Resistance exercise 2–3 days per week is recommended for apparently healthy adults because of the numerous health benefits (7) and association with reduced mortality (20). Despite these recommendations, the latest estimates indicate that 29% of US adults currently meet the muscle-strengthening guidelines of participating in resistance training twice per week (3). Although there are likely multiple reasons for nonparticipation, delayed onset muscle soreness (DOMS) that follows intense and novel exercise, especially if it involves eccentric contractions, may dissuade continued participation.
Damage to muscle fiber membranes allows the release of some cellular contents including the enzyme, creatine kinase (CK) and disrupts function including muscle strength and range of motion (ROM) (5). Inflammation stimulated by muscle damage may cause an initial increase in secondary damage but also helps to orchestrate the repair process and recruitment of satellite cells (9,22). Although repair that follows 1 muscle-damaging bout makes the muscle more resistant to future damage (5,9), limited research has assessed the impact of continued multiple resistance bouts such as would be prescribed for a novice resistance trainer.
Various pharmaceutical and dietary interventions have been studied regarding their ability to reduce damage or dampen inflammation after resistance exercise. Some studies report a negative influence on muscle growth when inflammation is inhibited (9,22), whereas others find improved adaptations (24). The potential value of omega-3 fats to reduce the acute inflammation caused by eccentric exercise damage has been explored in a few studies with contradictory outcomes (11,14,19,23).
The mechanism for an anti-inflammatory potential of these fats includes substrate competition of membrane-derived omega-3 fats with omega-6 fats for cyclooxygenase (COX) and lipooxygenase enzymes causing reduced production of inflammatory and increased generation of less inflammatory eicosanoids (2,27). In addition, omega-3 fats have nuclear effects as ligands for peroxisome proliferator-activated receptors and nuclear factor kappa B (NF-KB), thus influencing transcription of inflammatory factors such as cytokines and adhesion molecules (2,27). Most omega-3 fat supplements are derived from fish oil and contain both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). There is some evidence that DHA has more anti-inflammatory potential than EPA (17,28). Commercially available DHA produced by algae is available as a supplement (DSM, Parsippany, NJ, USA) but has not been evaluated in exercising individuals.
This investigation was designed to observe the effects of DHA supplementation on acute muscle function, damage, and inflammatory indicators after a novel eccentric exercise bout and to the subsequent initiation of a resistance training program in untrained men. The results could have implications for untrained individuals beginning a resistance training program that is known to induce muscle damage and soreness.
Experimental Approach to the Problem
The overall study design was planned to include an initial controlled eccentric resistance bout followed by initiation of a resistance exercise program devised for novices. Comparison between subjects who ingested DHA and a placebo (PL) would allow assessment of the influence of this fat on acute muscle damage and inflammation after a highly controlled damage-inducing bout as well as the response to initiation of a typical resistance training program. Subjects (21.8 ± 2.7 years; 78.4 ± 5.7 kg; 14.8 ± 5.3% body fat (10)) were randomly assigned to consume a dietary DHA supplement (DHA) or PL for 28 days (day −28 to day 1) before performing a set of baseline measures for muscle function, damage, and inflammation on the morning of day 1 in a fasted condition (Figure 1). Immediately after the baseline measures, the acute eccentric exercise protocol was performed. A resistance training program was begun on day 4 and continued 3 days per week through day 17. The functional measures of muscle damage (isometric muscle strength [STR], DOMS, and ROM) were performed on the mornings of days 1, 2, 3, 4, 7, 12, and 17. Blood indicators of muscle damage and inflammation were measured on all these days with the exception of day 3. Testing took place as consistently as possible within subject, in the morning hours between 6:30 AM and noon (8:31 AM ± 43 minutes) depending on the subject's schedule with the order as follows: blood withdrawal, ROM, DOMS, and STR.
Male subjects who had not participated in resistance training within 6 months (defined as less than 2 resistance training sessions per week) were not taking a supplement or medication that influences inflammation and did not have medical contraindications were recruited after approval by the university institutional review board. Fifty healthy nonsmoking adult males, aged between 18–28 years volunteered to participate, fit the criteria for inclusion, and provided written consent for participation.
Participants were instructed to cease all other vitamin/mineral and performance-enhancing supplements and avoid consumption of fatty fish for the duration of the study. During the supplement-loading period, subjects were instructed to consume the prescribed supplement at 2 pills per serving, twice daily with meals (4 pills total per day). Supplements contained either DHA (500 mg per pill) or corn oil (500 mg per pill) totaling a daily dose of 2 g of the prescribed treatment. Docosahexaenoic acid (produced by the algal species Crypthecodinium cohnii) and PL supplements were provided by Martek Biosciences Corporation (Columbia, MD, USA, now part of DSM, Parsippany, NJ, USA). The number of supplements consumed by each subject was measured by a pill count. Compliance was also evaluated through self-report in an exit survey.
Range of motion was measured on the nondominant arm using the average of 2 measurements for the arm relaxed and palm to shoulder joint using a goniometer (4). The joint angle was measured on the nondominant arm while it was relaxed at side and when flexed as subjects touched palm of hand to shoulder joint without lifting the elbow. Delayed onset muscle soreness was assessed by self-report after subjects completed 10 biceps curl repetitions using a 5-lb weight by indicating the level of soreness on a 100-mm visual analog scale (VAS). The VAS was anchored by the designations of “No Soreness” at 0 mm and “Unbearable Soreness” at 100 mm. Isometric muscle strength was tested at 90° of elbow flexion in their nondominant arm using a Biodex dynamometer (Biodex System 3 Pro Isokinetic Dynamometer, Shirley, NY, USA) after a warm-up biceps curl (8–10 repetition of 2.3 kg weight followed by 4–6 repetitions of a 6.8-kg dumbbell) and a 2- to 3-minute rest. Subjects were instructed to apply maximal isometric effort to the attached lever arm of the dynamometer for 3 seconds, 3 times with 30 seconds separating contractions. The average peak isometric strength for the 3 contractions was used for analysis.
The eccentric exercise bout load was based on a 1 repetition maximum (1RM) test with their nondominant arm resting on a preacher curl bench pad at approximately 45° of shoulder flexion and approximately 90° of elbow flexion. After a warm-up, subjects attempted a 1RM. If more than 1 repetition could be performed, higher weights were used with a 2-minute rest between to obtain the 1RM. Magnetic weights (PlateMate, Boothbay Harbor, ME, USA) in 1.25 and 2.5 lb increments were added to dumbbells to provide more precise testing. After 1RM testing, subjects performed 6 sets of 10 eccentric-only contractions to muscular failure at approximately 140% of their 1RM with 2 minutes between sets. The investigator placed the dumbbell in the subject's hand and instructed the subject to lower the dumbbell in rhythm with the investigators 1–5 counting. When the load was in the bottom position of the eccentric movement, the investigator moved the load back up to the superior position for the next repetition.
On day 4, subjects began a resistance exercise program with estimation of their 1RM for each of 6 exercises (leg press, machine chest press, cable row, machine shoulder press, lateral pull down, and cable biceps curl) using prediction of 1RM from 4 to 6RM with 2-minute rests between attempts (15). Five subsequent training bouts that included 3–4 sets of 8 repetitions for each exercise were performed on nonconsecutive days of the week (days 6, 9, 11, 13, and 16). The resistance for the 5 multijoint exercises was prescribed at 70% 1RM for multijoint and 60% 1RM for the single-joint exercise for the first week. These intensities increased to 75% 1RM and 65% 1RM, respectively, for the second week. The initial session was supervised by a research assistant; participation in subsequent workouts was validated through signature from the gym supervisor.
Blood samples were withdrawn using a serum separator tube and allowed to clot for 30 minutes before centrifugation at 3,000g for 15 minutes at 4° C. Serum was separated from whole blood and was stored at −80° C until analysis. Serum was analyzed for interleukin 6 (IL-6), IL-1ra, and C-reactive protein (CRP) on days 1, 2, and 4, for CK on those days plus 7, 12, and 17, and for serum DHA on days −28 and 1. Serum CK was assessed using an enzymatic spectrophotometric procedure from Pointe Scientific (Canton, MI, USA). Analyses of IL-1ra, CRP, and IL-6 were conducted through enzyme-linked immunosorbant assay kits from R&D Systems (Minneapolis, MN, USA). All measurements were completed in duplicates and samples were reassessed if coefficients of variation (CVs) were >20%. Intra- and interassay CVs were 7.8 and 26.8% for CK, respectively. For inflammatory markers, intra-assay CVs were 7.1, 8.2, and 7.2% for CRP, IL-1ra, and IL-6, respectively. Interassay CVs for inflammatory markers were 22.0, 12.5, and 11.5% for CRP, IL-1ra, and IL-6, respectively.
Serum DHA concentration was determined by a lipid extraction and methylation procedure (6). Serum fatty acid methyl esters were analyzed by gas chromatography (Agilent 6890N GC, Santa Clara, CA, USA) using a CP-Sil 88 capillary column (100 m × 0.25 mm inside diameter with 0.2 μm thickness; Varian, Inc., Palo Alto, CA, USA) and run in duplicate. Fatty acid peaks were identified by using pure methyl ester standards (Nu-Check Prep, Inc., Elysian, MN, USA).
Baseline subject data (age, weight, body fat, blood factors, ROM, and STR) during the eccentric bout were compared using a 2-sided t-test to determine whether there was uniformity between groups. The data from the acute phase, days 1–4 (serum IL-6 and CRP, ROM, STR, and DOMS), were analyzed using 2-way analysis of variance (ANOVA) with repeated measures as well as area under the curve (AUC) using the trapezoidal procedure to examine the acute responses to eccentric exercise and be comparable with most of the other literature on this topic. The data were also analyzed using days 1–17 with 2-way ANOVA with repeated measures and AUC to examine the overall response to resistance exercise training and the supplements. For missing data points, the average value of the points before and after the missing point was used. Natural log transformation of CK activity was used because these data were not normally distributed. Post hoc analysis was performed when there was a significant F ratio using a student t-test to determine differences in treatment at individual time points. All statistical analyses were performed using JMP 9.0 (SAS Institute, Inc., Cary, NC, USA). A p value <0.05 was considered significant.
Forty-one of the 50 subjects completed the entire study. Three subjects from the DHA group and 6 from the PL group did not complete the study for reasons unrelated to the study (6 subjects had scheduling difficulties, 2 no longer desired to participate, and 1 began using a new medication) and were excluded in the analysis. The 21 subjects who completed the study in the DHA group were similar in age, weight, body fat, and initial summed 1RM for the 6 exercises to the 20 subjects in the PL group. Body weight change over the experiment was 0.6 ± 0.3 kg for DHA and −0.1 ± 0.3 kg for PL (p = 0.102).
Seventy percent of the DHA and 30% of the PL subjects correctly guessed their treatment. In the DHA group, 8 of 20 subjects reported experiencing a fish-like aftertaste, but no other symptoms or adverse effects were reported. The DHA and PL group consumed 164 ± 4 and 164 ± 5 pills, respectively, of a total of 176 pills. Serum DHA increased by 380% over the supplementation period for the DHA group but did not change for the PL group (p < 0.0001) (Figure 2).
Muscle Function Response to Exercise
Isometric muscle strength and ROM were lowest 24 hours after and DOMS 48 hours after the eccentric exercise (Figure 3). The type of supplement had no effect on the reduction in STR either acutely or over the full exercise period. Differences in ROM between treatments, whether analyzed by ANOVA or AUC, were not significant for either the acute phase or the entire exercise period. During the acute phase, there was no significant effect of treatment on DOMS (p = 0.194 for AUC). Delayed onset muscle soreness response over the full resistance exercise period (days 1–17) was 182 ± 96.2 in the DHA group and 203.2 ± 120.9 in the PL group (p = 0.054).
Blood Markers Response
Docosahexaenoic acid significantly (p = 0.048) reduced the overall serum CK response during the acute phase after the eccentric exercise with post hoc analysis detecting a lower serum CK for DHA compared with PL on day 4 (p ≤ 0.05) (Figure 4). Examining the entire resistance exercise period, serum CK peaked on day 7 and was still 29% elevated on day 12 but was not different between treatments (p = 0.092).
Area under the curve for serum IL-6 was significantly lower for the DHA group (p = 0.046) during the acute phase (3.6 and 5.3 pg·ml−1 for DHA and PL, respectively) (Figure 5). Serum IL-1ra was not influenced by treatment (averages of 335.5, 298.6, 309.1 and 480.4, 454.0, 465.7 pg·ml−1 for DHA and PL on days 1, 2, and 4, respectively, p = 0.886).
Serum CRP was not affected by exercise or by treatment during the acute phase whether analyzed by ANOVA or AUC (Figure 4). When the full resistance training period was analyzed, there was a significant effect of exercise for serum CRP (p = 0.002), with concentrations peaking and significantly greater than baseline on day 7. There were no significant effects of the supplement on serum CRP response.
The purpose of this investigation was to examine whether DHA ingestion influenced the response of indicators of muscle damage and inflammation to acute eccentric exercise followed by initiation of a resistance training program. This study was unique in that it used an exercise protocol more in line with that actually performed by individuals beginning training and continued beyond a single exercise bout to the first few weeks of a resistance training program. The magnitude and pattern of approximately 41% maximum drop in isometric strength and approximately 24% in ROM 1 day and DOMS of ∼47 mm (of 100) 2 days after the eccentric exercise bout is consistent with studies using similar eccentric elbow contractions protocols (1,4).
Although the repeated bout effect predicts a muted damage response after a second eccentric bout, few studies have monitored muscle damage markers beyond 2 bouts. Jówko et al. (12) observed that serum CK increased over 5-fold at the end of the second week of a resistance training program and fell to be 2-fold over initial on the third week of the resistance training program. Nissen et al. (16) noted a peak in serum CK of 15,868 U/L after 1 week of resistance training that fell dramatically after 2 weeks. Our study showed peak concentrations after 1 week with substantial reduction by the second week of training to be near baseline levels. Taken together, these studies suggest that initiation of a resistance training program causes damage that peaks after about 1 week and declines as training continues.
The connection between the inflammatory response and recovery from muscle damage is complex and controversial. The balance between beneficial and damaging effects of the inflammatory response may depend on magnitude of the inflammatory stimulus (i.e., damage), the duration of the elevation of the inflammatory factors, and the subject population. Evidence for the role of inflammation in repair comes from studies using drug inhibitors of the COX enzyme such as nonsteroidal anti-inflammatory drugs (NSAIDs). Some studies demonstrate a reduction in exercise-induced muscle damage and enhanced recovery with the use of these anti-inflammatory drugs (9,24), whereas others see no effect (18,21) or an impairment (25).
Omega-3 fatty acids have anti-inflammatory potential for clinical conditions such as arthritis, Crohn's disease, and asthma (27). However, few studies have investigated the anti-inflammatory potential of this compound in athletes, particularly those performing resistance training. In this study, 28 days of DHA consumption dampened the magnitude of the acute serum CK and IL-6 response to damaging resistance exercise suggesting less myofibrillar disturbance and a lower inflammatory response. Although changes in these 2 markers of damage and inflammation, respectively, were reduced, other markers of muscle damage including muscle function were not affected by the supplement.
The dissociation between serum CK and muscle function markers of damage has been observed by others. Bloomer et al. (1) suggested that the antioxidant supplement they studied reduced serum CK through altered stability of the cell membrane allowing reduced leakage of CK without influencing sarcomere disruption. Since DHA is incorporated into cell membrane phospholipids with subsequent effects on membrane fluidity (2), it cannot be eliminated that the effect of DHA on CK and IL-6 in our study was due to a change in membrane permeability rather than muscle damage.
Several other studies have tested the effects of ingestion of omega-3 fatty acids on muscle damage and inflammation after eccentric exercise. For example, Phillips et al. (19) observed no effect of 7 days of ingestion of a multi-ingredient dietary supplement with 800 mg of DHA on markers of muscle damage after eccentric exercise. In a different study, the same duration of supplementation with a larger dose of omega-3 fat (3 g) attenuated the muscle soreness perception in subjects 48 hours after performing eccentric biceps extensions (11). Lenn et al. (14) used a longer supplementation period of 30 days with a dose of omega-3 fats similar to ours (1.8 g·d−1) before the eccentric exercise bout. Isometric strength was reduced after eccentric exercise but was not different in those who ingested the PL. It is worth noting that the serum CK and muscle strength reduction response, in that study (14), were substantially lower than we observed suggesting the protocol did not produce extensive damage. Another study using 30 days of low-dose EPA and DHA supplementation detected a reduction in several blood indicators of muscle damage after an eccentric bench stepping exercise bout (23). Thus, 2 of the 4 previously published studies plus ours observed that ingestion of omega-3 fatty acids reduced muscle damage indicators after eccentric exercise.
Compatible with the evidence that omega-3 fatty acids may influence skeletal muscle damage, fish oil (8,29) and DHA (20) have been shown to reduce damage of cardiac cells after ischemia assault. Specifically, omega-3 fat ingestion or infusion caused less myocardial dysfunction (20,26), release of CK after myocardial ischemia and reperfusion (8,20), infiltration of immune cells (8), and infarct size (20) in rats subjected to the damaging effects of ischemia compared with control rats. Interestingly, this protective effect of omega-3 fat infusion on serum CK has been further observed in human patients after the damage caused by coronary artery bypass surgery (26). Exploration of the mechanism for this protective effect of omega-3 fat ingestion on myocardial cell damage showed that DHA modified Notch signaling (20). Since Notch signals regulate cell differentiation, proliferation, and apoptosis signals that occur between adjacent cells through lipid or protein components of the cell membrane, this could affect muscle damage. Although these studies have used cardiac muscle rather than skeletal muscle, the observations that omega-3 fats (and specifically DHA) influenced muscle damage and mobilization of the immune system are intriguing and compatible with our findings of lower serum CK in the immediate days after eccentric exercise.
Three of the 4 previous studies examining the effect of omega-3 fatty acids after eccentric exercise assessed inflammation; 2 of these 3 investigative groups reported that these fatty acids reduced the inflammatory response to exercise. Phillips et al. (19) and Tartibian et al. (23) observed a lower elevation in IL-6 after exercise in those who consumed the supplement that contained DHA. Only Lenn et al. (14) failed to observe a difference in the IL-6 response to eccentric exercise over the 24 hours they measured. Since the values reported for IL-6 from that study were 235% different among groups at baseline, this may have impacted the likelihood of detecting a difference between groups.
Although we did not do invasive measures to determine the potential mechanism for a reduction in IL-6 response, other research demonstrates that higher cellular omega-3 fat content reduces production of inflammatory factors through substrate competition for COX enzymes and through nuclear binding of PPAR and NF-KB (2,27). Also, if muscle damage were reduced, as suggested by the lower serum CK, this could reduce the stimulation for an inflammatory response.
The potential value of muting the inflammatory response was suggested by the work of Lee and Clarkson (13) with the observation that those subjects who had lower increases in plasma CK after eccentric exercise had a more rapid return of muscle strength. This suggests that moderating the damage response through a dietary intervention may enhance the rate of muscle recovery.
In conclusion, DHA treatment reduced the acute serum CK and IL-6 responses to eccentric exercise compared with PL. Although the differences we observed are supportive of a reduction in muscle damage and inflammation from DHA ingestion, the lack of a fully consistent effect on other markers of damage and inflammation indicates that additional research is justified. Additionally, more invasive research would be useful to verify an effect of DHA on muscle damage.
Novel eccentric muscle contractions as part of resistance exercise cause muscle damage, reduction in muscle function, and a stimulation of the inflammatory response. Some research demonstrates a more rapid return of muscle function when damage, as indicated by serum CK, is blunted. Since infiltration of inflammatory cells can increase secondary damage, various pharmaceutical and dietary interventions have been studied regarding their ability to reduce damage and/or dampen inflammation after eccentric exercise. This study in combination with previous research suggests that the omega-3 fat, DHA, can reduce several markers of inflammation and muscle damage without influencing the acute recovery of isometric strength after damaging resistance exercise in young adult-untrained men. Additional research is required to determine whether these effects also occur in trained individuals or women. Longer term training studies would be useful to determine whether this reduction in inflammatory response and more rapid reduction in an indicator of muscle damage results in superior lean tissue gain during resistance training.
The authors would like to thank Martek Biosciences Corporation, Columbia, MD (now part of DSM, Parsippany, NJ) for providing the supplements and funding for the study. J. W. Rankin designed the study, supervised data collection, and lead the interpretation and writing of the article, whereas F. M. DiLorenzo and C. J. Drager recruited subjects, collected the data, analyzed the data, and contributed to interpretation and writing of the article. The authors appreciate the help of our research assistants and volunteer subject as well as Dr. Ben Corl of the Dairy Science Department, for his assistance in the serum fatty acid analysis. The authors thank the Department of Recreational Sports for allowing the use of their resistance training facilities. The authors do not have conflict of interest related to this study.
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