Dietary fish oil (FO) supplementation alters myocardial membrane fatty acid composition1,2 and modifies heart function in animals, providing direct antiarrhythmic effects2-4 and improved pumping performance.5,6 In addition, FO reduces myocardial O2 consumption without any decrement in cardiac work, indicating an increase in cardiac energy efficiency.6 In humans, the direct effects of dietary FO in the myocardium prevent fatal arrhythmia7,8 and reduce resting heart rate.9,10 A small but consistent reduction in heart rate has recently been distilled from many clinical trials through meta-analysis11 and indirectly supports the notion that myocardial oxygen consumption is decreased when fish is present in the diet. In view of the influential role of long-chain omega-3 polyunsaturated fatty acid (PUFA), which is found primarily in marine oils, in modifying cardiac function in disease states and preventing or treating cardiovascular disease, it is likely that they may play an important role in the healthy heart, including modifying myocardial O2 demand during aerobic exercise.
Erythrocyte membrane content of the omega-3 PUFA eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) is a known marker as a risk factor for cardiovascular disease being reflective of myocardial membrane composition.12,13 Dietary fats are also reflected in skeletal muscle membrane fatty acid composition.1,14,15 Compared with many other organs, both heart and skeletal muscle membranes incorporate high levels of DHA with FO feeding.1,15 Increased DHA levels in skeletal muscle membrane modifies muscle function, increasing insulin sensitivity16 and possibly substrate preference.17 To our knowledge, there has been no published work that investigates if changes in membrane fatty acid composition are associated with altered skeletal muscle O2 consumption as previously seen in the heart.6
It was the premise of this study that dietary FO may have direct effects on human heart function in well-trained men to enhance cardiac energy efficiency during exercise and in addition possibly enhance efficiency of oxygen use in exercising skeletal muscle.
SUBJECTS AND METHODS
Twenty healthy, well-trained male cyclists were recruited and 16 completed the dietary trial. Two subjects were eliminated from the study when their training patterns changed during the study and 2 subjects withdrew due to injury unrelated to the study. Cyclists were the subjects of choice due to their extended periods of steady-state training and the specificity of the cycle ergometer to this population. Furthermore, the highly trained characteristics of this group ensured central cardiovascular limitation rather than peripheral muscular fatigue during peak O2 consumption testing. The study was approved by the University of Wollongong's Human Research Ethics Committee. All subjects completed an informed consent.
Subjects were randomly allocated in a double-blind manner to 2 groups and supplemented with 8 × 1 g capsules per day of either olive oil (control) or omega-3 PUFA-rich tuna FO (Nu-mega; Clover Corporation, Sydney, Australia) for 8 weeks. Some anthropometric characteristics of those completing the trial were as follows-control: age 27.1 ± 2.7 years, height 177.3 ± 1.3 cm, weight: 75.2 ± 2.9 kg, skinfolds (sum of 7) 45.1 ± 1.4 mm; FO: age 23.2 ± 1.2 years, height 176.5 ± 1.6 cm, weight 69.3 ± 1.9 kg, skinfolds 51.8 ± 2.3 mm. The relative composition of fatty acids in the capsules was quantified using gas chromatography (Table 1). For the FO group, this provided 3.2 g of omega-3 PUFA per day (0.8 g of EPA and 2.4 g of DHA). Compliance was verified through capsule count and red blood cell fatty acid analysis.
To limit the influences of training variation, dietary supplementation and testing took place during a noncompetitive period of the Australian cycle calendar. All subjects were asked to provide records of their training, specifically their resting morning heart rate and the duration, in minutes, spent at particular training heart rates (as indicated by their personal heart rate monitors). A mean weekly training impulse (TI) representing intensity and duration of training was calculated according to the following formula.18
where duration = time spent in steady-state exercise, HRex = exercise heart rate during training, HRrest = resting heart rate, and HRmax = maximum heart rate recorded in the laboratory.
Peak O2 consumption tests were conducted before and after 8 weeks of supplementation, each followed by a sustained submaximal cycling test to exhaustion 1 week later. Subjects refrained from high-intensity cycling for 48 hours before testing. They were instructed to arrive at the laboratory on each testing day in a euhydrated (20 mL of fluid/kg of body weight) and fed state (2 g of carbohydrates/kg of body weight). Environmental room conditions were maintained at 18-20°C and 45%-55% relative humidity.
An electronically braked cycle ergometer (Lode Ergo, Groningen, The Netherlands) was used for exercise testing. Heart rate was recorded using a heart rate monitor (Polar, NY, USA). Respiratory data were collected using the SensorMedics Gas Analysis System (2900c; SensorMedics Corporation, Yorba Linda, CA, USA) over a 20 second rolling average. Ratings of perceived exertion were made using the 15-point Borg scale.19 Systolic blood pressure was recorded using the automatic oscillometric DINAMAP Vital Signs Monitor (Johnson and Johnson Pty Ltd, North Ryde, Sydney). To reduce operator error, all measurements of blood pressure during exercise were taken on the subject's left arm by the same person. Subjects were asked to relax the arm in a vertical plane next to their body.
Peak Oxygen Consumption Test
Subjects commenced with a 10-minute warm-up period at a workload of 150 watts. The workload was incremented by 2 watts every 3 seconds until a workload was reached at which the subject could not maintain a peddling cadence greater than or equal to 40 rpm. This point was defined as voluntary exhaustion. Peak O2 consumption, peak workload, submaximal heart rates and peak heart rate, and submaximal ratings of whole-body perceived exertion were assessed. Blood pressure was not recorded during this test due to the demanding nature of the exercise and the likely interference with performance. The peak O2 consumption test was repeated after dietary supplementation.
Submaximal Cycling Test
Workload for the submaximal exercise test was set at 55% of the peak workload derived from the presupplementation peak O2 consumption test. This same absolute workload was used after supplementation, allowing a direct comparison to be made for pre- to postsupplementation measurements of whole-body O2 consumption, heart rate, and systolic blood pressure. Subjects were instructed to continue to cycle until voluntary exhaustion. Pilot testing in our laboratory indicated that this level of steady-state work could be maintained for at least 60 minutes, thus ensuring that all tests represented prolonged steady-state exercise. Subjects consumed water ad libitum throughout the tests and cycled to voluntary exhaustion.
All data were collected for the first 60 minutes of submaximal exercise and during the final minutes before voluntary exhaustion. Heart rate was collected continuously (averaged over 5 seconds). Systolic blood pressure, respiratory data, and ratings of perceived exertion were taken every 10 minutes, and the rate pressure product (RPP) (product of the systolic blood pressure and heart rate) was calculated.
Fatty Acid Analysis
Omega-3 PUFA level in red blood cell membranes was used as a marker of general tissue omega-3 PUFA uptake after dietary supplementation.12,13,20 Before and after supplementation, blood samples were collected from the median cubital vein into ethylenediaminetetraacetic acid and stored on ice until separation. Cells were sedimented by centrifugation at 4°C, plasma was removed and frozen, buffy coat was removed, and the red blood cells were stored at −80°C.
For analysis, red blood cells were thawed on ice, lysed in 10 mL of Tris buffer (10 mM, pH = 7.4), and centrifuged at 4°C to separate red cell membranes. Membrane fatty acids were directly transesterified to produce methyl esters.21 The relative proportions of fatty acids incorporated into the red blood cell membranes were analyzed by flame ionization gas chromatography (Shimadzu GC-17A, 30 m × 0.25-mm internal diameter capillary column). Fatty acids were identified by comparison with known standards and reported as relative percent by weight.
Values are presented as mean ± SEM. A 2-way analysis of variance with repeated measures was used to detect significance between groups over time pre- and postsupplementation and within groups as an effect of supplementation. Differences between individual means, within and between dietary groups, were further analyzed by post hoc Bonferroni analysis. Statistical significance was accepted at P < 0.05 level. Statistical analysis was performed using Statistix for Windows (Analytical Software, Tallahassee, FL, USA).
There was no significant difference in fish consumption between the groups before dietary supplementation (control: 3.3 ± 0.3, FO: 2.8 ± 0.3 fish meals per month). The mean TI per week was consistent within groups during the 8 weeks of supplementation (data not shown), and there was no significant difference between dietary groups (control: 512 ± 26, FO: 462 ± 99 TI/week).
Red Blood Cell Membrane Fatty Acids
There were no significant differences in red blood cell fatty acid composition before supplementation. There were no changes in fatty acid composition after control supplementation. After FO supplementation, there were significant increases in membrane fatty acid levels of DHA (22:6n-3), the sum of PUFA and the sum of omega-3 PUFA (P < 0.05) (Table 2). The FO supplementation produced no change in the polyunsaturated/saturated (P:S) ratio (control: pre 1.05, post 1.06; FO: pre 1.02, post 1.07) but significantly decreased the (n-6)/(n-3) ratio (control: pre 1.48, post 1.44, FO: pre 1.6, post 1.17) (P < 0.05).
Peak Oxygen Consumption Test
There were no differences in peak O2 consumption or peak workload between groups before or after supplementation or within groups after supplementation (Table 3). Heart rate increased with increasing workload during the test. There was no significant difference in peak heart rate between control and FO groups before supplementation (Table 3). The heart rate response during increasing workload was not different after control supplementation; however, after the FO supplementation, the heart rate was significantly lower during increasing workload (P < 0.001), and a significant decrease in peak heart rate was seen within the FO group after supplementation (P < 0.05) (Fig. 1). Supplementation had no effect on ratings of perceived exertion (legs, chest, and whole body), reported at 4 submaximal workloads (data not shown).
Submaximal Cycling Test
There was no significant difference during the first 60 minutes of the test in mean whole-body submaximal O2 consumption between groups before supplementation (control: pre 49.2 ± 2.0; FO: pre 51.1 ± 1.1 mL kg−1 min−1). Whole-body O2 consumption in the control group was not significantly different after supplementation. Whole-body O2 consumption during exercise was reduced in the FO group, and the change was significantly different from that in the control group (P < 0.01) (Fig. 2). There was no significant difference in mean respiratory exchange ratio between groups before supplementation or within groups after supplementation (control: pre 0.91 ± 0.02, post 0.91 ± 0.03; FO: pre 0.92 ± 0.02, post 0.92 ± 0.03).
The FO group had significantly lower heart rate throughout sustained submaximal exercise (P < 0.01) after supplementation compared with before supplementation (Fig. 3). This reduction was such that the mean heart rate of the FO group over the entire exercise period was significantly lower than that of the control group after supplementation (P < 0.05) (Table 4). Systolic blood pressure showed no significant change with supplementation (data not shown).
The RPP (heart rate × systolic blood pressure) during the first 60 minutes of sustained submaximal exercise and the mean of the entire submaximal exercise trial were significantly lower after FO supplementation (Fig. 4), and the mean change over time was significantly different from that in the control group (P < 0.01) (Fig. 4). Table 4 shows absolute RPPs. The FO group approached significantly lower absolute values compared with the control group after supplementation (P = 0.08). There were no differences between groups in time to fatigue before or after supplementation and no significant differences after supplementation within groups (Table 4).
Ratings of perceived exertion (RPE) (legs, chest, and whole body) were significantly higher in the FO group before supplementation but were not significantly different afterward. Both groups reported changes in RPE; however, within the FO group, there were significantly larger RPE changes reported overtime for chest and whole body (P < 0.01), and this approached significance for legs (P = 0.07) (data not shown).
After dietary FO supplementation, already well-trained athletes exhibited lower heart rates throughout exercise across a wide range of workloads, with no change in peak oxygen consumption or peak workload. The heart rate, RPP, and whole-body O2 consumption were also reduced throughout 60 minutes of sustained submaximal exercise after FO supplementation. Thus, the present study indicates that efficiency of O2 use by the heart and skeletal muscle is increased after FO supplementation in humans as it is in rat hearts.6,22
Dietary supplementation with FO increased the incorporation of omega-3 PUFA into red blood cells to a level exceeding that observed with long-term habitual intake of 0.5 g/d.23 Such habitual intake and accompanying red cell omega-3 PUFA levels are associated with reduced relative risk of primary (arrhythmic) cardiac arrest. The antiarrhythmic effects of FO have been linked to direct effects in the heart,2,4,24,25 dependent on myocardial membrane incorporation of omega-3 fatty acids, especially DHA. Myocardial membrane omega-3 PUFA composition is strongly associated with red cell membrane composition in both humans and animals.12,13,15 Myocardial cells incorporate higher levels of omega-3 fatty acids than do red blood cells15,24 or serum phospholipids.26 Thus, the increase in red blood cell incorporation in cyclists not only confirmed compliance to the supplementation regimen but may be also indicative of even greater incorporation into skeletal muscle and myocardial membranes. Human skeletal muscle incorporates increased omega-3 PUFA with FO consumption,27 and several studies have shown that physical training itself is associated with increased human skeletal muscle omega-3 PUFA content independent of diet.28,29 The DHA content correlates with the muscle content of type I, slow oxidative fibers,29 which are more efficient in their use of oxygen, are fatigue resistant, and display higher insulin sensitivity.28,29 The hypothesis that FO supplementation could lead to altered cardiac or skeletal muscle energy efficiency was dependent on changes occurring in their membrane omega-3 PUFA composition. The observed changes in red blood cell membrane composition suggest that such changes were achieved. Importantly, in all these young well-trained subjects, whether supplemented with FO or not, the erythrocyte omega-3 index (sum of EPA + DHA) was above the low levels proposed to represent heightened risk of cardiac disease and above the minimum levels associated with cardioprotection.12,13
Previously, a study reported that peak O2 consumption was increased after FO feeding.30 The results of the current investigation do not concur with this finding. In fact, no change in peak O2 consumption is consistent with 2 later studies also showing effect of FO supplementation.31,32 Importantly, the present investigation used cyclists during a controlled stage of their training season, with peak O2 consumption indicative of well-trained individuals.33 This reduced the possibility of changes in peak O2 consumption occurring as an artifact of training, which could not be ruled out in the earliest study.30 Furthermore, all subjects in the present investigation were familiar with and highly competent in using the cycle ergometer, as the testing method, unlike the soccer players in an earlier investigation.32
FO supplementation reduces resting heart rate in humans11 not unlike the low resting34 and exercising heart rates35 associated with regular physical training. Although higher parasympathetic activity is in part responsible for the lower resting heart rates of trained athletes,34 intrinsic beat rate may also be reduced, which may be attributable to altered myocardial cell metabolism leading to more efficient energy generation or utilization.35 Studies of the isolated spontaneously beating heart show that FO can indeed reduce intrinsic heart rate2 and increase cardiac energy efficiency when the heart is paced at a constant rate.6 Skeletal muscle cellular metabolism is also altered with exercise.36 In humans, myocardial O2 consumption correlates strongly with heart rate but most strongly with the product of heart rate and aortic systolic pressure (also termed the index of cardiac effort).37 In FO-supplemented subjects, the lower heart rate and RPP observed throughout both peak and submaximal exercise in this study suggest that myocardial O2 consumption was reduced.
An additional, often small but consistent, effect of FO is to reduce resting heart rate in humans38 and rats.5,39 Regular fish consumption or erythrocyte DHA levels indicative of fish intake were associated with slowed heart rate at rest in a large epidemiological study of untrained adult males9 and in both stand-alone studies10,40 and distilled meta-analysis of randomized controlled dietary supplementation trials.11 In addition, heart rate is reduced in association with omega-3 PUFA supplementation not only in rat isolated spontaneously beating hearts2 but also in cardiac transplant patients in the absence of vagal tone, which excludes a neurogenic mechanism.41 Furthermore, reduction in postexercise recovery heart rate in this patient group is also improved after FO supplementation.42 The reduction in heart rate during exercise has been found in trained horses across a range of treadmill speeds43 in a manner very similar to the present study using trained cyclists. A slowed heart rate and associated prolonged cardiac diastole would provide more time per minute for coronary artery perfusion and myocardial oxygenation. Moreover, with heart rate proposed as a risk factor for cardiovascular mortality,44 its association with risk of death or hospitalization in patients with heart failure45 provides further links to omega-3 PUFA. For in addition to reducing heart rate,11 FO supplementation reduces mortality in patients with heart failure46 and fish consumption is associated with lower primary incidence of heart failure.47 The slowed heart rate and improved oxygen efficiency together with the reduced exercise-induced muscle damage and inflammation associated with omega-3 PUFA48 may also be important modulators of heart fatigue and even damage that is suggested to occur during extended exercise.49
The reduced whole-body O2 consumption seen after FO supplementation may reflect reduced (more efficient) use of O2 by active skeletal muscle (the largest consumer of oxygen during exercise). Skeletal muscle shares the capacity of cardiac tissue to avidly incorporate omega-3 PUFA, particularly DHA, well above circulating levels.1,15 In animals and humans, unsaturation of skeletal muscle membrane increases insulin sensitivity16,28,29 and results in an increased ability of skeletal muscle cells to take up glucose, which might be expected to maintain contractile performance. Long-chain omega-3 PUFA can also shift substrate preference to glucose in skeletal muscle,17 and because energy derived from the breakdown of 1 mole of glucose requires less O2 than the equivalent amount derived from fat,50 this may explain the reduced whole-body O2 consumption. However, the unchanged respiratory exchange ratio is contradictory. Alternatively, FO has been shown to improve calcium handling in the heart and reduce O2 consumption attributed to excessive sarcoplasmic reticulum calcium cycling.6 The sarcoplasmic reticulum membrane also avidly incorporates DHA when FO is present in the diet.51 Human skeletal muscle has been calculated to use up to 37% of energy in the Ca++ cycling of activation and relaxation.52 Improved calcium handling by skeletal muscle sarcoplasmic reticulum with FO supplementation could be a factor contributing to reduced O2 demand of contracting skeletal muscle as in the heart.25
Despite requiring the subjects to cycle submaximally until voluntary fatigue, this study did not attempt to link FO supplementation to altered exercise performance. Time to fatigue as used in the present study carries a high degree of within-subject variability and therefore is considered a weak performance indicator,53 and a more suitable indicator such as the cycling time trial would be better indicator of fatigue during endurance performance.54,55 However, it is unlikely that the FO-induced improved oxygen efficiency could lead to measurable improvement in endurance performance because this type of exercise is not entirely oxygen limited56 and elite performance is multifactorial in nature.57
This study showed that supplementing healthy well-trained male subjects with FO over 8 weeks significantly lowered heart rate, RPP, and whole-body O2 consumption during exercise. Importantly, the peak levels of whole-body O2 consumption and workload were not influenced, despite the reduced peak heart rate. These results confirmed that FO supplementation reduces myocardial O2 demand during exercise. Furthermore, there is evidence that skeletal muscle O2 consumption is also reduced after FO supplementation.
We sincerely thank Clover Corporation, Sydney, Australia, for the donation of the Nu-Mega high-DHA tuna fish oil capsules and olive oil control capsules used in this study.
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