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Laval University Hospital Research Center and Département de Réadaptation, Faculté de Médicine, Université Laval, Ste-Foy, Québec, Canada G1V 4G2
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Lengthening contractions trigger an adaptive response decreasing the susceptibility to exercise-induced muscle damage (EIMD). We hypothesized that 1) this adaptation can be observed when voluntary muscle recruitment is bypassed and 2) inflammation repression lessens the adaptive response. Rat ankle dorsiflexors were submitted to two bouts of elicited lengthening contractions 14 days apart; in vitro force production and macrophage concentrations were obtained before and 2 days after each bout in rats treated or not for 2 or 7 days with diclofenac. The first bout caused a 45% force deficit in the placebo group vs. 25% in the diclofenac group, whereas the ED1+ macrophage concentration increased by 10- and 5-fold, respectively. After the second bout, only diclofenac-treated rats (2 or 7 days) presented significant force deficits and increases in ED1+ and ED2+ macrophage concentrations, but this was more pronounced in the 7-day group. We conclude that adaptation to lengthening contractions does not depend on neural components but is likely mediated by strengthening of muscle structural/cellular elements and that inflammation is important for this process.
skeletal muscle; macrophage; repeated bout effect; repair; non-steroidal anti-inflammatory drug
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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EXERCISE WITH A SIGNIFICANT lengthening contraction component can produce skeletal muscle damage, an entity known as exercise-induced muscle damage (EIMD) that is associated with delayed-onset muscle soreness (2, 14). A prior bout of lengthening contractions, but not concentric ones, triggers a rapid adaptive response that drastically diminishes EIMD and the associated soreness after a second bout of the same nature (17). This protection afforded by the first bout of contractions is referred to as the repeated bout effect (17, 18).
Although several hypotheses have been considered to explain this adaptive response, the exact mechanisms involved are still debated. The so-called cellular and connective tissue hypotheses state that adaptation proceeds from successful muscle repair and/or reorganization of several contractile and structural components such as the sarcomeres (13), the extracellular matrix (23), and the cytoskeleton (14), making the muscle less vulnerable to EIMD. The repair process is presumably partially dependent on the inflammatory response triggered by the initial mechanical damage (14, 22). Generally, inflammation serves to remove damaged muscle tissue by recruiting neutrophils and macrophages, but it is also likely important for the processes governing muscle repair and/or reorganization after trauma (1, 7, 14, 19, 26). Neutrophils and ED1+ macrophages are the leukocytes recruited after most trauma in rats. However, in recent work from our laboratory, we showed that, in rats, neutrophil recruitment does not occur in EIMD (12). The resident ED2+ macrophages are believed to promote and assist the regeneration phase by influencing satellite cell proliferation and differentiation (4, 15). Macrophages could also influence fibroblasts found in skeletal muscle as they can modulate their proliferation and rate of collagen synthesis (3, 8). Interestingly, it was shown that macrophages can produce type I collagen (27). This fits elegantly with the proposal that synthesis of extracellular matrix and collagen in skeletal muscle can be part of the adaptive mechanism leading to a better resistance to lengthening contractions (10, 24, 25) and somehow supports the idea that the inflammatory response is an interesting candidate that could be closely linked to the repeated bout effect.
On the other hand, the documented rapid onset of the adaptive response led others to propose that changes in motor unit recruitment strategies were responsible for its appearance. When facing isometric or concentric contractions, it is widely accepted that motor units are recruited in a very orderly fashion, where slow motor units are activated first, followed by fast-twitch motor units. The neural hypothesis states that the nervous system, when facing unaccustomed lengthening contractions, uses an inappropriate recruitment pattern where type II fibers, which are more susceptible to EIMD compared with type I fibers, are preferentially recruited. However, when repeated, lengthening contractions would lead to a more typical pattern where slow motor units would become the main contributor to tension generation. This adaptation would also result in a decreased tension per active cross-sectional area as more muscle fibers are recruited, thus reducing damage and the associated loss of strength (18, 28). Although this neural hypothesis appears attractive, it has not been strongly supported by the results published so far (16). To obtain more conclusive evidence regarding the significance of changes in neural strategies for the establishment of the repeated bout effect, we have used an animal model where 1) normal voluntary recruitment was bypassed during the lengthening protocols and 2) maximum force production after EIMD was measured in vitro through direct muscle stimulation, again bypassing voluntary recruitment mechanisms. If the neural hypothesis is true, no repeated bout effect would be seen with such a protocol, which, to the best of our knowledge, has never been used to investigate that question.
Because the neural hypothesis can be efficiently tested in an animal model of EIMD and because the inflammatory reaction can modulate muscle degeneration and regeneration processes possibly critical for the establishment of the adaptive response, we opted to test the following hypotheses: 1) the repeated bout effect can be observed in an EIMD model when voluntary muscle recruitment is bypassed and 2) repression of the inflammatory reaction after a first damaging bout of lengthening contractions lessens the repeated bout effect.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal care and lengthening contraction protocol.
Female Wistar rats weighing 90-100 g at the beginning of the
protocol were anesthetized with an intraperitoneal injection of
ketamine-xylazine (87.5 and 12.5 mg/100 g body wt, respectively). The
peroneal nerve was carefully exposed, and the animal was transferred in
an apparatus allowing externally stimulated lengthening contraction of
the ankle dorsiflexors in the last 40° of plantar flexion. This
protocol is a modification of the one described previously (5). One tetanic contraction (120-Hz stimulation
frequency, 600-ms train duration, supramaximal voltage) was elicited
every 2 s for three 5-min periods separated by 5 min of rest for a
total of 450 lengthening contractions. When the protocol was completed, the muscle and fascia over the peroneal nerve were sutured (Vicryl 4-0) and the skin was closed with Michel suture clips.
Lactate-Ringer solution was then injected subcutaneously, and the
animal was placed under a heating lamp to maintain body temperature.
Rats were divided into four groups: 6 h after the end of the first lengthening contraction protocol, two groups received by gavage a
non-steroidal anti-inflammatory drug diluted in water (diclofenac, 1 mg/kg body wt, twice a day) for 2 or 7 days postprotocol (diclofenac 2-day and diclofenac 7-day groups) while two other groups received only
the vehicle solution (placebo 2-day and placebo 7-day groups). The
experimental design is depicted in Fig.
1. In all groups, the right hindlimbs
were submitted to lengthening contraction protocols while the left ones
were submitted to a sham procedure.
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Contractile properties measurement. Isometric contractile properties were obtained in vitro as described earlier (11). Measurements were performed just before and 2 days after each bout, because the deficit is maximal at that time point. Briefly, rats were first anesthetized with pentobarbital sodium (50 mg/kg body wt) and then received buprenorphin (0.1 mg/kg body wt ip). Extensor digitorum longus (EDL) muscles were incubated in a buffered solution (Krebs-Ringer) supplemented with glucose, bubbled with carbogen, and maintained at 25°C. Muscles were adjusted to their optimal length (Lo), defined as the length where maximum twitch tension was obtained, after a 20-min equilibration period. Stimulation consisted of 25-V square pulses of 0.2-ms duration delivered through platinum field electrodes. A force-frequency relationship was determined using one tetanic contraction of 400-ms duration every 60 s until maximum tetanic tension (Po) was obtained. On determination of Po, muscles were weighed to permit calculation of maximum specific tetanic tension (specific Po), which is absolute Po normalized for the cross-sectional area. Value used for muscle density was 1.062 g/cm3, and the ratio of fiber length to muscle length was 0.4 (21).
Immunohistochemical detection of inflammatory cells.
For the immunohistochemical measurements, EDL muscles were dissected,
embedded and frozen in isopentane cooled in liquid nitrogen, and then
stored at 
80°C. Three triplicates of transverse sections (10 µm)
were obtained at a 1-mm interval from a site corresponding to one-third
of Lo from both muscle ends. These 18 sections
were adhered to slides coated with chromium potassium sulfate and
gelatin and stored at 20°C for up to 5 days. On the day of the
experiment, slides were air dried for 30 min, placed in cold acetone
for 10 min, and air dried again. Quenching of the sections (0.3%
H2O2) was followed by a blocking period of 30 min. Afterward, either anti-ED1+ or anti-ED2+
macrophage antibodies (1:100 dilution, Serotec, Indianapolis, IN) were
applied to the sections for 2 h. Sections were then washed with
PBS and incubated with a secondary biotinylated antibody (anti-mouse
IgG diluted 1:200, Vector Laboratories, Burlingame, CA) for 1 h.
After a second wash, horseradish peroxidase was added to the slides
(1:1,000, Vector Laboratories) for 30 min and the antibody-antigen
complex was revealed by chromogenic development using a peroxidase kit
(AEC, Vector Laboratories). The number of labeled cells in each section
was counted, and the total area of the section was determined and
multiplied by its thickness to normalize the data as the number of
cells per cubic millimeter of muscle tissue.
Statistical analysis. All data are expressed as means ± SE. Student's t-test and analysis of variance, followed by the Tukey's post hoc test when significance was reached, were performed. Paired comparisons were used when appropriate. In all cases, the alpha level was set at P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Preliminary experiments showed that the sham procedure and the gavage with diclofenac for 2 or 7 days did not affect muscle function or body mass assessed at 2, 7, or 28 days later in control rats. Diclofenac treatment almost totally abolished the increase in serum PGE2 level consecutive to the lengthening protocol (data not shown). Because body weight and muscle mass values did change between the two protocols, we also verified that the susceptibility to lengthening contractions did not change during these 2 wk, which was the case (results not shown).
Contractile properties.
The first bout of lengthening contractions led to significant deficits
in absolute and specific Po, whereas a 2-day diclofenac treatment prevented part of this loss (Fig.
2). At the time they were submitted to a
second bout of lengthening contractions 14 days later, all groups had
returned toward sham values for absolute and specific Po,
as pre-first and pre-second bout values were not significantly
different. Two days post-second protocol, only the diclofenac 7-day
group showed a significant deficit in absolute Po compared
with its pre-second protocol value; it was also significantly weaker
than the placebo 7-day group. Both treatment durations resulted in a
statistically significant decrease for specific Po compared
with the pre-second bout.
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Leukocyte concentration in EDL muscles.
Because neutrophil concentration was previously found to be unchanged
after a protocol of lengthening contractions, immunohistochemical counting of these cells was not performed. Concomitantly with the first
decrease in tension production for the placebo group, there was a
significant eightfold increase in the concentration of ED1+
macrophage in this same group (Fig.
4A). This parameter also increased after the first protocol in the diclofenac 2-day group but to
a much lower extent. Interestingly, the inflammatory reaction seemed
to persist in both treated groups, as the concentration of
ED1+ macrophages did not return to basal values by the
second protocol but instead remained ~35% higher compared with the
placebo group. There was no significant change in ED1+
macrophage concentration in the placebo group after the second protocol. However, in both treated groups, statistically significant increases in ED1+ macrophage concentration, although less
important than those observed after the first bout, were observed.
These increases were, to some extent, dependent on treatment duration.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The first important finding of this study is that we observed an impressive repeated bout effect, allowing complete protection in a model where neural recruitment strategies were completely bypassed in pre- and post-EIMD measurements. Indeed, during both bouts of lengthening contractions, the same maximal nonvolitional external stimulation set-up and parameters were used; thus on both occasions all muscle fibers were submitted to the same mechanical insult. It can therefore be concluded that, in this model of EIMD, changes in motor unit recruitment strategies appear to play little role, if any, in the rapid adaptive response observed after a first damaging bout of lengthening contractions. It should be emphasized that most studies supporting the hypothesis that the repeated bout effect is dependent on neural adaptations used protocols where maximal voluntary force and/or repeated muscle biopsies were obtained on human subjects. Several confounding factors often limit the interpretation of these studies. For example, the ability of subjects to produce consistent and real maximum voluntary force increases with the number of sessions (6). Furthermore, pain can lead to a decrease in maximum voluntary force, masking the real maximum tetanic tension of the muscle. Differences in force deficits after the first and second bout of lengthening contractions then become difficult to interpret in this context. In our protocol, none of the above factors is present, which strengthens our conclusion.
To the best of our knowledge, only two studies so far have used an animal model to study the repeated bout effect. Although our results are generally in agreement with their findings, it should, however, be pointed out that some important differences can be found that make the present study unique. Sacco and Jones (20) used the tibialis anterior muscle of mice, and measurement of Po after the two lengthening protocols was obtained in situ using nerve stimulation, whereas we obtained Po values on isolated rat EDL muscles stimulated directly in vitro. They observed an adaptive response when the two bouts were separated by 10 and 20 days, but the protection afforded by the first bout was not complete, as they observed a 20% deficit compared with control muscle, whereas no significant deficit was seen in the present study. Because Po was obtained through nerve stimulation, any lengthening protocol-associated denervation could lead to a submaximal muscle fiber recruitment and possibly to an underestimation of the maximum force that could be produced, something impossible with in vitro measurement of Po on field-stimulated muscles. In the study by McBride et al. (16), adult and old rats were submitted to two lengthening protocols where both dorsi- and plantiflexor muscles were stimulated at the same time. However, although an adaptive response was apparently observed, it should be noted that their protocol induced much less important muscle damage than what is frequently seen in animal studies, probably because both muscle groups were allowed to contract, a protocol rarely used. Furthermore, absolute and specific Po values were not presented; instead, force measurements were normalized for dry muscle mass, which limits the interpretation regarding the adaptive response, as it was shown that force production and contractile protein content are dissociated in the early days after EIMD (9). So the present study is the first to present absolute and normalized contractile data in a model where, contrary to the study by McBride (16), the extent of muscle damage induced was important (>40% force deficit) and where values for Po were obtained through direct muscle stimulation.
The second important finding is that repressing the inflammatory reaction with diclofenac significantly impaired the repeated bout effect, with the longer treatment leading to a more pronounced modification. Such observation has never been documented before. In nontreated rats, where the repeated bout effect was most prominent in terms of force production, the inflammatory reaction consecutive to the second bout was almost nonexistent. This latter result, based on immunohistochemical identification, is in agreement with Sacco and Jones (20), who observed a decreased cellular infiltration as well as a better preservation of muscle maximal tension and fiber morphology based on nonspecific muscle histological staining. In our model, the first bout produced muscle damage that was associated with an increase in ED1+ macrophage concentration at 48 h, which fits well with the accepted phagocytic function of this subpopulation. The modest increase in the concentration of ED2+ macrophages at this early time point was expected on the basis that this subpopulation has been postulated to participate in the subsequent repair process. It was found that ED2+ macrophages do not phagocytose damaged tissue but produce signals stimulating satellite cells and hence muscle regeneration (4).
After the second bout, no significant change in the concentration of both subpopulations of macrophages in the untreated EIMD group may signify that no muscle damage was present with no need for removal of necrotic tissue and repair, again supporting the implementation of a strong repeated bout effect. The fact that diclofenac administration after the first bout resulted in a diminished concentration of both macrophage subpopulations probably led to an incomplete or slower removal of necrotic fibers by ED1+ macrophages, which could have significantly impaired and/or prolonged the repair phase necessary for the adaptive response. This lengthened time devoted to the repair and/or adaptive process would explain why ED2+ macrophage concentration was still elevated 14 days after the first bout in the treated groups. The postulated altered repair probably led to an incomplete or inadequate muscle adaptation compared with the untreated group based on the observation that muscles from the two treated groups were damaged by a second bout of lengthening contractions and that both subpopulations of macrophages increased again. Hence, our results support the idea that diclofenac treatment may interfere with the adaptive process in a treatment duration-dependent way.
In summary, a potent adaptation to lengthening contractions was observed in an experimental model where voluntary control of skeletal muscle contractility by the nervous system was bypassed, which does not support the hypothesis that the repeated bout effect exclusively depends on adaptations of motor unit recruitment strategies. Treatment with diclofenac, a widely used non-steroidal anti-inflammatory drug (NSAID), affected in parallel the concentration of macrophage subpopulations and the adaptive response. These effects were particularly evident when administration was continued after the acute phase of the inflammatory reaction, likely reflecting an impairment of skeletal muscle repair and adaptation. As a whole, these results rather support the cellular and connective tissue hypotheses stating that repair or strengthening of the various muscle components is the basis for the repeated bout effect; it is also suggested that inflammation is likely a key element in this process.
Perspectives
Clarifying the processes underlying the phenomenon of adaptation to damaging lengthening contractions is a very active research area with future possible impacts in several fields related to musculoskeletal health. The finding that inflammation is intimately implicated in the adaptive response to damaging contractions is in agreement with previous work showing that the inflammatory process is needed for regeneration of skeletal muscle. Such observations open new insights that will allow innovative avenues of investigation to be pursued. It, for one, challenges the position that the acute inflammatory process must be repressed to favor recovery of form and function. Repeated use of anti-inflammatory drugs over extended periods covering the repair phase of muscle-tendon unit may not be appropriate in the context that some inflammatory components are needed for both repair and adaptation. A more precise identification of the molecules and cells implicated in the degenerative and regenerative cascades should lead to the development of more specific drugs that will repress negative actors of inflammation and not the entire process such as is the case presently. Repressing the catabolic phase may be warranted in some cases while stimulating the anabolic cascades should be emphasized. This study has to be added to the long list of clinical questions regarding what is often referred to as the abusive use of NSAIDs in soft tissue injury. Such questioning can have major impact in both the fields of sports medicine and work-related injury. Thus inflammation should be seen as an integral and essential step of the repair and adaptive response of skeletal muscle to trauma.| |
ACKNOWLEDGEMENTS |
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We thank J. Frenette and D. Marsolais for fruitful discussions and for critically revising the manuscript.
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FOOTNOTES |
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This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada to C. H. Côté. B. M. Lapointe was the recipient of a scholarship from the Fonds de la recherche en santé du Québec.
Address for reprint requests and other correspondence: C. H. Côté, Laval Univ. Hospital, Research Center, Rm. 9600, 2705 Blvd Laurier, Ste-Foy, Qc, Canada, G1V 4G2 (E-mail: claude.h.cote{at}crchul.ulaval.ca).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00339.2001
Received 14 June 2001; accepted in final form 26 September 2001.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Significantly different from diclofenac 2-day groups and their
respective placebo value, P < 0.05. #Significantly
different from respective placebo group only, P < 0.05. ND, not determined.
Significantly different from respective placebo group,
P < 0.05.