Acta Physiol Scand 2001, 171, 233±239

Exercise-induced muscle damage and in¯ammation:

fact or ®ction?

C. MALM
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden and
Stockholm University College of Physical Education Sports, Stockholm, Sweden

ABSTRACT
Physical exercise is necessary for maintaining normal function of skeletal muscle. The mechanisms
governing normal muscle function and maintenance are vastly unknown but synergistic function of
hormones, neurosignalling, growth factors, cytokines and other factors, is undoubtedly important.
Because of the complex interaction among these systems the lack of complete understanding of
muscle function is not surprising. The purpose of exercise-induced changes in muscle cell function is
to adapt the tissue to a demand of increased physical work capacity. Some of the approaches used to
investigate changes in skeletal muscle cell function are exercise and electrical stimulation in animals
and human models and isolated animal muscle. From these models, it has been concluded that
during physical exercise, in an intensity and duration dependent manner, skeletal muscle is damaged
and subsequently inflamed. The purpose of the inflammation would be to repair the exercise-induced
damage. Because of the design and methods used in a majority of these studies, concerns must be
raised, and the question asked whether the paradigm of exercise-induced muscle inflammation in
fact is fiction. In a majority of conducted studies, a non-exercising control group is lacking and
because of the invasive nature of the sampling methods used to study inflammation it does not
appear impossible that observed inflammatory events in human skeletal muscle after physical
exercise are methodoligical artefacts.

Keywords adaptation, biopsies, creatin kinase, immune system, immunohistochemistry, leuco-

cytes, physical, repair.

Received 12 December 2000, accepted 24 January 2001

Exercise-induced muscle damage and in¯ammation in
both human and animal studies are well-described in
the literature (Armstrong et al. 1991, Smith 1991, Friden
& Lieber 1992, Fielding et al. 1993, Sorichter et al. 1995,
Hellsten et al. 1997, Child et al. 1999). The main
conclusions made in these studies are that: (1) exercise
can induce damage and in¯ammation in human muscle
tissue; (2) the severity of the in¯ammation depends on
the type, duration and intensity of exercise; and (3)
exercise with eccentric contractions will cause more
damage and in¯ammation than concentric exercise of
equal intensity and duration.
In¯ammation is a well-described series of events, in
some instances initiated by tissue injury and concluded
upon tissue repair. The in¯ammation can be of acute
character, initiated by a number of different traumatic
factors such as burns, chemicals, virus and bacteria
(Sheldon 1992) or secondary to a speci®c immune
reaction to muscle, as in myositis (Hohlfeld et al. 1997)
where the initiating agent may or may not be known.
Although success is not always guaranteed, the objec-
tive of any in¯ammation is to repair injury and restore
tissue function. Several studies have demonstrated
muscle tissue damage after physical exercise (for review
see Kuipers 1994, Clarkson & Sayers 1999), and it has
also been shown that damaged muscle will induce an
in¯ammatory response (Tidball 1995). Some investiga-
tors have also demonstrated increased leucocyte in®l-
tration in human muscle tissue after physical exercise
(Round et al. 1987, Fielding et al. 1993). Based on these
®ndings, exercise-induced muscle in¯ammation appears
to be an obvious and well-described phenomenon.
However, because of methodological considerations
in many of these studies, the existence of exercise
induced muscle damage and in¯ammation may be
debated.
This short review will discuss the possibility that
the exercise-induced, in¯ammation-related changes

Correspondence: Christer Malm, Department of Physiology and Pharmacology, Karolinska Institute, Box 56 26, S-114 86 Stockholm, Sweden.

Ó 2001 Scandinavian Physiological Society 233

 Exercise induced muscle in¯ammation
C Malm
observed in blood and muscle are manifestations not of
muscle in¯ammation, but adaptive processes involving
immunological events. In this context, the role of the
immune system in muscular adaptation to physical
exercise will also be considered [reviewed in more detail
1 by Pedersen (1997) and Mackinnon (1999)].
E X E R C I S E - IN D U C E D M U S C L E D AM AG E
In order for in¯ammation to occur, tissue damage or
alteration must precede to initiate the release mediators
of in¯ammation. It has been postulated that physical
exercise can cause damage to muscle cells in terms of
disrupted contractile structures and cytoskeletal
components (Friden & Lieber 1992, Fielding et al.
1993), loss of desmin (Lieber et al. 1996) and perme-
abilization of the muscle cell plasma membrane
(McNeil & Khakee 1992, Malm et al. 1996). Several
previous review articles have discussed this topic
(Evans & Cannon 1991, Kuipers 1994, Clarkson &
Sayers 1999). When scrutinizing published results, the
concept of exercise-induced damage in human skeletal
muscle during and after voluntary muscle contraction
associated with physical exercise and training may
appear somewhat questionable.
Firstly, many of the published studies on exercise-
induced muscle damage, where damage has actually
been measured in the muscle, were performed on ani-
mals (Armstrong et al. 1983, Kuipers et al. 1983, Lieber
et al. 1991, McNeil & Khakee 1992, Lieber & Friden
1993, Komulainen et al. 1994, Lieber et al. 1996, Smith
et al. 1997). The advantage with this approach is that an
entire muscle can be removed and examined. Because
of differences in numerous physiological and anatom-
ical variables between species, results from animal
studies may or may not apply to voluntary physical
exercise in humans. For example, ®bre type distribu-
tion, oxygen delivery, oxidative potential and enzyme
activity varies considerably between species (Gollnick
et al. 1972, Tonkonogi & Sahlin 1997, Tonkonogi et al.
1999). The relative physical and psychological stress
induced on the body, e.g. by downhill running on a
treadmill, may thus differ between normally trained
human and cage-raised animals. These differences may
result in different relative strain on structural compo-
nents in the muscle. Another common model for
studying the effects of muscle contraction on muscle
cell damage is the use of electrically stimulated animal
muscle (Friden 1984b, Jackson et al. 1991, Lieber et al.
1991, Lieber & Friden 1993, Friden & Lieber 1996,
Hesselink et al. 1996, Lieber et al. 1996). Compared
with voluntary contraction, electrical stimulation can
result in higher force (Allen et al. 1998) and over a
period of time, considerable larger total work may be
performed by the muscle before exhaustion. This can in
234
Acta Physiol Scand 2001, 171, 233±239
turn cause changes in the muscle cell that never occur
with voluntary physical exercise. No animal model, with
or without electrical stimulation, can thus be considered
to accurately describe voluntary physical exercise in
humans.
Secondly, of all published studies on exercise
induced muscle damage using human subjects, few
have actually measured muscle cell damage (Friden et al.
1983, Jones et al. 1986, O'Reilly et al. 1987, Round et al.
1987, Fielding et al. 1993, Goodman et al. 1997).
Instead, analysis of presumable markers for muscle cell
damage in blood is a commonly used approach to
assess structural damage to muscle tissue (Clarkson &
Dedrick 1988, Donnelly et al. 1992, Sorichter et al.
1997). This approach was recently criticized in a
publication by Warren et al. (1999) where the authors
argue that even if muscle damage is present, it can
never be correctly estimated by any marker in circula-
ting blood. This conclusion is based on the fact that the
concentration of any substance present in blood is
simply a re¯ection of the difference between release
and uptake by other tissues. Several previous studies
have indicated that the appearance of muscle protein in
the blood is not a relevant marker of tissue damage
(Van der Meulen et al. 1991, Kuipers 1994, Komulainen
et al. 1995). In one study leucocytosis is suggested to be
an indicator of tissue damage (Kayashima et al. 1995),
but several other possible factors such as infections
(Kuby 1994) and increase in plasma catecholamine
concentration (Benschop et al. 1996) can also result in
leucocytosis. Thus, leucocytosis cannot possibly be a
reliable marker for estimation of muscle tissue damage.
If any relevant information regarding muscle cell
damage is to be obtained from blood samples, it would
be necessary to calculate the arterial±venous difference
across the muscle tissue investigated. Consequently,
studies where muscle damage is investigated only by the
measurement of creatine kinase (CK) activity,
myoglobin concentration (Mb) or other intracellular
muscle proteins in venous blood must be questioned.
In fact, in one study by Fielding et al. (1993) where both
z-band streaming and blood CK activity were investi-
gated, no correlation between the two were found. This
may not be surprising because the appearance of
muscle proteins in blood should depend on leakage of
the muscle cell membrane. In rat, disruptions of muscle
®bre plasma membranes were increased after exercise
(McNeil & Khakee 1992), but rather than interpreting
this as a sign of damage, the authors suggested that the
observed disruptions could have a biological function
in the release of growth factors from the muscle cells.
No study has yet directly investigated the possible
relationship between sarcolemma permeability and the
appearance of intracellular protein in blood after
physical exercise. In one in vitro study (Jackson et al.
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 Acta Physiol Scand 2001, 171, 233±239
1991) the release of intracellular muscle proteins was
not related to the size of the in¯icted injury, and could
be inhibited by the removal of calcium from the
medium. These ®ndings further support the arguments
against intracellular muscle protein in blood as a rele-
vant marker for muscle damage, and suggest that other
mechanisms than passive diffusion across the
membrane may be involved in the release of intracel-
lular proteins from muscle to blood.
Thirdly, only a few studies have used a non-exerci-
sing control group (Friden 1984a, Friden et al. 1988a,
Staron et al. 1992). This is surprising because of the
obvious muscle damage in¯icted by the biopsy proce-
dure itself. The possibility that some of the damage
observed in studies without control group is caused by
the sampling procedure cannot be ruled out. Although
no statistical analysis was made, Friden et al. (Friden
2 1984a) concluded that there were more z-band
disruptions in the exercise compared with the control
group. Staron et al. (1992) observed increased number
of degenerating±regenerating ®bres in both the control
and exercise group. No statistical analysis was made,
but the average percent affected ®bres was four times
higher in the exercise group (8.53 vs. 2.08%). Intra-
cellular disorganization (z-band streaming, myo®brillar
disruption) was, on the other hand only observed in the
exercise group.
Skeletal muscle damage caused by voluntary physical
exercise is not convincingly and repeatedly demon-
strated in published scienti®c studies using human
subjects. The limited number of well-conducted studies,
the lack of statistical analysis, circumstantial evidence
and theoretically plausible arguments has turned a
theoretical possibility into a well-documented scienti®c
fact. The need for studies where non-exercising control
groups are included and statistically suf®cient data
collected is necessary to determine whether or not
exercise induced muscle damage is a physiological
reality.
If intracellular structural anomalies are a conse-
quence of physical activity, the term `damage' may be
somewhat misleading if these changes are normally
occurring events in the adaptation process. It appears
contradictory that muscle tissue would be damaged by
physical activity, the very task for which it has evolved.
EXERCISE-INDUCED MUSCLE
INFLAMMATION
In¯ammation is a pathological event, which occurs
according to a well-described temporal scheme. In
brief, the major events are: (1) tissue injury, (2) release
of vasoactive substances by the injured tissue, (3)
vasodilation, (4) leucocyte adhesion, (5) leucocyte
migration from blood to the injury site and eventually
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C Malm
Exercise induced muscle in¯ammation
(6) tissue repair (Kuby 1994). Thus, if exercise-induced
muscle damage a natural consequence would be
muscle in¯ammation. Early observations of exer-
cise induced leucocytosis date back to 1893 (Schultz
1893). Numerous subsequent studies have con®rmed
large changes in circulating leucocyte with physical
exercise (Pedersen 1997, Mackinnon 1999). These
observations, together with the appearance of in¯am-
mation-related substances in blood and muscle (e.g. C-
reactive protein, CK, interleukin-6 and interleukin-1),
muscle swelling and the sensation of delayed onset of
muscle soreness (DOMS) have led researchers to the
conclusion that physical exercise causes muscle
in¯ammation, especially if the exercise is strenuous
and/or involves eccentric contractions. Because the
relevance of blood-borne markers of muscle damage
and in¯ammation can be questioned (Warren et al.
1999), and the lack of studies including a non-exercising
control group, the above-mentioned ®ndings of exer-
cise-induced muscle in¯ammation must be categorized
as circumstantial. Direct investigations of exercise-
induced muscle in¯ammation in humans are relatively
scarce (Round et al. 1987, Fielding et al. 1993, Hellsten
et al. 1997) and in no study was a non-exercising control
group included. In a recent study by Aronson et al.
(1998) it was demonstrated that a single needle biopsy
increased the activity of mean arterial pressure (MAP)
kinase in a subsequent biopsy taken 30±60 min later
from the same incision. Adenosine triphosphate (ATP)
and glycogen re-synthesis after exercise was impaired by
multiple biopsies taken 2.5 cm apart (Constantin-
Teodosiu et al. 1996). In addition, intramuscular injec-
tion of saline has been shown to cause mast cell
in®ltration (Rafael et al. 1996) and because mast cells
are very potent immunomodulators, it is likely that not
only the needle biopsy but also the anaesthetic injection
preceding tissue sampling can affect various marker of
muscle in¯ammation. In our own laboratory, the
muscle tissue expression of several leucocyte speci®c
antigens (CD11b, CD15, CD56, CD163) as well as
interleukin-1b increased similarly in the exercise and
control group (Malm 2000) over a period of 7 days and
seven consecutive biopsies. In addition, interleukin-1a
decreased in the third biopsy in the control group only.
Because the ®rst two biopsies were taken in the right
leg 1 h apart, and the third biopsy taken in the left leg
and 6 h after the ®rst biopsy, muscles distal from the
biopsy site also appear to be affected, as indicated by
the increased IL-1a expression. In this study, exercise
consisted of 30 min eccentric cycling at a maximal or
close to maximal (250±300 W) work rate, resulting in
severe muscle soreness as well as changes in circulating
leucocyte numbers and activity. The effects on circu-
lating leucocytes were detected in the exercised group
only. Another important conclusion, and in contrast to
235
Exercise induced muscle in¯ammation
C Malm
previous investigations by Round et al. (1987) and Shek
& Shephard (1998) concerns the use of physical exer-
cise as a model for the study of in¯ammatory myopa-
thies. Our own investigation did not ®nd any changes
in T cell antigens (CD3 and CD8) in muscle in neither
the exercise nor the control group, indicating that there
is not a speci®c immune response in exercised skeletal
muscle. Because in¯ammatory myopathies involves T
cells (Engel & Arahata 1986) physical exercise does not
appear to be a suitable model for the study of these
diseases. In the study by Round et al., CD4 positive
cells were classi®ed as T helper cells although they were
not double-labelled with CD3. Later studies have
con®rmed the presence of CD4 on monocytes and
macrophages (Rafael et al. 1996) and the observed CD4
positive cells by Round et al. could therefore have been
monocytes or macrophages.
Suggestions have been made that the phenomenon
of DOMS is caused by muscle in¯ammation (Hikida
et al. 1983, Smith 1991), or the swelling of the muscle
®bres (Friden et al. 1988b, Smith 1991, Nosaka &
Clarkson 1996) that may or may not be caused by
muscle in¯ammation. According to the above discus-
sion, exercise-induced muscle in¯ammation may not be
the cause of DOMS. One possible explanation for
DOMS could be in¯ammation of the perimysium or
epimysium. Muscle pain could also be in¯icted by the
release of substances from the muscle cells (Stebbins
et al. 1990) or from non-muscle cells such as endothelial
cells, tissue mast cells or macrophages. A number of
such substances (e.g. bradykinin, substance P, PGE2)
are known to cause pain (Dray & Perkins 1993,
Babenko et al. 1999) and nociceptors have been found
in the interstitial space in human skeletal muscle
(Marchettini et al. 1996). At the moment of writing, the
author is not aware of any published study which has
investigated any of these substances in muscle tissue
after DOMS-in¯icting exercise in human subjects. A
second possible explanation of DOMS could be muscle
swelling caused by other factors than in¯ammation,
such as increased protein metabolism in the muscle cells
and subsequent increase in osmotic pressure. Because
DOMS decreases the likeliness that the affected person
will undertake any strenuous physical exercise, DOMS
could serve a physiological purpose in allowing
adequate time for muscle recovery and adaptation.
Muscular adaptation to physical exercise
Although muscle in¯ammation may not be a conse-
quence of physical exercise, even when the exercise is
strenuous and eccentric, the presence of immuno-
competent cells and various growth factors appears
inevitable for optimal muscle function (Robertson et al.
1992, Tidball 1995, Chambers & McDermott 1996,
236
Acta Physiol Scand 2001, 171, 233±239
Hellsten et al. 1996, Husmann et al. 1996, Gustafsson
et al. 1999). In these studies, macrophages have
repeatedly been shown to enhance muscle recovery and
satellite cell proliferation and in future studies other
circulating or tissue resident non-muscle cells may turn
out to serve similar functions. One non-muscle cell that
may be of interest for future studies of muscular
adaptation to physical exercise is the mast cell.
Mast cells, resident in many different tissues (inclu-
ding muscle and connective tissue), originate from bone
marrow mononuclear cells but mature under the
in¯uence of the local environmental factors. Therefore,
mast cells are an extremely heterogeneous cell popula-
tion (Metcalfe et al. 1997). Mast cells can be activated by
a number of different stimuli including temperature,
cytokines and hormones. Upon activation mast cells
can release a myriad of substances involved in immuno-
modulation, tissue repair and angiogenesis (Metcalfe
et al. 1997). No study has yet investigated the possible
role of mast cells in muscular adaptation to physical
exercise.
Muscle cells can also themselves release factors with
potential autocrine roles in muscle function and adap-
tation to different stimuli (Husmann et al. 1996,
Goldspink 1998, Sheehan et al. 2000). Several cytokines
have been reported to be present by muscle homo-
genate (Lundberg et al. 1997, Ostrowski et al. 1998) and
at least some of them (IL-1b) appears to be located
within the muscle cells (Malm 2000). A muscle-speci®c
growth factor, the mechano growth factor (MGF) has
recently been reported (Goldspink 1998) and deserves
further attention. Investigations are needed to identify
potential factors involved in muscular adaptation to
physical exercise, and the potential therapeutical
usefulness of these factors in treatment of disease and
muscle hypotrophy. Many of these factors, if not most
of them, are yet to be discovered.
Based on data both from previously published
studies as well as data from our own laboratory (Malm
2000) a crude model for the interaction between the
immune system and human skeletal muscle is presented
(Fig. 1). The purpose of this model is to demonstrate
that two different stimuli (biopsy or exercise + biopsy)
can result in similar changes in human skeletal muscle,
but via different pathways that are partially common,
partially discrete. This model uses the appearance of
CD56 positive cells (activation satellite cells, myoblasts
or denervated muscle cells) as the ®nal outcome of
muscle degeneration±regeneration, and demonstrates
that because some factors are common and some
different when comparing the two pathways, it would
be impossible to draw correct conclusions without a
control group. The model is not intended to explain
muscular adaptation to physical stress, but rather to
serve as a possible guide for further research strategies.
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Acta Physiol Scand 2001, 171, 233±239
Figure 1 Simpli®ed scheme of possible interactions between skeletal
muscle and the immune system (compiled with data from Malm et al.
J Physiol, 2000). The initial stimulus begins with either multiple muscle
biopsies and eccentric exercise, with arrows indicating a temporal
subsequent event correlated to the previous (R2 > 0.9 and P < 0.05
in all cases). Resting NK cell number in blood appeared to have a
central governing role in blood and muscle changes in the exercised
group. No correlation was found between changes in blood NK cell
numbers and exercise. Correlation between blood (open ®gures) and
muscle (shaded ®gures) variables demonstrate different pathways
resulting in similar changes (activation of satellite cells) in muscle
tissue from exercised and non-exercised muscle.
C O N C LU S I O N
Despite a considerable number of conducted studies
aimed at investigating exercise induced muscle damage
and in¯ammation, unfortunately few withstand a critical
review. The main ¯aw in the design of conducted studies
is the lack of a non-exercising control group. Circum-
stantial evidence and methodological discrepancies have
formed the paradigm of exercise induced muscle
in¯ammation. If the muscle tissue anomalies observed
in several studies are caused by muscle contractions and
not by the sampling procedure, these anomalies may
very well be a natural occurring and inevitable, event in
muscular adaptation to physical exercise.
With the rapid development of new and more
sensitive methods for the analysis of gene transcription,
mRNA formation and protein expression, more detailed
knowledge regarding muscle function in health and
disease is just around the corner. The importance of
this knowledge should not be underestimated because it
can generate methods to cure diseases and repair tissue
damage that today leave the struck person disabled for
life.
As a result of some very recent ®ndings discussed
above, measurements must be taken to avoid false-
positive or false-negative results in future investigations.
Caution must be taken when collecting tissue
samples. When working in the nanomolar or picomolar
range, detecting structural changes of individual amino
acid, or using powerful ampli®cation methods such as
polymerase change reactions, the need for relevant
controls becomes more and more apparent. Small
changes and disturbances caused by sampling proce-
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C Malm
Exercise induced muscle in¯ammation
dures can be detected by the methods used today, and
even smaller changes by tomorrow's technology. Non-
exercising control subjects must be included in future
studies, and should perhaps be a criterion asked for by
journal editors.
Other modi®cations in the study design, not covered
in this review, are perhaps also necessary in order to
achieve accurate results and draw the correct conclu-
sions in future studies.
Past studies must be carefully re-evaluated by the
research community in order to determine conclusively
whether the paradigm of exercise induced muscle
damage and in¯ammation is fact or ®ction.
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