al.
[45]
demonstrated a 16% in-
crease in eccentric strength and a 15% increase in
isometric strength in the untrained limb following
8 weeks of unilateral eccentric quadriceps training.
These findings
[44,45]
emphasise the ability of the
central nervous system to adapt to eccentric exercise.
2.3 Indirect Evidence for
Neural Adaptations
Indirect evidence of a neural adaptation with a
repeated bout of eccentric exercise has been demon-
strated in several studies.
[1,5,7,14]
In 2 studies
[1,14]
a
Potential Mechanisms for the Repeated Bout Effect 161
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repeated bout prior to full recovery did not exacer-
bate the symptoms, while in other studies
[5,7]
the
initial bout did not have to cause appreciable dam-
age to afford a protective effect. Nosaka and Clar-
kson
[1]
had individuals repeat a bout of eccentric
exercise after only 3 days when muscle soreness
and creatine kinase (CK) levels were significantly
elevated. Decreases in soreness and CK on the days
following the repeated bout indicated that the pro-
tective effect was not dependent on full recovery.
Similarly, Mair et al.
[14]
showed that a repeated
bout of eccentric quadriceps exercise after 4 days
did not further impair vertical jump or affect CK
on the following days. These effects may have been
caused by de-recruitment of motor units with in-
jured fibres and increased activity in healthy motor
units.
The initial bout of eccentric exercise does not
have to cause appreciable damage to provide a pro-
tective effect.
[5,7]
Clarkson and Tremblay
[7]
had in-
dividuals perform 70 maximum eccentric contrac-
tions of the elbow flexors with one arm and 24
maximum contractions with the other arm. Two
weeks later, the arm that had initially performed 24
contractions now performed 70 contractions. Fol-
lowing the initial bout, changes in strength, pain
and muscle soreness were significantly lower in the
arm that performed 24 contractions compared with
the arm performing 70 contractions. Peak strength
loss was 41% in the arm performing 70 contrac-
tions compared with 15% in the arm performing 24
contractions. When the arm that had initially per-
formed 24 contractions performed 70 contractions
2 weeks later, strength loss was only 11%. Al-
though the authors suggested that the protective
effect may have been a result of increased strength
of the cell membrane or surrounding connective
tissue, a neural adaptation would also be a plausible
explanation.
Brown et al.
[5]
recently demonstrated results
similar to Clarkson and Tremblay.
[7]
An initial bout
of 10, 30 or 50 eccentric contractions of the knee
extensors provided equal protection for a bout of
50 contractions 3 weeks later. Marked elevations
in CK activity were found on the days following
the initial bout of 30 and 50 reps. However, CK
activity was not elevated following the initial bout
of 10 repetitions. Three weeks later when all indi-
viduals performed a bout of 50 repetitions none of
the groups demonstrated an increase in CK activity.
Similar responses were seen for strength and sore-
ness. While the initial bout of 10 repetitions did not
cause appreciable damage, it provided protection
from a repeated bout which would have been ex-
pected to cause considerable muscle damage. Al-
though not discussed, a neural adaptation to the
initial exercise is a plausible explanation since the
effects were not dependent on the occurrence of
muscle damage. It remains to be determined how
many contractions are sufficient to provide a pro-
tective effect.
2.4 Evidence Against a Neural Adaptation
The repeated bout effect has been demonstrated
with electric stimulation of rat tibialis anterior
muscles.
[18]
In unconditioned muscles, force was
48% of the non-exercised control muscle 3 days
after exercise. In eccentrically preconditioned
muscles, force was 80% of the control muscles 3
days following repeated bouts (10 or 21 days after
the initial bout). The protection afforded to the pre-
conditioned muscles could not be attributed to a
neural adaptation since the exercise involved stim-
ulated contractions. While these results prove a
peripheral component to the repeated bout effect, a
concomitant neural adaptation may occur with vol-
untary contractions which results in less severe
damage. Additionally, the 20% force loss in the
preconditioned muscles suggests that the repeated
bout still caused significant damage.
3. Connective Tissue Theory
3.1 Mechanical Factors Associated with
Muscle Damage
Muscle damage has been referred to as mechan-
ical failure of individual myofibrils consistent with
materials fatigue typical of ductile material subjected
to cyclic tensile loading.
[24,46]
Materials fatigue re-
fers to structural failure caused by cumulative tensile
162 McHugh et al.
Adis International Limited. All rights reserved. Sports Med 1999 Mar; 27 (3)
stress and is distinct from failure caused by the
application of a single stress that exceeds the ma-
terial’s ultimate tensile strength. A ductile material
under tensile stress experiences plastic deforma-
tion prior to failure, in contrast to a brittle material
which fails without prior deformation. Skeletal
muscle is a ductile material and its behaviour dur-
ing repeated eccentric contractions is consistent
with materials fatigue.
[46]
Armstrong et al.
[24]
have proposed that the pas-
sive elements of skeletal muscle experience exces-
sive strain during eccentric contractions at muscle
lengths on the ‘descending limb’ of the length-tension
curve. In this situation the ability to produce active
tension is decreasing while passive tension is in-
creasing.
Data from isolated whole muscle preparations
in animals
[47-49]
and voluntary contractions in hu-
mans
[50]
have clearly shown that the length of the
muscle during eccentric contractions appears to be
a critical factor in determining the extent of dam-
age. Lieber and Fridén
[49]
demonstrated that dam-
age to rabbit tibialis anterior muscles was a func-
tion of the length to which the muscle was
elongated during stimulation rather than the mag-
nitude of the contractile stimulus. Muscles actively
strained 12.5% beyond resting length experienced
a 40% decrease in maximum tetanic tension. Mus-
cles strained 25% beyond resting length experi-
enced a 60% decrease in tetanic tension. Newham
et al.
[50]
demonstrated that eccentric contractions
of the elbow flexors performed at longer muscle
lengths resulted in greater symptoms of muscle
damage. On the following day, muscles which ex-
ercised from 45° to full elbow extension (long) had
20% strength loss compared with 9% in the mus-
cles exercised from full flexion to 60°. Two days fol-
lowing the initial exercise, muscle tenderness was
almost twice as high in the long group. These stud-
ies
[47-50]
support the theory of disruption occurring
on the ‘descending limb’ of the length-tension curve.
3.2 Role of the Intermediate Filaments
The length-tension curve is determined by myo-
filament overlap which is a function of sarcomere
length.
[51,52]
Sarcomere elongation during eccen-
tric contractions is highly non-uniform with some
sarcomeres maintaining length while others are
stretched beyond the point of filament overlap.
[53-55]
This excessive stretch has been referred to as sar-
comere ‘give’
[53]
or ‘popping’.
[55]
When a sarcomere
is stretched beyond filament overlap (‘popped’), a
greater dependence is placed on the passive struc-
tures to maintain serial tension as the serial
sarcomeres shorten.
[55]
Muscle damage is not a re-
sult of the actual ‘popping’ (which is thought to
occur with most eccentric contractions) but is
thought to be caused by the cyclic stress placed on
the supporting passive structures by continued ec-
centric contractions following ‘popping’.
[55]
These
elements are referred to as intermediate filaments
and consist of the proteins desmin, vimentin and
synemin.
[56,57]
The intermediate filaments are re-
sponsible for maintaining the structural integrity of
serial and parallel sarcomeres.
[56-58]
Force transmission within skeletal muscle can
be augmented by the intermediate filament sys-
tem.
[58,59]
Street
[59]
demonstrated that the interme-
diate filament system provides a link to bypass
damaged areas and maintain serial force produc-
tion. While this may be beneficial for maintaining
force production during eccentric exercise, the ul-
timate effect may be to increase subsequent dam-
age. When sarcomeres are stretched beyond myo-
filament overlap the intermediate filament system
must bear the load of subsequent contractions. Re-
peated loading will result in mechanical failure of
the intermediate filament system. Electron micro-
scopic analysis of muscle damage shows signifi-
cant disruption of the intermediate filaments char-
acterised by Z band streaming and loss of
registration of Z bands in parallel myofibrils.
[56,57]
The ability of the intermediate filaments to
withstand these cyclic stresses may effect the de-
gree of muscle damage resulting from a bout of
eccentric exercise. Intermediate filament remodell-
ing may also play a role in the repeated bout effect.
In a study of eccentric bicycle ergometry training,
Fridén et al.
[10]
proposed several mechanisms by
which the muscle became resistant to damage. It
Potential Mechanisms for the Repeated Bout Effect 163
Adis International Limited. All rights reserved. Sports Med 1999 Mar; 27 (3)
was suggested that a structural reorganisation of
the intermediate filament system could have pre-
vented further damage. This explanation was offered
because intermediate filament repair took 7 to 10
days and this corresponded with the duration of
symptoms of muscle damage. Newham et al.
[15]
demonstrated a repeated bout effect following
bouts of maximal eccentric contractions of the el-
bow flexors separated by 2 weeks. Pain and stiff-
ness following the initial bout was attributed to
shortening of the noncontractile connective tissue
in parallel with the contractile elements. Adapta-
tion of this connective tissue was proposed as a
possible mechanism for the decreased pain and
stiffness following repeated bouts. This possibility
was restated in subsequent studies
[7,8]
but no addi-
tional supporting evidence was provided.
3.3 Intramuscular Connective Tissue
There is indirect evidence that a connective tis-
sue adaptation can provide protection against mus-
cle damage.
[60]
Lapier et al.
[60]
increased the intra-
muscular connective tissue of rat extensor digitorum
longus muscles by immobilising the ankle joint for
3 weeks with the muscle in either a shortened or
lengthened position. Muscles immobilised in the
lengthened position had 63% more intramuscular
connective tissue and 86% lower mass than contra-
lateral control muscles. Muscles immobilised in
the shortened position had 47% more intramuscu-
lar connective tissue and 21% lower mass than con-
trol muscles. Subsequent bouts of stimulated ec-
centric contractions resulted in 50% force loss in
control muscles compared with 40% in muscles
immobilised in the shortened position and 8% in
muscles immobilised in the lengthened position.
The protective effect was attributed to the ability
of the increased connective tissue to dissipate myo-
fibrillar stresses. The authors suggested that tissue
repair following a damaging bout of eccentric exer-
cise is characterised by a similar increase in intra-
muscular connective tissue thereby protecting
against damage from repeated bouts.
Alternatively, these findings with respect to im-
mobilisation could be interpreted as a cellular adap-
tation in the muscle tissue. The fact that the effect
occurred primarily in the muscles immobilised in
the lengthened position suggests that protection
may have been a result of the longitudinal addition
of sarcomeres (see section 4.3).
An increase in intramuscular connective tissue
would be expected to result in increased muscle
stiffness.
[61]
Isometric strength training of the ham-
strings has been shown to increase passive muscle
stiffness.
[62]
Klinge et al.
[62]
demonstrated that a
43% increase in isometric strength was associated
with a 25% increase in passive stiffness. It is un-
likely that increased tissue cross-sectional area
could account for the increased stiffness and the
effects were, in part, attributed to connective tissue
adaptations. The greater strength improvements
and early structural damage with eccentric strength
training suggest the possibility of greater connec-
tive tissue adaptations than with isometric training.
3.4 Changes in Passive Muscle Stiffness
Passive muscle stiffness has been measured fol-
lowing eccentric exercise.
[63-65]
Stiffness has been
shown to be elevated by as much as 125%
[63]
and
by 138%
[64]
2 days following eccentric elbow
flexion. Stiffness remained elevated by 61
[63]
and
42%,
[64]
respectively, 5 and 10 days after eccentric
elbow flexion. Correspondingly, strength remained
significantly depressed at these follow-up times.
Possible mechanisms for the increase in stiffness
include soft tissue oedema, contractile resistance to
painful passive extension or injury-induced
changes in the mechanical properties of the con-
nective tissues.
[63-65]
Soft tissue oedema is thought
to be important
[63]
while neuromuscular activity is
not thought to play a role.
[65]
Stiffness changes
have not been followed to the point when strength
has fully recovered. It is possible that the repair pro-
cess results in a permanent increase in passive stiff-
ness as a result of remodelling of the connective
tissue as suggested by Lapier et al.
[60]
In contrast, a recent study examining the effect
of fatigue and warm-up prior to a bout of eccentric
exercise suggests that decreased muscle stiffness
may be protective against muscle damage.
[66]
In an
164 McHugh et al.
Adis International Limited. All rights reserved. Sports Med 1999 Mar; 27 (3)
initial experiment, individuals performed 12 max-
imum eccentric contractions of the elbow flexors
with each arm. In one arm the 12 eccentric contrac-
tions were preceded by 100 maximum concentric
contractions. The concentric exercise resulted in a
20% decrease in isometric strength but did not af-
fect eccentric force production which was similar
between arms. In the arm exercising without prior
concentric exercise, isometric strength loss was
40% 1 day later and 20% 5 days later. In the arm
subjected to prior concentric exercise, isometric
strength loss was only 25% 1 day later and had
returned to baseline within 5 days. Other indices of
muscle damage showed similar differences between
arms during the 5 days following the respective
exercise bouts. Paradoxically, these results sug-
gested that whole muscle fatigue (induced concen-
trically) protected the muscle from damage. The
authors performed an additional experiment to
help explain these effects.
In the second part of the study the eccentric ex-
ercise was preceded by 100 concentric elbow flex-
ions without resistance to simulate warm-up exer-
cise. The eccentric exercise preceded by warm-up
resulted in significantly less strength loss and min-
imal changes in CK activity compared with the ec-
centric exercise without prior warm-up. These pro-
tective effects of prior concentric exercise (fatiguing
and nonfatiguing) were attributed to decreased pas-
sive muscle stiffness. This is supported by data from
Magnusson et al.
[67]
who demonstrated a 20% re-
duction in passive hamstring stiffness immediately
following 40 maximum concentric contractions. Al-
ternatively, a change in motor unit recruitment fol-
lowing warm-up and fatigue could explain the re-
sults of Nosaka and Clarkson.
[66]
While these data
demonstrate a protective effect, they do not pro-
vide an insight into a mechanism for the repeated
bout effect.
4. Cellular Theory
4.1 Sarcomere Disruption
Sarcomere disruption is characterised by Z band
streaming with associated A band disruption.
[56]
In
addition, there is a loss of lateral registration of
parallel myofibrils.
[56]
20% of fibres were dis-
rupted 3 days following an initial 30-minute bout of
eccentric cycling with only 4% of fibres disrupted 4
weeks later, following several repeated bouts.
[10]
At the cellular level muscle contraction occurs
by the sliding filament action caused by the cyclic
formation of actin-myosin crossbridges.
[52]
During
isometric and concentric contractions, adenosine
triphosphate (ATP) is required to detach cross-
bridges. However, during eccentric contractions,
crossbridges are forcibly detached without split-
ting ATP.
[52]
The term ‘popping’ has been used to
describe what happens when a sarcomere is
strained sufficiently that all crossbridges are forci-
bly detached and there is no longer any myofila-
ment overlap.
[55]
As previously stated (section 3.1),
sarcomere length changes are thought to be highly
non-uniform during eccentric contractions.
[53-55]
Morgan’s theory
[55]
predicts that some sarcomeres
are ‘popped’ while others maintain length or actu-
ally shorten. Upon relaxation most sarcomeres re-
cover interdigitation but some of them remain
overextended. With repeated eccentric contrac-
tions more sarcomeres are ‘popped’. These ‘popped’
sarcomeres are repeatedly strained and the cell
membrane is ultimately disrupted.
Evidence in support of this theory was provided
by Wood et al.
[68]
who demonstrated that strength
loss in the frog sartorius muscle immediately fol-
lowing a series of eccentric contractions was asso-
ciated with a shift to the right in the length-tension
relationship. These findings are consistent with the
intact sarcomeres adopting a shorter length sub-
sequent to strain of disrupted sarcomeres. Electron
micrographs of damaged sarcomeres provided ad-
ditional support. More recently, Saxton and Don-
nelly
[69]
demonstrated greater strength loss at short
muscle lengths in human elbow flexors following a
bout of eccentric exercise. The disproportionate
strength loss at short muscle lengths was also at-
tributed to intact sarcomeres adopting a shorter
length subsequent to strain of disrupted sarcomeres.
Potential Mechanisms for the Repeated Bout Effect 165
Adis International Limited. All rights reserved. Sports Med 1999 Mar; 27 (3)
4.2 Potential Cellular Adaptations
Cellular adaptations explaining the repeated bout
effect may occur at the level of the muscle fibre,
the myofibril or the sarcomere itself. Proposed the-
ories include strengthening of the cell membrane,
[7]
removal of a pool of weak fibres or sarcomeres
following the initial damage
[6,14,70]
and longitudi-
nal addition of sarcomeres.
[10,13]
Clarkson and Tremblay
[7]
suggested that strength-
ening of the cell membrane could be an alternative
explanation to a connective tissue adaptation. Sar-
colemmal disruption results in the loss of calcium
homeostasis which initiates the cellular necrosis
evident on electron micrographs.
[24]
Strengthening
of the sarcolemma or the sarcoplasmic reticulum
could prevent disruption during eccentric contrac-
tions thereby preventing the calcium influx and
avoiding the subsequent cellular necrosis.
Injury following downhill running in rats was
explained by Armstrong et al.
[70]
as disruption of a
pool of stress ‘susceptible’ fibres. Accordingly, re-
duced injury following repeated bouts of downhill
running
[6]
and eccentric quadriceps exercise
[14]
has
been explained by the removal of the ‘susceptible’
fibres following the initial injury. Removal of a
pool of stress ‘susceptible’ myofibres or sarco-
meres, as opposed to whole fibres, would be more
consistent with the electron micrographic evidence
of damage. The initial bout may serve to identify
and remove a select population of weak sarco-
meres. The lack of further damage when the re-
peated bout occurs before full recovery supports
such a theory.
[1,14]
However, a limitation to this the-
ory is the fact that the initial bout does not have to
cause appreciable damage in order to provide a pro-
tective effect.
[3,5,7]
If the weak sarcomeres are still
intact and functional then they should be disrupted
by the repeated bout and damage would be evident.
This was clearly not the case in the studies by
Schwane and Armstrong,
[3]
Brown et al.
[5]
and
Clarkson and Tremblay.
[7]
4.3 Direct Evidence for Cellular Adaptation
Since muscle damage can be explained in terms
of sarcomere mechanics it is plausible that the re-
peated bout effect could be explained by an adap-
tation in sarcomere mechanics. Such a theory was
proposed by Morgan
[55]
whereby longitudinal ad-
dition of sarcomeres following an initial bout of
eccentric exercise would reduce sarcomere strain
for a given muscle excursion during a repeated
bout. Reduced sarcomere strain would allow the
myofilaments to maintain overlap, limit sarcomere
‘popping’ and avoid the ensuing cellular disrup-
tion.
The possibility that repair of muscle damage oc-
curs by serial addition of sarcomeres within a myo-
fibril was previously discussed by Fridén et al.
[10]
Electron microscopic observations of biopsies
from vastus lateralis muscles of women following
8 weeks of eccentric bicycle ergometry indicated
lengthening of the myofibrils by addition of new
sarcomeres.
[10]
However, the authors failed to elab-
orate on their observations and did not provide any
specific evidence of such an adaptation.
More recently Lynn and Morgan
[13]
tested Mor-
gan’s theory of longitudinal addition of sarcomeres
by comparing the number of serial sarcomeres in
rat vastus intermedius muscles following either up-
hill or downhill running. One week of training with
downhill running resulted in an 8% increase in se-
rial sarcomeres compared with a sedentary control
group. Similar uphill training resulted in a 4% de-
crease in serial sarcomeres relative to control rats.
These results directly support Morgan’s original
theory
[55]
and provide a specific cellular mech-
anism for the repeated bout effect.
The plausibility of this theory depends on the
time course for the cellular adaptation and the stimu-
lus required to initiate the adaptation. As previously
mentioned, human studies have demonstrated a re-
peated bout effect prior to full recovery from the
initial bout.
[1,14]
All criterion measures indicated sig-
nificant muscle damage 3 days following an initial
bout of eccentric exercise yet a repeated bout at that
time did not exacerbate the damage.
[1]
In fact, in-
dices of muscle damage were reduced following
166 McHugh et al.
Adis International Limited. All rights reserved. Sports Med 1999 Mar; 27 (3)
the repeated bout. Morgan’s theory would not be
plausible in this instance since the sarcomeres were
given inadequate time to regenerate. Additionally,
Morgan’s theory predicts that the initial myofibril-
lar disruption is the stimulus for the addition of
sarcomeres. However, as stated before (section 2.3),
the initial bout does not have to cause appreciable
damage in order to provide a protective effect.
[3,5,7]
The concept of sarcomere strain as the initial
step in the initiation of muscle damage is supported
by a shift in the length-tension curve to the right
immediately following a series of eccentric con-
tractions.
[68]
If longitudinal addition of sarcomeres
occurs, one would expect the length-tension curve
to be shifted to the right following repair. With
more sarcomeres in series a greater muscle length
would be required to reach optimal sarcomere
length. However, the length-tension curve has been
shown to return to normal within 5 hours in toad
sartorius muscles
[68]
and within 2 days in human
triceps surae muscles.
[71]
5. Other Mechanisms
Force loss following eccentric contractions may
not be entirely caused by mechanical disruption.
Impairment of calcium-mediated E-C coupling has
been shown to contribute to force loss following
active stretches of isolated whole muscle
[22]
and
single fibre preparations
[21]
from mice. These re-
sults
[21,22]
suggest impaired calcium release or sen-
sitivity following myofibrillar disruption. An ad-
aptation in E-C coupling may explain the reduced
strength loss following a repeated bout. Strength-
ening of the sarcoplasmic reticulum, as suggested
by Clarkson and Tremblay,
[7]
may prevent impair-
ment of E-C coupling with a repeated bout.
Reduced muscle damage following a repeated
bout has been attributed to a blunted inflammatory
response.
[16]
Decreased neutrophil and monocyte
activation were seen on the days subsequent to the
repeated bout. It was not clear whether these ef-
fects reflected a blunted immune response to tissue
damage, or the lack of tissue damage following the
repeated bout. An adaptation in the inflammatory
response may explain the lack of further damage
when the repeated bout is performed prior to recov-
ery from the initial bout.
[1,14]
6. Future Directions
Although a plethora of data exist on the neural
basis of muscle fatigue (for a review see Enoka and
Stuart
[72]
), very little data are available on the neu-
ral basis of muscle damage. Low motor unit acti-
vation during eccentric contractions has been im-
plicated in the occurrence of muscle damage
[27]
but
has not been specifically studied. Additionally, re-
cruitment patterns during eccentric contractions
have not been examined with respect to the sub-
sequent damage. The possibility of selective re-
cruitment of fast twitch fibres for eccentric exer-
cise remains controversial but may in part explain
preferential damage to those fibres. Despite sev-
eral studies suggesting a neural adaptation to ex-
plain the repeated bout effect,
[1,12,14,16]
no studies
have tested such an hypothesis.
Muscle damage has been described as mechan-
ical failure of individual myofibrils subjected to
cyclic tensile loading.
[24,46]
Surprisingly, the me-
chanical properties of muscle have not been exam-
ined in relation to muscle damage. Data from Lap-
ier et al.
[60]
suggest that increased passive stiffness
may be protective against muscle damage and may
explain the repeated bout effect. In contrast, recent
indirect evidence from Nosaka and Clarkson
[66]
suggest that decreased passive stiffness may be
protective. However, the specific effects of passive
muscle stiffness on the initiation of muscle damage
and the repeated bout effect have not been exam-
ined.
Studies examining the role of muscle length
[47-50]
and longitudinal addition of sarcomeres
[13]
sug-
gest that the ability to maintain myofilament over-
lap during eccentric contractions is critical to lim-
iting damage. The possibility that an increase in
crossbridge binding strength could prevent sarco-
mere ‘popping’ and maintain myofilament overlap
during eccentric contractions has not been exam-
ined. Quick release techniques in stimulated iso-
lated muscle fibres have been used to measure the
elastic elements (stiffness/compliance) within the
Potential Mechanisms for the Repeated Bout Effect 167
Adis International Limited. All rights reserved. Sports Med 1999 Mar; 27 (3)
crossbridges.
[52,73]
However, in whole muscle, con-
tributions from the tendon cannot be ruled
out.
[74,75]
Using the quick release technique, Pous-
son et al.
[76]
demonstrated a 10 to 20% reduction in
compliance of the elbow flexors, at fixed submaxi-
mal loads, following 6 weeks of eccentric training.
It was not possible to distinguish between an adap-
tation in the tendon or an adaptation in the contrac-
tile material. Although the authors favoured the lat-
ter explanation, an increase in crossbridge binding
strength could have accounted for the observed ef-
fects. Similar effects have not been studied with
respect to the repeated bout effect.
7. Conclusions
Despite the numerous studies that have clearly
demonstrated the repeated bout effect there is little
consensus in the literature as to the actual mecha-
nism. Various neural, connective tissue and cellular
theories have been discussed (fig. 1). It is clear that
one theory cannot explain all of the various dem-
onstrations of the repeated bout effect found in the
literature. The fact that the effect was demonstrated
with electrically stimulated contractions in an ani-
mal model precludes an exclusive neural adapta-
tion. However, connective tissue and cellular adap-
tations seem unlikely in studies that demonstrated
a repeated bout effect prior to full recovery. Addi-
tionally, the fact that the initial bout does not have
to cause appreciable damage in order to provide a
protective effect does not support connective tissue
or cellular adaptations. It is possible that the re-
peated bout effect occurs through the interaction of
various neural, connective tissue and cellular fac-
tors that are dependent on the particulars of the
eccentric exercise bout and the specific muscle
groups involved.
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Initial bout of eccentric exercise
Muscle damage
Adaptation
Neural theory
Increased motor
unit activity
Increased slow-twitch
fibre recruitment
Increased motor
unit synchronisation
Connective tissue theory
Increased intramuscular
connective tissue
Intermediated filament
remodelling
Cellular theory
Strengthening of
cell membranes
Removal of
weak fibres
Longitudinal addition
of sarcomeres
Repeated bout of eccentric exercise
Less muscle damage
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Correspondence and reprints: Malachy P. McHugh, Nismat,
Lenox Hill Hospital, 130 East 77th Street, New York, NY
10021, USA.
E-mail: mchugh@nismat.org
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