The differences between concentric (shortening) and eccentric (lengthening) muscle contractions have extensively been investigated (11,47). Although it is known that the magnitude of neuromuscular adaptations (i.e., gains in muscle mass, maximal strength, and neural activation) may be larger after prolonged eccentric strength training (35), eccentric contractions are also likely to acutely induce exercise-induced muscle damage (EIMD) (46). EIMD is typically characterized by mechanical disruptions of the myofilaments and streaming alterations of the Z lines, with a consequential effect on cellular homeostasis and interaction with peripheral immune cells (9). Eccentric EIMD seems to be particularly pronounced in inexperienced subjects and patients who are unaccustomed to this type of muscle contractions (29).
Previous studies have attempted to provide methods that may blunt the magnitude of EIMD. These included dietary supplements (42), low-intensity eccentric muscle actions (5), and maximal voluntary isometric muscle contractions (4). In fact, EIMD may primarily occur after the initial bout of maximal eccentric contractions, but the magnitude may be much lower during subsequent exercise sessions, a phenomenon typically referred to as the repeated bout effect (RBE) (5).
We have previously hypothesized that ischemic preconditioning (IPC) performed before strenuous strength exercise may also blunt EIMD (12). Support for this hypothesis stems from medical studies in which brief periods of ischemia preoperatively (i.e., IPC) led to a lower formation of muscle damage induced by prolonged ischemic disposition with subsequent reperfusion (I/R injury) during orthopedic surgery (1), supposedly through a reduced formation of metabolic stress (45) and proinflammatory responses (44). It has been shown that the conditioned skeletal muscle tissue develops several protective mechanisms on cellular (2), immunological (21), and genetic level (27), leading to a smaller magnitude of muscle damage after prolonged ischemia or I/R (1).
Although the primary source of eccentric EIMD and muscular I/R injury is different (i.e., mechanical strain vs ischemia and reperfusion), both scenarios follow a biphasic pathophysiological cascade with subsequent alterations in muscle physiology, resulting in prolonged and substantial tissue damage (12). From animal studies, it is known that disturbances in ionic handling induced by eccentric exercise or ischemia will lead to an intracellular accumulation of Ca2+ (3,41) with associated increases in the generation of reactive oxygen species (22,32). Although during eccentric exercise, the mechanical strain induces these alterations through morphological damage (i.e., disruptions of myofilaments and several cellular components, e.g., mitochondria and sarcoplasmic reticulum) (43), the damaging cascade in I/R injury is primarily triggered by substrate exhaustion during prolonged ischemia, subsequently followed by a failure of ATP-depending systems (e.g., Na+/K+-ATPase) and increased oxidative stress during reperfusion (24). These acute alterations substantially affect the morphology and regular function of cellular components (e.g., mitochondria) as well as the integrity of skeletal muscle cells through membrane or protein degradation by radical oxidation or proteases activation (e.g., calpain) (43,49). Thus, animal studies indicate that a secondary damaging cascade may then be generated in both EIMD and I/R injury by an equal sequence of immune reactions (13,23). A similar pathogenesis is also observed in human studies, where the postexercise and post-I/R phase is etiologically characterized by an increased activation of nuclear factor κB with subsequent expression of proinflammatory cytokines and chemokines (26,48). Subsequently, the complement system is activated (28,38), initiating an increased interaction of the attracted antigens with the circulating immune cells. The increased activation and migration of immune cells into the stressed tissue causes further tissue damage also to nearby healthy muscle cells (18,30).
On the basis of the described similarities between the pathophysiological formation of eccentric EIMD and muscular I/R injury, the purpose of the present study was to investigate whether IPC performed before a bout of eccentric contractions in the elbow flexors can protect against EIMD and maintain contractile function in previously untrained men.
MATERIALS AND METHODS
Subjects
Nineteen male subjects volunteered for this study (Table 1). All subjects reported not having performed regular strength training during the 6 months before the start of the study. Subjects were free of acute and chronic illness, disease, and musculoskeletal injury and did not report the use of dietary supplements or any medications that would contraindicate the performance of intense physical training. Subjects were informed about the experimental procedures and possible risks and signed an informed consent document before the investigation. The study was approved by the local research ethics committee and was performed according to the Declaration of Helsinki.
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TABLE 1: Baseline characteristics of all subjects.
Study design
A cross-sectional parallel design was used to investigate the effects of IPC on muscle damage responses. To avoid the effects of the RBE, the present study did not include a crossover. All subjects reported to the laboratory for two testing sessions and follow-up measurements, 2 wk apart. During the first visit, subjects’ individual concentric one-repetition maximum (1RM) of the elbow flexors was determined. Subjects were matched to the eccentric-only control group (ECC) or the IPC intervention group (IPC + ECC) on the basis of the measures of serum creatine kinase (CK) activity after the 1RM test. Venous blood samples for the analysis of CK were collected both, before, and 2 d after the 1RM test. On the basis of these results, high and low responders for CK were ranked and then equally allocated to ECC or IPC + ECC (Table 1).
During the second visit, the experimental loading was carried out and followed up for the subsequent 3 d. Subjects in IPC + ECC performed an eccentric strength protocol preceded by IPC, whereas ECC performed the strength protocol only (Fig. 1). For comprehensive monitoring of EIMD, serum concentrations of muscle damage markers, reversible muscle swelling, muscle contractility, and subjective pain intensity were measured at the following time points (Fig. 1): pre-IPC intervention (pre-IPC; in IPC + ECC only), preexercise (pre-Ex; i.e., post-IPC intervention in IPC + ECC), immediately postexercise (post-Ex), 20 min postexercise, and 2 h postexercise. Additional follow-up measurements were performed at the following time points: 24 h postexercise, 48 h postexercise, and 72 h postexercise. All subjects were requested to restrain from strenuous physical activity 48 h before testing and throughout the testing days.
FIGURE 1: Study design.
1RM test
Subjects’ concentric 1RM of the biceps muscles was determined using bilateral biceps curls (horizontal rod, 10 kg). After a warm-up, a maximum of five trials separated by 5 min of recovery was allowed to obtain a true 1RM. With an accuracy of 1.00 kg, the greatest load that the subject was able to lift to an elbow flexion of approximately 50° was accepted as 1RM.
IPC intervention
The IPC intervention was performed by three 5-min cycles of tourniquet-induced ischemia, separated by 5 min of reperfusion after each cycle (27). IPC was induced by an 8-cm-wide cuff, which was applied proximally to the right and left upper extremities to occlude the brachial artery entirely with a pressure of 200 mm Hg (17). The duration between the IPC intervention and the beginning of the exercising protocol was set at 5 min.
Eccentric exercise protocol
The eccentric exercise protocol consisted of bilateral biceps curls using a barbell (ScSports, Emmerich, Germany) and was performed with 3 × 10 repetitions at 80% of subjects’ individual concentric 1RM. The rest between sets was 1 min. Subjects were standing in an upright position, with the back leaning against a wall. Throughout the execution of the exercise, both elbows continuously held contact with the wall. To load the muscles eccentrically only, after each repetition, the barbell was lifted up to a full elbow flexion (~50°) by two assistants. Thus, the full range of motion was used for each eccentric contraction. The duration of each eccentric repetition was set to 2 s, subsequently followed by a rest of 2 s during the external uplift of the bar (“concentric phase”).
Blood sampling and analysis
For evaluation of eccentric EIMD, venous blood samples were collected at each corresponding time point (Fig. 1). Serum CK activity was measured by an enzymatic kinetic assay method (Roche Diagnostic, Mannheim, Germany) using a Hitachi 912 Automatic Analyzer (Roche Diagnostic) in the Department of Laboratory Medicine of the University Hospital Dusseldorf.
Muscle swelling and pain
The development of reversible muscle swelling was monitored by assessing the circumference of the dominant arm at the midportion of the upper arm, defined as 50% of the length between the acromion process and the lateral epicondyle of the humerus. Subjective pain intensity was recorded on a 100-mm visual analog scale (VAS).
Muscle contractility
The contractile properties of the biceps brachii muscle of the dominant arm were assessed using tensiomyography (TMG; TMG-BMC, Ljubljana, Slovenia). This technique induces a radial displacement of the muscle belly by an external electrical stimulus and records the displacement of each contraction over time. Subjects were seated on a chair while the investigated arm was taken into a prefabricated thermoplastic frame. Thus, the investigated arm was reliably fixed in neutral position (i.e., 90° elbow flexion). The arm was additionally laid on an adaptable arm support to ensure that the shoulder joint was kept in a neutral position during the measurement.
Two self-adhesive bipolar electrodes (Compex Medical SA, Ecublens, Switzerland) were placed on the investigated muscle. The proximal electrode was placed underneath the region where the pectoralis major and the deltoid muscle overlap the biceps muscle (crista tuberculi minoris), whereas the distal electrode was placed at the start of the distal tendon of the muscle. The attachment for the displacement-measuring sensor (GK40; Panoptik, Ljubljana, Slovenia) was anatomically determined as a point of maximal muscle belly contraction, detected by palpation during premeasurements of electrical-evoked muscle contractions. Both the position of the electrodes and the measuring point were marked to ensure the same location was used in consecutive measurements. Throughout the measurement, the sensor was placed on the skin perpendicularly to the muscle surface. The subjects were instructed to remain relaxed to ensure minimum tension in the investigated arm. A single square wave with monophasic subsiding 1-ms pulses was delivered from a TMG-S1 stimulator (EMF Furlan and Co. do.o., Ljubljana, Slovenia). To receive maximal peripheral mechanical muscle responses, the stimulation was increased by 10 mA at a frequency of 10-s intervals to minimize effects of fatigue and potentiation. The stimulation was gradually increased until no further displacement of the muscle belly was observed.
In the present study, we analyzed five parameters, which were calculated on the basis of the radial displacement over time: The maximal radial displacement (Dm) is expressed in millimeters and assesses muscle stiffness and contractile force (14). The delay time (Td) represents the time in milliseconds between the electrical impulse and 10% of the Dm. The sustained time (Ts) is the calculated time where the evoked contraction is maintained, defined by the time of a muscle response greater than 50% of Dm. The duration between 10% and 90% of Dm refers to the contraction time (Tc) and is associated with the muscle fiber–type composition and the speed of force generation. Lastly, the relaxation time (Tr) reflects the period of time for Dm to decrease from 90% to 50%.
Statistics
A two-way repeated-measures ANOVA was used to assess significant main effects (group, bout, time) and interactions within TMG and arm circumference data. Assessment for normality of data was carried out by using the Kolmogorov–Smirnov test. Because normal distribution was rejected in CK and pain data even after correction by logarithmic transformation, the Friedman test as a nonparametric alternative to the one-way ANOVA was used to determine differences over time within each group. To compare groups for CK and pain at each measurement time, Mann–Whitney U tests were performed. For analysis of CK, differences between baseline and each time of assessment were used in mean comparisons to reduce the effect of differences at baseline. Given that the IPC + ECC had one time point more than ECC (i.e., pre-IPC; Fig. 1), the measurement values at pre-IPC of the IPC + ECC were compared only with the pre-Ex of ECC, but the pre-Ex values of IPC + ECC were not used for between-group statistics. Statistical significance was set at α < 0.05 for all analyses, and means with respective SD are used to present data, both in tables and in the running text. Vertical bars in figures represent SD. All statistical analyses were performed using the Graphpad Prism 7 software package (Graphpad Software, San Diego, CA).
RESULTS
Muscle damage marker
Baseline activity for CK did not statistically differ between IPC + ECC and ECC (Table 2). After the loading, CK differed significantly from baseline only in ECC at 48 h (P < 0.001) and 72 h (P < 0.001), whereas a small but significant increase in IPC + ECC was observed at 72 h only (P = 0.034). Thus, at 24, 48, and 72 h, the CK response in ECC was significantly larger compared with that in IPC + ECC (P24h = 0.004, P48h < 0.001, P72h < 0.001; Table 2).
TABLE 2: Indirect markers of muscle damage after eccentric exercise with and without IPC.
Pain and arm circumference
Subjects of both groups reported no perceived pain on the VAS at baseline (Fig. 2A). After the loading, pain values significantly increased in ECC at 24 h (P = 0.022), 48 h (P < 0.001), and 72 h (P 0.004) compared with baseline, whereas pain in IPC + ECC increased after 24 h (P = 0.005) and 48 h (P < 0.001) only. Furthermore, pain in IPC + ECC was significantly lower at 24 h (P < 0.001), 48 h (P < 0.001), and 72 h (P < 0.001) compared with ECC.
FIGURE 2: Comparison of indirect marks of EIMD between IPC + ECC and ECC. A, Subjective perceived pain, illustrated by VAS values. B, Changes in contractile function of biceps brachii muscle by illustration of Dm. *Significantly different from baseline (P < 0.05). #Significantly different from ECC (P < 0.05).
The arm circumference of both groups remained statistically unchanged over time, and no group differences were observed (Table 2).
TMG
Dm did not differ significantly between IPC + ECC and ECC (DmIPC+ECC = 13.8 ± 2.7 mm, DmECC = 11.6 ± 3.9 mm; P > 0.05) at baseline (Fig. 2B). After the loading, in ECC, Dm was significantly decreased at all post–eccentric exercise measurements compared with baseline (P < 0.001). In IPC + ECC, Dm remained statistically unaltered. The changes in Dm differed significantly between IPC + ECC and ECC at 48 h (P = 0.003) and 72 h (P = 0.001).
Tc was significantly increased in ECC at 2 h (P = 0.006), 48 h (P = 0.018), and 72 h (P < 0.001) following the exercise protocol, whereas in IPC + ECC, it was significantly decreased at post-Ex only (P < 0.001). Tr was significantly decreased at post-IPC (P = 0.002). Td was significantly reduced at post-Ex in both groups (P < 0.001) and after 20 min only in IPC + ECC (P = 0.002). Ts was significantly reduced in IPC + ECC at post-Ex (P = 0.013).
DISCUSSION
The aim of this study was to investigate whether a tourniquet-induced IPC performed before an eccentric strength training session of the elbow flexors blunts muscle damage responses induced by the eccentric loading. The main findings were that IPC of the upper limbs led to a significant reduction of CK activity and perceived pain, whereas the associated postexercise decline in the contractile ability of the biceps brachii muscle was attenuated.
To date, most of the studies investigating the mechanisms of IPC were conducted in a clinical context and showed a significant effect of IPC on the formation of I/R injury (1,27). A recent study by Hong and colleagues (16) indicated that IPC may protect skeletal muscle from I/R injury, represented by a lower magnitude of necrosis, apoptosis, and alterations in morphological cell structures. Thereby, the effects of IPC seem to occur in a biphasic manner. Early adaptations seem to be reflected by significant increases in the antioxidant defense capacity (27), Ca2+ metabolism, and neural pathways (39). Late effects, on the other hand, are thought to be reflected by altered gene expressions and peripheral immune responses (21). This was especially shown by a down-regulation of proinflammatory signaling with associated declines in leukocyte–endothelial cell interaction through IPC (36).
We have previously hypothesized that the underlying mechanisms of I/R injury–induced muscle damage and EIMD are similar (12), and thus, IPC may blunt the damaging responses induced by eccentric exercise. To quantify the magnitude of EIMD, a decline in force generation is typically considered as a primary marker (7). However, as previously shown, declines in force are strongly associated with changes in CK, muscle swelling, and perceived pain (7). Although we were not able to measure force in the present study, we observed an acute decrease in TMG data in both groups right after the eccentric loading (i.e., reductions in Dm, Td, Ts, and Tr). These acute increases in muscle stiffness may represent a postexercise potentiation (10), induced by a modified Ca2+ responsiveness and stiffness of the contractile apparatus (14). Although short-term increases in muscle stiffness may acutely aid the muscles to prevent potential upcoming contractile stress, long-term increases in resting muscle tonus have previously been associated with muscle damage (20).
Consistent with these findings, Hunter and colleagues (19) have shown that the decline in TMG-assessed Dm after an eccentric exercise protocol for the elbow flexors is positively correlated with declines in MVC for up to 4 d postexercise, indicating TMG measurements to be similarly indicative of muscle damage as MVC measurements. Our present results further showed that in ECC, the decline in Dm remained statistically significant throughout the 3 recovery days, whereas in IPC + ECC, Dm measurements returned to baseline already after 2 d. This finding supports our hypothesis that IPC protects the muscle from eccentric EIMD and aids in restoring complete contractile function and, thus, reduces recovery time.
When interpreting the present TMG data, it should be noted that TMG measurements are highly affected by postexercise muscle swelling induced by edema formation through increased vascular permeability and overstrained lymphatic efflux. However, because significant edema formation may take at least 24–48 h (6), it is likely that the immediate increase in muscle stiffness may rather be associated with modifications in contractile function.
The underlying mechanisms by which the mechanical strain of eccentric loading affects muscle stiffness remain to be investigated. Muscle stiffness is regulated through posttranslational modifications of cytoskeletal proteins and alterations in muscle viscoelasticity. During strenuous exercise, the structure of titin may be altered, in turn, leading to an increase in muscle stiffness by phosphorylation or elevated intracellular Ca2+ concentrations (15). In fact, muscle stiffness is also one of the discussed mediators of the protective effect of RBE (25). Short-term increases in muscle stiffness could aid in maintaining muscle integrity when exposed to contractile stress (31) and at the same time improve the effectiveness of contractions (8). This hypothesis finds support by our results of acute nonsignificant alterations in TMG-assessed muscle contractility (i.e., decrease in Dm, Td, Ts, and Tr), which were observed in IPC + ECC immediately after the preconditioning, before commencing the exercise loading. Although this finding was not statistically significant, it is likely that the acute increases in muscle stiffness originating from IPC protect against subsequent exercise-induced damage. In fact, although it did not reach statistical significance, this decrease was somewhat similar to the reduction of Dm observed from preexercise to postexercise in both groups, indicating that an IPC alone seems to affect muscle contractibility in a similar manner to that of exercise.
In addition to the functional assessments by TMG, the present results show that an IPC performed before a bout of eccentric exercise may significantly blunt indirect markers of muscle damage as well. The increases in postexercise CK and pain in the present study were significantly lower in IPC + ECC compared with ECC (CK activity: 24 h, −93%; 48 h, −95%; 72 h, 96%; perceived pain intensity: 24 h, −80%; 48 h, −79%; 72 h, −88%). A similar trend was also observed for the circumference assessments, where subjects of the ECC group showed greater muscle swelling on the postexercise days, although the changes did not reach statistical significance. Because muscle pain and swelling are known markers for inflammation (40), our findings also provide some indications of lower proinflammatory responses in IPC + ECC. The observed blunted damage response is well in line with findings of Chen et al. (4), who showed that the RBE induced by a prior bout of eccentric exercise performed 3 wk earlier may attenuate the CK activity for up to 98% and the onset of subjective pain intensity to around 64%. Thus, our results indicate IPC to be similarly effective to that of the RBE in blunting the magnitude of damage responses.
Although we have shown a significant reduction of damage responses after eccentric exercise when IPC was applied, the present study does not provide conclusions concerning the chronic adaptations when IPC and subsequent eccentric exercise are repeated for a prolonged time. In fact, possible damaging cascades induced by EIMD may be essential triggers for prolonged training–induced neuromuscular adaptations (37), which may be suppressed by IPC. A similar phenomenon was previously shown by studies investigating cold water immersion (CWI) after strength loadings in an attempt to enhance recovery. Although CWI leads to acute reductions in inflammatory responses and, thus, enhanced postexercise recovery (33), it is known that chronic CWI impairs neuromuscular adaptations (34). As for IPC, however, one should bear in mind that the underlying mechanisms for blunted muscle damage responses seem to be diverse, and it is yet to be investigated which inflammatory pathways are affected. Thus, at present, long-term effects of IPC on neuromuscular adaptations remain to be investigated.
In conclusion, the present study indicates that IPC applied immediately before a bout of eccentric exercise of the elbow flexors may blunt the skeletal muscle damage responses as indicated by a lower magnitude of CK activity, reduced pain and muscle swelling, and a faster restoration of muscle contractility. Future studies should try to investigate the underlying mechanisms of these protective effect and subsequently for practical application its effect in training studies.
We thank TMG-BMC Ltd. (Ljubljana, Slovenia) for providing us a TMG device for the duration of the study.
All authors declare that there are no financial and personal relationships with third parties or organizations that could have inappropriately influenced the present work. The authors further state that no funding was received.
The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation, and the results of the present study do not constitute endorsement by the American College of Sports Medicine.
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