Recent advances in the understanding of the repeated bout effect: The protective effect against muscle damage from a single bout of eccentric exercise

Abstract

The repeated bout effect refers to the adaptation whereby a single bout of eccentric exercise protects against muscle damage from subsequent eccentric bouts. While the mechanism for this adaptation is poorly understood there have been significant recent advances in the understanding of this phenomenon. The purpose of this review is to provide an update on previously proposed theories and address new theories that have been advanced. The potential adaptations have been categorized as neural, mechanical and cellular. There is some evidence to suggest that the repeated bout effect is associated with a shift toward greater recruitment of slow twitch motor units. However, the repeated bout effect has been demonstrated with electrically stimulated contractions, indicating that a peripheral, non-neural adaptation predominates. With respect to mechanical adaptations there is evidence that both dynamic and passive muscle stiffness increase with eccentric training but there are no studies on passive or dynamic stiffness adaptations to a single eccentric bout. The role of the cytoskeleton in regulating dynamic stiffness is a possible area for future research. With respect to cellular adaptations there is evidence of longitudinal addition of sarcomeres and adaptations in the inflammatory response following an initial bout of eccentric exercise. Addition of sarcomeres is thought to reduce sarcomere strain during eccentric contractions thereby avoiding sarcomere disruption. Inflammatory adaptations are thought to limit the proliferation of damage that typically occurs in the days following eccentric exercise. In conclusion, there have been significant advances in the understanding of the repeated bout effect, however, a unified theory explaining the mechanism or mechanisms for this protective adaptation remains elusive.

Full text

Review
Recent advances in the understanding of the repeated bout effect: the
protective effect against muscle damage from a single bout of eccentric
exercise
Malachy P. McHugh
The Nicholas Institute of Sports Medicine and Athletic Trauma, Lenox Hill Hospital, New York, NY, USA
Corresponding author: Malachy McHugh, Director of Research, The Nicholas Institute of Sports Medicine and Athletic Trauma,
Lenox Hill Hospital, New York, NY, USA. E-mail: mchugh@nismat.org
Accepted for publication 21 October 2002
The repeated bout effect refers to the adaptation whereby a
single bout of eccentric exercise protects against muscle
damage from subsequent eccentric bouts. While the mech-
anism for this adaptation is poorly understood there have
been significant recent advances in the understanding of this
phenomenon. The purpose of this review is to provide an
update on previously proposed theories and address new
theories that have been advanced. The potential adaptations
have been categorized as neural, mechanical and cellular.
There is some evidence to suggest that the repeated bout
effect is associated with a shift toward greater recruitment of
slow twitch motor units. However, the repeated bout effect
has been demonstrated with electrically stimulated contrac-
tions, indicating that a peripheral, non-neural adaptation
predominates. With respect to mechanical adaptations
there is evidence that both dynamic and passive muscle
stiffness increase with eccentric training but there are no
studies on passive or dynamic stiffness adaptations to a
single eccentric bout. The role of the cytoskeleton in regu-
lating dynamic stiffness is a possible area for future re-
search. With respect to cellular adaptations there is
evidence of longitudinal addition of sarcomeres and adapta-
tions in the inflammatory response following an initial bout
of eccentric exercise. Addition of sarcomeres is thought to
reduce sarcomere strain during eccentric contractions
thereby avoiding sarcomere disruption. Inflammatory adap-
tations are thought to limit the proliferation of damage that
typically occurs in the days following eccentric exercise. In
conclusion, there have been significant advances in the
understanding of the repeated bout effect, however, a unified
theory explaining the mechanism or mechanisms for this
protective adaptation remains elusive.
It has been well established that a single bout of un-
familiar, predominantly eccentric exercise causes symp-
toms of muscle damage such as strength loss, pain and
muscle tenderness. It is equally well established that a
repeated bout of the same, or similar eccentrically
biased exercise results in markedly reduced symptoms
of damage than the initial bout (for review see
McHugh, Connolly, Eston, Kremenic, Gleim, 1999b).
This protective adaptation to a single bout of eccentric
exercise has been referred to as the repeated bout effect
(Nosaka & Clarkson, 1995). The repeated bout
effect has been demonstrated in both human and animal
models. It has been shown to last several weeks, and
possibly up to 6 months (Nosaka, Sakamoto, Newton,
Sacco, 2001a). It is apparent that the initial bout of
eccentric exercise does not have to cause appreciable
damage in order to confer a protective adaptation
(Clarkson & Tremblay, 1988; Brown, Child, Day,
Donnelly, 1997; Nosaka, Sakamoto, Newton, Sacco,
2001b). In fact, as few as 10, six, or even two maximal
eccentric contractions of the elbow flexors have
been shown to confer a protective adaptation for a
subsequent bout of 24 (Nosaka & Sakamoto, 2001b)
or 50 (Brown et al., 1997) maximal contractions.
However, it appears that the contraction intensity
must be close to maximum in the initial bout in order
to confer a protective effect when the repeated bout
involves high intensity contractions. Eight weeks of
eccentric training at submaximal levels (50% of one
repetition maximum) did not confer any protection
for a subsequent bout of maximal eccentric exercise
(Nosaka & Newton, 2002c). The repeated bout effect
is specific to the exercised muscle groups, with no evi-
dence of a cross-transfer to contralateral muscle groups
not exposed to the initial bout (Clarkson, Byrnes,
Gillisson, Harper, 1987; Connolly, Reed, McHugh,
2002). However, the muscle group does not have to be
exercised in the same manner in both bouts in order
to see a protective effect. Eston, Finney, Baker,
Baltzopoulos (1996) demonstrated that 100 maximal
eccentric isokinetic quadriceps contractions provided
protection against quadriceps damage following a sub-
sequent downhill run. Of note the protection was
limited to the preconditioned quadriceps.
While the conditions required to induce a protective
adaptation are fairly well understood the actual
88
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mechanism for the repeated bout effect is not well
understood. Several theories have been proposed to
explain the repeated bout effect (for review see
McHugh et al., 1999b). Since this initial review of the
potential mechanisms to explain the repeated bout
effect (McHugh et al., 1999a) numerous studies have
added to the understanding of this phenomenon. The
purpose of this current review is to: (1) summarize the
current evidence for and against previously proposed
theories; (2) describe any new theories that have been
proposed; and (3) identify future areas of research. The
various theories explaining the repeated bout effect are
divided into three broad categories: neural adaptations
(fig. 1), mechanical adaptations (fig. 2) and cellular
adaptations (fig. 3). Understanding the mechanism or
mechanisms for the repeated bout effect is important
for sports medicine and science in so far as it represents
one of the most basic adaptations of skeletal muscle to
use. Furthermore, eccentric contractions and/or eccen-
trically biased exercises have been shown to be effect-
ive in reducing muscle strains (Holmich, Uhrskou,
Ulnits et al., 1999; Tyler, Campbell, Nicholas,
Donellan, McHugh, 2002), reversing muscle atrophy
(Hortobagyi et al., 2000) and treating tendonopathies
(Silbernagel, Thomee, Thomee, Karlsson, 2001). A
greater understanding of the mechanisms involved in
acute and chronic adaptations to eccentric exercise is
necessary for refining interventions for injury preven-
tion, injury treatment and strength training. Since the
repeated bout effect represents the first adaptation to
eccentric exercise, this review focuses on adaptations
to a single bout of eccentric exercise.
Neural theory
Neural theory of muscle damage
It has been proposed that ªeccentric contractions re-
quire unique activation strategies by the nervous
systemº (Enoka, 1996). Specifically, eccentric contrac-
tions require less motor unit activation for a given
muscle force (Bigland & Lippold, 1954; Komi &
Buskirk, 1972; Moritani, Muramatsu, Muro, 1988)
and involve preferential recruitment of fast-twitch
motor units (Nardone & Schieppati, 1988; Nardone,
Romano, Schieppati, 1989; Howell, Fuglevand, Walsh,
Bigland-Ritchie, 1995; Enoka, 1996; McHugh et al.,
2002) when compared to concentric contractions.
Moritani et al. (1988) proposed that muscle damage
results from a high stress on a small number of active
fibers during eccentric contractions. Fast-twitch fibers
have been shown to be more susceptible to disruption
with eccentric contractions (Fride
Ân, Sjùstrùm, Ekblom,
1983b; Lieber & Fride
Ân, 1991; MacPherson, Schork,
Faulkner, 1996) and this may in part be explained by
the preferential recruitment of fast-twitch motor units.
It follows that a change in activation that reduces high
fiber stresses could limit the subsequent myofibrillar
disruption. Nosaka & Clarkson (1995) suggested that
a neural adaptation ªwould better distribute the work-
load among fibers.
Evidence for a neural adaptation
Changes in motor unit activation between repeated
bouts have been examined using surface electromyo-
graphy (EMG) in humans (Warren, Hermann, Ingalls,
Neural Adaptation
Increased recruitment of
slow-twitch motor units
Activation of larger
motor unit pool
Evidence AgainstEvidence Against Evidence ForEvidence For
Decreased EMG
median frequency for
repeated bout
Repeated bout effect
demonstrated with
stimulated
contractions
EMG/torque
increases with
eccentric training
EMG/torque not
different between
initial and repeated
eccentric bouts
Fig. 1. Potential neural mechanisms for the repeated bout effect. EMG/torque refers to the amplitude of the EMG signal relative to
torque production (See text for specific references related to evidence for and against the proposed theories).
Repeated bout effect
89

Increased dynamic
muscle stiffness
Increased passive
muscle stiffness
Evidence For Evidence For
Dynamic muscle
stiffness increases
with eccentric
training
Desmin content is
increased during
repair process to
reinforce sarcomere
Evidence Against Evidence Against
Muscles without
desmin are less
susceptible to
damage
Muscles with greater
passive muscle
stiffness are more
susceptible to
damage from initial
bout
Passive muscle
stiffness is increased
with eccentric
training
Mechanical Adaptation
Fig. 2. Potential mechanical mechanisms for the repeated bout effect. Dynamic stiffness refers to the extensibility of active muscle while
passive stiffness refers to the extensibility of relaxed muscle (See text for specific references related to evidence for and against the
proposed theories).
Cellular Adaptation
Longitudinal addition of
sarcomeres
Eccentric training results in
addition of sarcomeres
Submaximal eccentric
training does not protect
against damage from
maximum contractions
Rightward shift in length-
tension curve following
initial bout
Blunted inflammatory
response to repeated bout
Passive stretches and
isometric contractions initiate
inflammatory response and
confer protection
Strength loss following initial
bout is primarily due to
impaired E−C contraction
coupling
Adaptation in inflammatory
response
Adaptation to maintain
E−C coupling
Evidence For
Evidence Against
Inflammatory mediated
adaptation does not explain
reduced mechanical
disruption immediately
following repeated bout
Evidence Against
Similar strength loss is
evident immediately post
initial and repeated bouts
(differences evident on
subsequent days)
Evidence Against
Evidence For Evidence For
Fig. 3. Potential cellular mechanisms for the repeated bout effect. E±C coupling refers to excitation±contraction coupling (See text for
specific references related to evidence for and against the proposed theories).
McHugh
90

Masselli, Armstrong, 2000; McHugh, Connolly, Eston,
Gleim, 2001). Theoretically an increase in the ampli-
tude of the EMG signal relative to torque production in
the repeated bout would indicate a redistribution of
contractile stresses among a greater number of fibers.
Such an effect is evident with eccentric strength training
(Komi & Buskirk, 1972; Hortoba
Âgyi et al., 1996a;
Hortoba
Âgyi, Hill, Houmard, Fraser, Lambert, Israel,
1996b). Furthermore, a decrease in the frequency con-
tent of the EMG signal in the repeated bout would
theoretically indicate a shift to the recruitment of
slow-twitch motor units and/or increased motor unit
synchronization. There was no evidence of a change in
EMG amplitude between repeated eccentric bouts in
hamstring (McHugh et al., 2001) or tibialis anterior
(Warren et al., 2000) muscles. However, median fre-
quency was decreased in the repeated bout for the
tibialis anterior and this effect was attributed to in-
creased recruitment of slow-twitch motor units
(Warren et al., 2000). Alternatively, this effect could
be attributed to increased motor unit synchronization.
Either effect would be indicative of a neural adaptation
to a single bout of eccentric exercise.
Evidence against a neural adaptation
While the results of Warren et al. (2000) are the first
direct evidence of a neural adaptation to a single bout
of eccentric exercise, it is apparent that the repeated
bout effect can occur independent of a neural adapta-
tion (Sacco & Jones, 1992; Nosaka, Newton, Sacco,
2002a). The repeated bout effect has been demon-
strated with electrically stimulated eccentric contrac-
tions in mouse tibialis anterior muscles (Sacco &
Jones, 1992) and more recently in human elbow flexors
(Nosaka et al., 2002a). In humans the initial bout of
electrically stimulated eccentric contractions resulted in
marked strength loss, increased relaxed elbow angle,
decreased flexed elbow angle, increased upper arm cir-
cumference, increased muscle thickness in ultrasound
images, elevated plasma CK activity and myoglobin
concentration and increased muscle soreness. Fol-
lowing a repeated bout of the same stimulation proto-
col 2 weeks later there were significantly blunted
responses in all eight markers of damage. The authors
concluded that ªinvolvement of the central nervous
system in the repeated bout effect is minimal, and per-
ipheral adaptations play a more important role.º How-
ever, they did not allude to any specific peripheral
adaptations.
Mechanical theory
Mechanical theory of muscle damage
Muscle damage has been described as materials fatigue
typical of ductile material subjected to cyclic tensile
loading (Warren, Hayes, Lowe, Prior, Armstrong,
1993). The eccentric contraction-induced injury is
thought to begin with a mechanical disruption of myo-
fibrils. It follows that an adaptation serving to protect
against damage might alter the mechanical properties
of the musculoskeletal system. In this review mechan-
ical adaptations refer to peripheral adaptations in
the non-contractile elements of the musculoskeletal
system. Included are discussions of adaptations at the
whole muscle and muscle fiber level as well as adapta-
tions at the myofibrillar level, specifically in the cyto-
skeleton. Much of the relevant work in this area has
dealt with mechanical adaptations to chronic eccentric
exercise rather than adaptations to a single bout.
Evidence for a mechanical adaptation
Adaptations to eccentric training
Increases in both passive and dynamic stiffness
following eccentric training have been demonstrated
in human elbow flexors (Pousson, Van Hoecke,
Goubel, 1990) and rat triceps brachii muscles (Reich,
Lindstedt, LaStayo, Pierotti, 2000). For these purposes
dynamic stiffness refers to the elastic properties or ex-
tensibility of active muscles and passive stiffness refers
to those properties in relaxed muscles. Pousson et al.
(1990) demonstrated an increase in active stiffness of
the elbow flexors following eccentric training. This
effect was attributed to either increased tendon stiffness
or increased cross-bridge stiffness. More recently,
Reich et al. (2000) demonstrated increased passive
and dynamic muscle stiffness following eccentric
training in rat triceps brachii muscles. These effects
were attributed to adaptation in the cytoskeletal pro-
teins responsible for maintaining the alignment and
structure of the sarcomere.
Cytoskeletal adaptations
Cytoskeletal proteins such as desmin and titin are re-
sponsible for the longitudinal and horizontal orienta-
tion of sarcomeres (Waterman-Storer, 1991). Electron
micrographs of normal myofibrils reveal perfect paral-
lel alignment of sarcomeres in adjacent myofibrils.
Eccentric contractions disrupt this alignment between
myofibrils, with sarcomeres in one myofibril no longer
aligned with the sarcomeres in adjacent myofibrils.
Within myofibrils disruption is primarily seen at the Z
bands which appear wavy or in extreme cases are indis-
tinguishable from the rest of the sarcomere (Patel &
Lieber, 1997). Disruption of the cytoskeleton, specific-
ally desmin, is one of the earliest events in eccentric
contraction-induced damage (Lieber, Thornell,
Fride
Ân, 1996). Therefore it would seem plausible that
an adaptation in the cytoskeleton may be the first line
of defense in protection against repeated damage.
While there is no direct evidence of an adaptation in
the cytoskeleton explaining the repeated bout effect, a
Repeated bout effect
91

recent study in a rat model demonstrated increased
desmin content 3±7 days following damaging cont-
ractions (Barash, Peters, Fride
Ân, Lutz, Lieber, 2002).
This effect was thought to represent remodeling of
the intermediate filament system to ªprovide mech-
anical reinforcement against excessive sarcomere
strain.º
Intramuscular connective tissue
Lapier, Burton, Almon, Cerny (1995) theorized that an
increase in passive muscle stiffness secondary to in-
creased intramuscular connective tissue might protect
muscle from eccentric contraction-induced damage.
They examined the role of intramuscular connective
tissue in the susceptibility to damage in rat extensor
digitorum longus muscles (Lapier et al., 1995). The
ankle joints were immobilized for 3 weeks with the
muscle in either a shortened or lengthened position.
After 3 weeks, the muscles were subjected to an ec-
centric injury protocol. Muscle tissue samples were
stained for collagen content as an indicator of intra-
muscular connective tissue. Muscles immobilized in the
lengthened position had 63% more intramuscular con-
nective tissue and 86% lower mass than contralateral
control muscles. Muscles immobilized in the shortened
position had 47% more intramuscular connective
tissue and 21% lower mass than contralateral control
muscles. Subsequent bouts of stimulated eccentric con-
tractions resulted in 50% force loss in control muscles
compared to 40% in muscles immobilized in the
shortened position and 8% in muscles immobilized in
the lengthened position. The protective effect was at-
tributed to the ability of the increased connective tissue
to dissipate myofibrillar stresses but changes in passive
muscle stiffness were not documented. The authors
suggested that tissue repair following a damaging bout
of eccentric exercise is characterized by a similar increase
in intramuscular connective tissue thereby protecting
against damage from repeated bouts.
Evidence against a mechanical adaptation
The role of passive muscle stiffness
While increased passive muscle stiffness following ec-
centric training (Reich et al., 2000) and adaptations in
intramuscular connective tissue following immobiliza-
tion (Lapier et al., 1995) indirectly indicate that in-
creased passive muscle stiffness may protect against
muscle damage, there is contradictory evidence that
passive muscle stiffness increases the susceptibility to
muscle damage (McHugh, Connolly, Eston, Gleim,
1999a). Subjects categorized as having stiff hamstrings
experienced greater strength loss, more pain, greater
muscle tenderness and higher elevations in creatine
kinase activity than subjects categorized as having
compliant hamstrings (McHugh et al., 1999b). Based
on the premise that stiffer muscles are more susceptible
to damage, it follows that a decrease in passive muscle
stiffness might serve a protective effect. Dramatic in-
creases in passive stiffness in the elbow flexors (Howell,
Chelboun, Conaster, 1993; Chelboun et al., 1995) and
plantarflexors (Whitehead, Weerakkody, Gregory,
Morgan, Proske, 2001) have been demonstrated in the
days following a damaging bout of eccentric exercise.
These effects were thought to be due to the develop-
ment of ªinjury contractures in the damaged muscle
fibersº (Whitehead et al., 2001). However, passive stiff-
ness was not followed to the point of full recovery in
these studies and changes in passive stiffness with
respect to the repeated bout effect are unknown.
The findings with respect to immobilization (Lapier
et al., 1995) may be due to a sarcomere adaptation
rather than a change in intramuscular connective
tissue. The fact that the effect occurred primarily in
the muscles immobilized in the lengthened position
indicates that protection may in part have been due to
longitudinal addition of sarcomeres (see section on
Cellular Theory). In contrast to these results, 5 weeks
of unilateral lower limb non-weight bearing has been
shown to increase susceptibility to damage (Ploutz-
Snyder, Tesch, Hather, Dudley, 1996).
Cytoskeletal adaptations
While increased desmin content during repair was
thought to reflect a ªmechanical reinforcementº to
protect the sarcomere from damage (Barash et al.,
2002) somewhat contradictory findings were previously
reported (Sam, Shah, Fride
Ân, Milner, Capetanaki,
Lieber, 2000). In a mouse model, eccentric contrac-
tion-induced damage was compared between normal
muscles and muscles lacking desmin. It was hypothe-
sized that the muscles lacking desmin would be more
susceptible to damage because desmin is partly respon-
sible for myofibrillar alignment. Surprisingly the op-
posite was demonstrated, with less disruption in the
muscles lacking desmin. This effect was attributed to
less dynamic stiffness in the muscles lacking desmin
during the eccentric contraction. Less stiffness was
thought to enable greater sarcomere shortening thereby
avoiding sarcomere strain. This is consistent with the
finding that compliant muscles are less susceptible to
damage (McHugh et al., 1999b) but is inconsistent with
the findings of increased passive stiffness with eccentric
training (Reich et al., 2000) and increased desmin
content 3±7 days post eccentric contraction-induced
damage (Barash et al., 2002).
Cellular theory
Potential adaptations discussed in this section include
adaptations in the contractile machinery (longitudinal
addition of sarcomeres and excitation±contraction
McHugh
92

coupling changes) and adaptations in the inflammatory
response to eccentric contractions.
Evidence for a cellular adaptation
Sarcomere strain theory
Morgan (1990) has suggested that muscle damage is
due to irreversible sarcomere strain during eccentric
contractions and, in particular, contractions at muscle
lengths on the descending limb of the length±tension
curve. In agreement with this theory data from isolated
whole muscle preparations in animals (Lieber &
Fride
Ân, 1991; Brooks, Zerba, Faulkner, 1995; Hunter
& Faulkner, 1997) and voluntary contractions in
humans (Newham, Jones, Ghosh, Aurora, 1988;
Child, Saxton, Donnelly, 1998) have clearly shown
that the length of the muscle during eccentric contrac-
tions appears to be a critical factor in determining the
extent of damage. Contractions performed at longer
muscle lengths result in greater symptoms of damage.
Based on the sarcomere strain theory of muscle
damage, Morgan (1990) predicted that the repair pro-
cess results in an increase in the number of sarcomeres
connected in series and that this serves to reduce sarco-
mere strain during a repeated bout thereby limiting the
myofibrillar disruption. Data from animal studies has
provided evidence of addition of sarcomeres with ec-
centric exercise (Lynn & Morgan, 1994; Lynn, Talbot,
Morgan, 1998). Additionally, indirect evidence of
longitudinal addition of sarcomeres in humans was
recently demonstrated following a damaging bout of
eccentric hamstring contractions (Brockett, Morgan,
Proske, 2001). A rightward shift in the length±tension
relationship following recovery from the initial
bout was attributed to longitudinal addition of
sarcomeres.
Excitation±contraction coupling
Strength loss following a bout of eccentric exercise
could theoretically be due to (1) an inability to volun-
tarily activate motor units secondary to pain or
damage, (2) physical disruption of the force-generating
structures (including a loss of myofibrillar contractile
proteins) or (3) a failure to activate intact force-
generating structures within the muscle fiber
(excitation±contraction coupling). Voluntary acti-
vation of motor units is not thought to be impaired
following damaging eccentric exercise (Saxton &
Donnelly, 1996; McHugh, Connolly, Eston, Gleim,
2000). Strength loss is thought to be due to a combin-
ation of physical disruption and an impairment
of excitation±contraction coupling (E±C coupling)
(Warren, Ingalls, Lowe, Armstrong, 2001). E±C
coupling refers to ªthe sequence of events that starts
with the release of acetylcholine at the neuromuscular
junction and ends with the release of Ca
2
from
the sarcoplasmic reticulumº (Warren et al., 2001).
Impaired E±C coupling has been estimated to account
for 50±75% of strength loss in the first 5 days following
a damaging eccentric bout (Warren et al., 2001).
However, this estimate is based on electrically stimu-
lated maximal contractions in an animal model, and
little is known about effects in human skeletal muscle
with voluntary contractions. An adaptation in E±C
coupling may explain the reduced strength loss
following a repeated bout. Strengthening of the sarco-
plasmic reticulum, as suggested by Clarkson &
Tremblay (1988), may prevent impairment of E±C
coupling with a repeated bout, however, direct evidence
in support of such a theory is lacking.
Inflammatory response
With eccentric contractions the initial injury is a mech-
anical disruption of myofibrils. This initial injury trig-
gers a local inflammatory response which leads to an
exacerbation of the damage prior to signs of recovery
(Pizza et al., 1996; Pizza, Koh, McGregor, Brooks,
2002). These events can be referred to as primary and
secondary damage. Decreased neutrophil and mono-
cyte activation have been demonstrated following a
repeated bout of eccentric exercise (Pizza et al., 1996).
A blunted inflammatory response to a repeated bout
could reflect an adaptation to avoid proliferation of the
mechanical disruption of myofibrils. Two recent stud-
ies point to the possibility that reduced damage in a
repeated bout may be attributable to an adaptation
mediated by the inflammatory response. At first, Koh
& Brooks (2001) demonstrated in an animal model that
an initial bout of passive stretches or isometric contrac-
tions provided some protection against a subsequent
eccentric bout. The protective effect was not as pro-
found as that conferred by eccentric contractions, but
was notable in that the initial bout of passive stretches
or isometric contractions did not result in any damage.
Subsequently Pizza et al. (2002) demonstrated in the
same model that both passive stretches and isometric
contractions initiated an inflammatory response des-
pite the absence of any overt injury. Neutrophils were
elevated 3 days following either passive stretches, iso-
metric contractions or eccentric contraction when
compared to neutrophils from control animals. The
neutrophil response to passive stretches and isometric
contractions was approximately half the magnitude of
the response to eccentric contractions. Then when the
muscles were subjected to a subsequent eccentric bout
a blunted inflammatory response was seen for the
muscles that were previously exposed to passive
stretches, isometric contractions or eccentric contrac-
tions. Surprisingly, the blunted inflammatory response
following the eccentric bout was similar for the muscle
preconditioned with eccentric contractions, passive
stretches or isometric contractions. The authors pro-
posed that the initial inflammatory response to the
initial bout ªmay contribute to the induction of a
Repeated bout effect
93

protective mechanismº. A reduced inflammatory re-
sponse to a repeated eccentric bout may simply reflect
the fact that there was a reduced mechanical disruption
in the repeated bout and therefore less of a stimulus for
an inflammatory response. It is difficult to resolve this
issue since it is not clear whether the repeated bout
effect reflects (1) less myofibrillar disruption during
the actual repeated exercise bout, (2) a decrease in the
secondary proliferation of damage or (3) a combination
of both.
Evidence against a cellular adaptation
Longitudinal addition of sarcomeres
One of the most attractive theories to explain the
repeated bout effect is the longitudinal addition of
sarcomeres theory. While there is experimental evi-
dence to support such a theory (Lynn & Morgan,
1994; Lynn et al., 1998; Brockett et al., 2001) there is
also some conflicting evidence. For example, the
length-tension relationship has been shown to return
to normal within 5 hours in toad sartorius muscles
(Wood, Morgan, Proske, 1993) and within 2 days in
human triceps surae muscles (Jones, Allen, Talbot,
Morgan, Proske, 1997; Whitehead et al., 2001).
Furthermore, while submaximal eccentric training has
been shown to result in longitudinal addition of sarco-
meres in rats (Lynn & Morgan, 1994; Lynn et al., 1998)
submaximal training did not confer protection from
subsequent maximal contractions in humans (Nosaka
& Newton, 2002b). It also remains to be determined if
the protective effect of the initial bout is evident if the
repeated bout is performed at a longer length than the
initial bout. Exercising at the longer muscle length in
the repeated bout would tend to counteract any sarco-
mere strain reduction due to addition of sarcomeres. If
the adaptation is simply due to the addition of sarco-
meres then a repeated bout at a longer muscle length
would be expected to result in similar damage to the
initial bout.
Excitation-contraction coupling
Studies demonstrating the repeated bout effect in
humans do not directly support an adaptation related
to E±C coupling. Impairment of E±C coupling is
greatest immediately post-eccentric exercise, account-
ing for 75% of the reduction in force (Ingalls, Warren,
Williams, Ward, Armstrong, 1998) but strength loss
immediately following eccentric exercise has been
shown to be similar between initial and repeated
bouts (Newham, Jones, Clarkson, 1987; Clarkson &
Tremblay, 1988; Ebbeling & Clarkson, 1990; Balnave
& Thompson, 1993; Brown et al., 1997). It was only on
subsequent days that reduced strength loss was seen
with a repeated bout in these studies. If the repeated
bout effect was due to an adaptation in E±C coupling
reduced strength loss should be seen immediately
following the repeated bout as well as on subsequent
days.
Other theories
A relatively new area of muscle damage research has
focused on the role of heat shock proteins (HSPs) in
protection against eccentric contraction-induced injury
(Thompson, Scordilis, Clarkson, Lohrer, 2001; Koh,
2002; Thompson, Clarkson, Scordilis, 2002). HSPs
play an important role in cell survival following various
stressors, most notably thermal stress (hence the name).
With respect to eccentric exercise HSP27 and HSP70
have been shown to be increased following damaging
eccentric exercise of the elbow flexors (Thompson
et al., 2001; Thompson et al., 2002). It has been postu-
lated that this response serves to protect the tissue
from damage following a repeated eccentric bout
(Thompson et al., 2002). The HSP response to repeated
bouts of eccentric elbow flexor exercise revealed an
apparent decrease in basal levels of HSP27 and
HSP70 4 weeks following the initial bout with smaller
absolute increases in these HSPs following the repeated
bout. However, since the relative (%) increase in HSPs
was similar between the two bouts it was unclear
whether the results reflected a similar HSP response
between bouts or a down-regulated response. It is pos-
sible that the HSP response to the initial damaging bout
resulted in an acquired stress tolerance for the repeated
bout. Interpretation of these findings is difficult given
the methodological problems inherent in a study re-
quiring biopsy samples. Since the biopsy procedure
involves tissue damage the authors chose not to take
baseline (pre-eccentric exercise) biopsies in the arm to
be exercised, as the procedure itself may have initiated a
HSP response. Therefore, biopsies were taken 48 h
post-exercise from both the exercised and non-
exercised arms (control). This procedure was repeated
following the second bout 4 weeks later. The difficulty
in interpreting the results arose from the apparent de-
crease in HSPs in the control arm following the
repeated bout. This could be interpreted as a down-
regulation of HSP bilaterally or that the initial HSP
measurements in the control arm reflected a systemic or
bilateral increase secondary to damage in the contral-
ateral arm. Clearly this is an important new area of
research, however, it remains to be determined whether
the HSPs serve a protective function in eccentric con-
traction-induced injury (Koh, 2002).
One of the earliest theories proposed to explain the
repeated bout effect was that the initial bout resulted in
damage to a pool of weak muscle fibers and that
following recovery these weak fibers were replaced by
stronger fibers (Armstrong, Ogilvie, Schwane, 1983).
Given the apparent association between sarcomere
strain and subsequent muscle damage this theory may
McHugh
94

be more applicable to weak sarcomeres. An initial
eccentric bout may result in irreversible strain in a
pool of weak sarcomeres. The non-uniformity of sarco-
mere length during eccentric contractions indicates that
some sarcomeres are more easily strained than others.
During the repair process these weak sarcomeres are
replaced by stronger, strain resistant sarcomeres. Based
on this theory a greater uniformity of sarcomere length
would be expected during eccentric contraction in the
repeated bout compared to the initial bout. While a
weak sarcomere theory may be difficult to prove experi-
mentally it would be consistent with some of the experi-
mental findings that are inconsistent with the other
theories. For example, symptoms of damage are not
exacerbated when a repeated bout is performed prior to
full recovery from the initial bout (Mair et al., 1992;
Nosaka & Clarkson, 1995). If the weak sarcomeres
have already been disrupted then only the stronger
sarcomeres will be contributing to force production in
the repeated bout and these sarcomeres are apparently
resistant to damage. It has also been shown that the
initial bout does not have to result in significant symp-
toms of damage in order to confer a protective effect
(Clarkson & Tremblay, 1988; Brown et al., 1997;
Nosaka et al., 2001b). However, it appears that a high
contraction intensity is needed to provide protection
against damage from a subsequent bout of high inten-
sity contractions (Nosaka & Newton, 2002c). A few
high intensity eccentric contractions may be sufficient
to strain the weak pool of sarcomeres without complete
myofibrillar disruption. This stimulus may be sufficient
for remodeling or replacement of the pool of weak
sarcomeres.
Conclusions and future directions
As was previously stated, in order to understand the
mechanism(s) for the repeated bout effect it is necessary
to first establish whether this phenomenon reflects (1) a
decrease in myofibrillar disruption during the actual
exercise bout (primary damage), (2) a decrease in the
secondary proliferation of damage associated with the
inflammatory response (secondary damage) or (3) a
combination of both. The fact that some repeated
bout effect studies have shown similar strength losses
immediately post-exercise in the initial and repeated
bouts (Newham et al., 1987; Clarkson & Tremblay,
1988; Ebbeling & Clarkson, 1990; Balnave &
Thompson, 1993; Brown et al., 1997; Nosaka et al.,
2002a) supports the contention that the repeated bout
reflects a protection against the secondary damage.
However, it is likely that there is some reduction in
primary damage with the repeated bout effect. Fride
Ân
et al. (1983b) found damage in 20% of micrographs
from vastus lateralis biopsies taken 3 days following
30 min of eccentric cycling. Only 4% of micrographs
showed damage following 4 weeks of eccentric cycling
training (Fride
Ân, Seger, Sjùstrùm, Ekblom, 1983a). It is
likely that more than 4% of micrographs would have
shown damage immediately following the initial bout
and therefore these findings may represent a protection
against primary damage. Notably, this was a training
study and did not examine adaptations to a single
eccentric bout. Comparison of electron micrographs
from muscle biopsies taken immediately following ini-
tial and repeated eccentric bouts would provide some
clarification on the extent of protection against the
primary damage.
Some of the discrepancies between plausible mech-
anisms for the repeated bout effect and actual experi-
mental data may be explained by the distinction
between primary and secondary damage. For example,
the sarcomere strain theory and longitudinal addition
of sarcomeres cannot explain the results of studies
demonstrating a repeated bout effect where the initial
bout resulted in minimal or no signs of damage (Koh &
Brooks, 2001; Nosaka et al., 2001b). Two eccentric
contractions (Nosaka et al., 2001b) or passive stretch-
ing (Koh & Brooks, 2001) are unlikely to be sufficient
stimuli for addition of sarcomeres yet they provided
some protection. In these instances the protective adap-
tation may be explained by an inflammatory mediated
response that serves to limit secondary damage.
However, other experimental data fails to fit any of
the proposed theories. For example, submaximal ec-
centric training did not provide any protection against
a subsequent bout of maximal eccentric contractions
(Nosaka & Newton, 2002b). The submaximal eccentric
training resulted in clear signs of damage in the early
weeks of training and this should have been a sufficient
stimulus to induce both a sarcomere adaptation and an
inflammatory mediated adaptation. It is possible that
the myofibrils damaged by the maximum contractions
were in muscle fibers of motor units that were not active
during the submaximal training.
In conclusion, our understanding of the repeated
bout effect has improved with the increased volume of
research in this area. In recent years important
Table 1. Potential questions to be addressed in future research
1. Does dynamic or passive muscle stiffness change between initial
and repeated eccentric bouts?
2. What changes occur in the cytoskeleton between an initial and
repeated eccentric bout?
3. Is the rightward shift in the length-tension curve a consistent
finding with the repeated bout effect?
4. Does an initial bout at a short muscle length confer protection for a
repeated bout at a longer muscle length?
5. What role do heat shock proteins play in the repeated bout effect?
6. Are sarcomere lengths more uniform during a repeated vs. an initial
bout?
7. To what extent does the repeated bout effect reflect a decrease
in myofibrillar disruption (primary damage) vs. a decrease
in the proliferation of damage on subsequent days (secondary
damage)?
Repeated bout effect
95

advances have been made with respect to our under-
standing of neural control of eccentric contractions,
eccentric sarcomere mechanics, heat shock protein ex-
pression, E-C coupling and inflammatory responses to
eccentric contractions. This information can be used to
stimulate additional studies to clarify conflicting find-
ings or expand on preliminary findings (Table 1). There
may be several mechanisms for the repeated bout effect
and these mechanisms may compliment each other or
operate independently of each other. Despite the ad-
vances in our understanding of the repeated bout effect
a unified theory explaining the mechanism or mechan-
isms remains elusive.
Key words: muscle damage; eccentric contractions;
sarcomere.
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