1183
BRIEF COMMUNICATION Effect of resveratrol on exercise capacity: a randomized placebo-controlled crossover pilot study Nha Voduc, Charles la Porte, Caroline Tessier, Ranjeeta Mallick, and D. William Cameron
Abstract: To assess the effect on exercise capacity and tolerability of resveratrol, 13 healthy, sedentary adult volunteers were enrolled in a randomized crossover study comparing resveratrol and placebo over two 4-week periods, with a 2-week time between periods when subjects received no treatment. No significant changes in exercise duration or aerobic capacity (peak oxygen uptake) were observed. Gastrointestinal side effects were more common during resveratrol treatment (77% vs. 15%, p = 0.0048). A small reduction in fasting glucose and small but statistically significant increases in liver enzymes, total cholesterol, and triglycerides were observed, although mean results remained within normal limits. There was no change in complete blood count, inflammatory markers, renal function, or other measures of liver function. Key words: resveratrol, exercise capacity, safety, tolerability. Résumé : Pour évaluer l’effet du resvératrol sur la tolérabilité et la capacité physique, treize adultes sédentaires en bonne santé se portent volontaires dans une étude croisée aléatoire pour comparer le resvératrol a` un placebo au cours de deux périodes de 4 semaines intercalées de 2 semaines lorsque les sujets ne reçoivent aucun traitement. On n’observe pas de différence significative de durée d’effort et de puissance aérobie (consommation d’oxygène de pointe). On souligne des malaises gastrointestinaux plus fréquents durant le traitement au resvératrol (77 % vs 15 %, p = 0,0048). On observe une légère diminution du glucose a` jeun et une légère augmentation significative des enzymes hépatiques, du cholestérol total et des triglycérides, mais les moyennes des résultats s’inscrivent en-deça` des valeurs normales. Il n’y a pas de modification de l’hémogramme, des marqueurs inflammatoires, de la fonction rénale et d’autres variables de la fonction hépatique. [Traduit par la Rédaction] Mots-clés : resvératrol, capacité physique, sécurité, tolérabilité.
Introduction
Materials and methods
Resveratrol is a naturally occurring substance found in certain foods, including grapes and red wine. Preliminary laboratory and animal experiments have suggested that resveratrol could have a broad range of health benefits, including anti-inflammatory, cardioprotective, chemopreventative, and neuroprotective effects (Vang et al. 2011). Recently, human studies have suggested beneficial metabolic effects (Crandall et al. 2012; Timmers et al. 2011) and anti-inflammatory effects (Tomé-Carneiro et al. 2012) with resveratrol supplementation but the majority of health benefits found in animal studies have yet to be replicated in human subjects. Rodents given resveratrol supplements significantly increased their aerobic capacity, resistance to fatigue, exercise time, muscle strength, and muscle fibre oxygen consumption (Lagouge et al. 2006; Murase et al. 2009; Dolinsky et al. 2012; Hart et al. 2013; Wu et al. 2013), although these benefits have not yet been demonstrated in humans (Malaguti et al. 2013). We designed this pilot study to assess the tolerability of resveratrol and the effects of resveratrol supplementation on exercise performance in healthy sedentary adults.
For a comprehensive description of study methods and full study results, please refer to the supplementary material file1. Ethics statement The study protocol and methodology were reviewed and approved by the Ottawa Hospital Research Ethics Board (protocol no. 2008540-01H). The study protocol and risks were discussed with all participants prior to enrolment and written consent was obtained. Design We conducted a randomized, phase II, placebo-controlled, doubleblind parallel 2-arm, 2-period crossover trial, with a 2-week washout period, which is a period of time when subjects received no treatment, and crossover, for assessment of tolerance, safety, and clinical effects of oral resveratrol versus placebo in healthy sedentary adults. Participants This study enrolled healthy, sedentary adults between the ages of 18–65 years. Potential participants were screened (on visit 1)
Received 27 November 2013. Accepted 20 April 2014. N. Voduc. Department of Medicine, Division of Respirology, University of Ottawa at The Ottawa Hospital, General Campus, 501 Smyth Road, Box 211, Ottawa, ON K1H 8L6, Canada. C. la Porte.* Molecular Medicine, Department of Medicine, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. C. Tessier. The Ottawa Hospital Pulmonary Function Lab/Bronchoscopy, The Ottawa Hospital, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. R. Mallick. Ottawa Hospital Research Institute, The Ottawa Hospital, General Campus, 501 Smyth Road, Office # L1213B, Ottawa, ON K1H 8L6, Canada. D.W. Cameron. Department of Medicine, Division of Infectious Diseases, University of Ottawa at The Ottawa Hospital, General Campus, 501 Smyth Road, Box 228, Ottawa, ON K1H 8L6, Canada. Corresponding author: Nha Voduc (e-mail: [email protected]). *Present address: Janssen-Cilag BV, Dr. Paul Janssenweg 150, Tilburg, the Netherlands. 1Supplementary data are available with the article through the journal Web site at http://nrcresearchpress.com/doi/suppl/10.1139/apnm-2013-0547. Appl. Physiol. Nutr. Metab. 39: 1183–1187 (2014) dx.doi.org/10.1139/apnm-2013-0547
Published at www.nrcresearchpress.com/apnm on 30 April 2014.
1184
with the help of a questionnaire, physical examination, fasting laboratory tests, pulmonary function tests, and an incremental exercise test (visit 1, see supplementary Table S11). Exclusion criteria included the finding of any clinically significant abnormality, including pre-existing medical conditions that could potentially affect exercise capacity or ability to tolerate resveratrol. Participants with a body mass index of less than 20 kg/m2 or greater than 30 kg/m2 were excluded. Only sedentary adults were recruited to avoid any potential interaction between exercise training and resveratrol. All testing was performed at the General campus of the Ottawa Hospital, a tertiary care academic hospital that is affiliated with the University of Ottawa. Intervention The study intervention was resveratrol, administered orally twice daily, during one of two 4-week treatment periods. For the first week, resveratrol (Transmax (Biotivia, Arlington, Va., USA)) was administered at a dose of 500 mg bid. This was increased to 1000 mg bid for the remaining 3 weeks if tolerated by the patient. We had previously confirmed the bioavailability of Transmax in healthy subjects (la Porte et al. 2010). Outcomes The primary outcomes of interest were exercise capacity and tolerability of resveratrol. Assessment of exercise capacity All exercise testing was conducted at the pulmonary function laboratory of the Ottawa Hospital, using SensorMedics Vmax 229 Series metabolic cart. Exercise capacity was assessed via 2 methods: exercise duration on constant load exercise at 75% of maximum workload and peak oxygen uptake (V˙O2peak) attained on incremental exercise testing. V˙O2peak is highly reproducible and is a conventional measure of exercise capacity, although studies in patients with chronic obstructive pulmonary disease have suggested that exercise duration on constant-load exercise may be more responsive to therapeutic intervention (Oga et al. 2000). Because the reproducibility of constant-load exercise duration has not been well established in a healthy patient population, we chose to measure both in our study. During the initial screening (visit 1), subjects underwent an incremental exercise test. This was performed on an electronically braked cycle ergometer (Ergoline – ergometrics 800), using 20 W increments every 2 min. Exercise testing was symptom-limited (the subjects were encouraged to exercise until exhaustion). Seventy-five percent of the peak workload attained during the incremental exercise test was used as the workload for all future constant-load exercise tests. During visit 1, a “practice” constant-load exercise test was also performed. This practice test was used to familiarize the subject with the constantload protocol and reduce learning effects for subsequent tests O the data from the practice test was not analyzed. After visit 1, all subjects underwent 4 exercise testing sessions: 1 at the beginning and end of each treatment period (visits 2, 6, 7, and 11). To minimize variation, all exercise sessions were scheduled at the same time of day for all 4 visits. During each session, both constant-load and incremental testing was conducted, with a1-h rest period in between. Assessment of tolerance During the treatment periods, all subjects underwent weekly assessments and laboratory testing to assess tolerability of resveratrol. During each assessment, subjects were questioned specifically about any new symptoms and adverse events. Laboratory testing included complete blood count, renal function, liver function, electrolytes, urine analysis, prothrombin time, C-reactive protein, and erythrocyte sedimentation rate.
Appl. Physiol. Nutr. Metab. Vol. 39, 2014
Table 1. Baseline demographics, biochemistry, pulmonary function, and exercise performance. Variable
Baseline (mean±SD)
Age (y) Male Female Body mass index (kg/m2) Resting SBP (mm Hg) Resting DBP (mm Hg) FEV1 (% predicted) Total lung capacity (% predicted) Diffusing capacity (% predicted) Glucose (mmol/L) Creatinine (umol/L) ALT (U/L) AST (U/L) GGT (U/L) Cholesterol (mmol/L) Triglycerides (mmol/L) C-Reactive protein (mg/L) Incremental exercise V˙O2peak/kg (mL/(kg·min)) V˙O2peak (% predicted) Peak heart rate (% predicted) Peak ventilation (% predicted) Peak respiratory quotient Anaerobic threshold (% predicted V˙O2max)
42.7±9.4 6 6 25.0±2.3 119±19 69±9 94.3±10.1 97.0±8.8 82.8±6.2 5.3±1.3 82±16 26±8 16±5 17±9 4.5±0.8 1.1±0.4 2.1±2.6 26.3±5.8 76.2±13.1 99.6±4.8 63.9±13.5 1.17±0.07 47.8±8.9
Note: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; FEV1, forced expiratory volume in the first second of expiration; GGT, gamma-glutamyl transferase; SBP, systolic blood pressure; V˙O2max, maximal oxygen uptake; V˙O2peak, peak oxygen uptake.
Sample size A formal sample size calculation was not possible as there had been no prior studies evaluating the effects of resveratrol on exercise capacity in humans at the time our pilot study was designed. A convenience sample size of 12 participants was chosen for this pilot study. Randomization After eligibility was confirmed and informed consent obtained, all participants were randomly allocated to 1 of the 2 following groups, using a computer-generated variable-block randomization schedule. Allocation occurred after baseline testing on visit 2. Medications were dispensed by the study nurse. •
•
Group A (n = 6): Participants received resveratrol for 4 weeks, followed by no resveratrol for 2 weeks (washout period) and then placebo for twice daily for 4 weeks. Group B (n = 6): Participants received placebo daily for 4 weeks, followed by no placebo for 2 weeks and then resveratrol 4 weeks.
Blinding Physicians, research staff, and participants were blinded to the treatment allocation. The research pharmacist provided the medication/placebo to the research staff based on the randomization schedule. Study medication (resveratrol) and placebo were supplied to the patient in identical-appearing capsules. Statistical methods The baseline characteristics were summarized using the mean ± SD for continuous measurements (Table 1). For assessment of exercise capacity, data from patients who completed all exercise assessments was used. For each subject the difference in each variable (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc.; Table 2) was calculated under both the resveratrol and the placebo. To account for the fact that each patient received both the treatment and placebo, the Published by NRC Research Press
Voduc et al.
1185
Table 2. Comparison of resveratrol and placebo during treatment periods. Period 1 Variable Laboratory data ALT (U/L) AST (U/L) Cholesterol (mmol/L) Creatinine (umol/L) C-Reactive protein (mg/L) GGT (U/L) Glucose (mmol/L) Triglycerides (mmol/L) Exercise data Exercise duration (s) Heart rate (% predicted) Isotime heart rate (beats/min) Isotime RQ Isotime ventilation (L/min) Isotime V˙O2/kg (mL/(kg·min)) RQ Ventilation (% predicted) V˙O2peak/kg (mL/(kg·min)) V˙O2peak (% predicted) Anaerobic threshold (% predicted V˙O2max)
Period 2
Paired t test p value
Treatment
Start
End
Start
End
Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol
29.00 23.67 18.33 12.67 4.40 4.60 77.83 86.50 1.58 2.57 15.00 19.80 5.02 5.57 1.21 0.95
34.50 36.83 15.50 19.83 4.18 5.00 72.33 79.67 0.52 4.58 13.33 17.50 5.48 5.50 0.95 1.24
27.50 30.33 14.17 13.67 4.80 4.50 85.83 70.83 1.68 0.80 17.17 14.50 5.53 5.95 1.27 1.08
27.83 46.50 13.67 23.83 4.90 4.80 82.67 68.67 2.33 0.75 17.00 14.83 5.85 5.35 1.25 1.40
Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol
737.17 689.67 98.0 96.0 167.83 159.33 1.10 1.13 60.73 64.92 25.65 23.30 1.10 1.12 46.0 62.0 26.52 24.63 74.0 74.0 46.0 45.0
922.67 922.33 97.0 96.0 162.50 158.83 1.09 1.15 60.38 58.47 25.47 22.05 1.09 1.10 56.0 63.0 26.60 24.83 75.0 75.0 49.0 43.0
1006.50 777.33 98.0 95.0 160.17 162.50 1.12 1.10 61.80 61.58 24.47 25.37 1.12 1.12 68.0 59.0 26.92 26.50 81.0 75.0 50.0 51.0
905.17 753.50 97.0 96.0 159.00 163.67 1.09 1.11 68.42 64.47 26.15 25.77 1.06 1.13 64.0 60.0 27.65 26.35 84.0 75.0 48.0 47.0
0.035 0.0016 0.0155 0.9642 0.5556 0.7373 0.0302 0.0132
0.6745 0.2334 0.3415 0.194 0.2102 0.2973 0.0658 0.7358 0.8025 0.7081 0.6192
Note: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; RQ, respiratory quotient; V˙O2max, maximal oxygen uptake; V˙O2peak, peak oxygen uptake.
treatment and placebo differences per variable were compared using a paired t test (Table 2). To assess for a carryover effect, the observations at the beginning of each period for each variable were also compared using a paired t test (supplementary Table S21). For assessment of tolerance, an intent-to-treat approach was used. All analyses were conducted using the entire cohort of participants. The proportion of participants reporting side effects and (or) adverse events were compared between the 2 groups using the Fisher’s exact test. The frequency of each symptom was compared between the 2 treatment arms (supplementary Table S31).
Results
sequently, a thirteenth subject was enrolled to ensure that complete exercise data was available for 12 subjects. Six healthy men and 7 healthy women were enrolled. Mean age was 43 years (range 27–55 years) and mean body mass index was 25.0 kg/m2 (SD 2.3). Baseline patient data are presented in Table 1. Complete laboratory and exercise data for the 12 subjects with complete study data across treatment periods is presented in Table 2. Adverse event data from the subject who “dropped out” was still included in the analysis of tolerance (13 subjects in total). Patient compliance was confirmed with pill counts. Resveratrol and placebo capsules were assayed to confirm content.
Consenting participants were recruited from a list of healthy volunteers at the Clinical Investigation Unit of the Ottawa Hospital. A total of 25 adult volunteers were assessed between 2010 and 2011. Twelve did not meet inclusion criteria and did not undergo randomization (see supplementary Fig. S21 for participant flow diagram). We originally planned to enroll and randomize 12 patients. However, 1 subject developed a skin rash during the second treatment period and dropped out before her final exercise visit. Con-
Exercise responses Resveratrol did not have any significant effect on exercise capacity as reflected by changes in V˙O2peak during incremental exercise testing or exercise duration during constant-load exercise (Table 2). There were also no significant effects on other exercise parameters, such as heart rate, ventilation, peak respiratory quotient, or anaerobic threshold. Published by NRC Research Press
1186
Laboratory investigations Laboratory testing demonstrated small but statistically significant increases in AST, ALT, total cholesterol, and triglycerides at the end of the 4-week treatment period in patients receiving resveratrol (Table 2). Fasting glucose was also reduced by a mean of 0.7 mmol/L. None of these changes were felt to be clinically significant in any of the cases. There were no significant changes in other liver function tests, complete blood count, renal function, electrolytes, prothrombin time, C-reactive protein, or erythrocyte sedimentation rate. Exercise and laboratory test results obtained at the beginning of each treatment period were also compared in order to demonstrate stability of these variables between study periods. There was no significant difference in any of these measurements between periods (supplementary Table S21). Tolerance Overall, 12 of 13 subjects were able to tolerate resveratrol at the full dose of 2 g/day (1000 mg bid). Gastrointestinal complaints (diarrhea, nausea, cramping) were significantly more common with resveratrol than placebo (77% (10 of 13) vs. 15% (2 of 13), p = 0.005), although they were not severe enough to require medical attention or result in discontinuation of the medication in any of the cases (supplementary Table S31). Other adverse events include dermatological complaints (pruritus, rash) (1 subject from the placebo group and 1 subject from the resveratrol group), headache (2 subjects from the placebo group and 1 subject from the resveratrol group), and upper respiratory symptoms (1 subject from the placebo group and none from the resveratrol group). None of these events occurred more frequently during resveratrol treatment (no significant differences were observed). As mentioned above, 1 subject developed a pruritic rash that was resolved following discontinuation of resveratrol (supplementary Table S31).
Discussion We did not find any significant effect of resveratrol on exercise capacity or any other exercise parameters but did find that resveratrol was associated with small changes in laboratory measurements and minor gastrointestinal effects. The major limitations to this study are its small size and relatively short duration. A much larger and (or) longer study may detect a beneficial effect on exercise capacity. When our study was designed, there were no studies evaluating the effects of resveratrol in humans, thus a convenience sample of 12 was used to confirm tolerability. It can also be argued that the duration of the treatment period in our study (4 weeks) may be too short to allow for any beneficial effects on exercise capacity to appear. Given the limited tolerability data available at the time of our study design (2009), the duration of the treatment period our study was limited by our regulatory body, Health Canada, to 4 weeks. The mechanism of benefit of resveratrol on exercise capacity may be an augmentation of effects of exercise training. Many of the previous exercise studies demonstrating an improvement in exercise capacity in animals treated with resveratrol also included an exercise training component (Lagouge et al. 2006; Dolinsky et al. 2012) and it is possible that exercise training is required to obtain a benefit from resveratrol supplementation. A recent study has suggested that resveratrol may actually blunt training effects (Gliemann et al. 2013) although their conclusions have been challenged (Smoliga and Blanchard 2013; Buford and Anton 2014). For this pilot study, we did not include an exercise training component as we first wanted to assess the effects of resveratrol on exercise capacity in isolation, prior to conducting a more complicated study with an exercise training component. We did find that high-dose resveratrol supplementation is associated with gastrointestinal side effects in the majority of subjects. Similar side effects were observed previously at our centre
Appl. Physiol. Nutr. Metab. Vol. 39, 2014
(la Porte et al. 2010) and by other investigators (Chow et al. 2010; Brown et al. 2010; Howells et al. 2011), but the frequency of side effects in the present study was higher than reported in other studies. We do not have a definitive explanation for this. It may be partly due to the higher dose of resveratrol used in our study (for example Brown et al. did not observe gastrointestinal side effects at 1 g of resveratrol/day but did at ≥2.5 g/day). It is possible that the gastrointestinal side effects were related to the formulation of resveratrol we used. It should be emphasized that the side effects we observed were mild. No subject discontinued the study medication because of gastrointestinal symptoms. We also observed statistically significant but small elevations in liver enzymes, triglycerides, and total cholesterol. We felt that the observed elevations in liver enzymes were not clinically significant as the AST and ALT remained within normal limits for our laboratory and were not associated with changes in international normalized ratio or bilirubin. The impact of a longer treatment period on liver function is unknown. We did not find any beneficial effects on lipid profile or anti-inflammatory effect with resveratrol which is in contrast to the literature (Timmers et al. 2011; Tomé-Carneiro et al. 2012). In this study we did observe a small reduction in fasting glucose following resveratrol supplementation. The significance of this reduction is unknown. The treatment period was too short to affect longer term measurements of glucose control. Pollack and Crandall (2013) reported that in subjects with impaired glucose regulation, resveratrol shows modest, consistent benefit. Our study population was different than some of the other resveratrol studies (Timmers et al. 2011; Magyar et al. 2012). We excluded obese subjects as well as those with any significant medical conditions, including diabetes, cardiac disease, and dyslipidemia. Because our subjects did not have any major metabolic derangements, it may not be reasonable to detect a beneficial change in metabolic parameters that are already normal, as suggested by Smoliga et al. (2013). Pollack and Crandall (2013) have suggested that resveratrol’s effects may best observed under conditions of metabolic stress, such as insulin resistance or impaired glucose regulation. Taken together, the lack of effect on exercise performance and the statistically significant increases in triglycerides, cholesterol, and liver enzymes observed in our study would suggest that 4 weeks of 500–1000 mg bid resveratrol supplementation is not useful to improve exercise performance in healthy, nonobese patients. Future studies evaluating the effects of resveratrol on exercise capacity should include a component of exercise training and future studies evaluating the effects of resveratrol on metabolism may wish to focus on patients with pre-existing disease. Other information The trial is registered at ClinicalTrials.gov, no. NCT01615445, http:// clinicaltrials.gov/ct2/show/NCT01615445?term=RESVERATROL+ SUPPLEMENTATION&rank=1. Resveratrol capsules were provided by Biotivia (Biotivia.com). No individuals employed or contracted by the funders or Biotivia played any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Acknowledgements The authors would like to thank Ms. Rosalie Labelle and Ms. Katy Wedgwood for preparation and editing of this manuscript. The study was funded by the Ontario Thoracic Society block term grant (http://www.on.lung.ca/page.aspx?pid=567). Assistance with trial execution was received from the OHRI Clinical Investigation Unit. Salaries were partially supported by the University of Ottawa Department of Medicine. Published by NRC Research Press
Voduc et al.
References Brown, V.A., Patel, K.R., Viskaduraki, M., Crowell, J.A., Perloff, M., Booth, T.D., et al. 2010. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 70(22): 9003–9011. doi:10.1158/ 0008-5472.CAN-10-2364. PMID:20935227. Buford, T.W., and Anton, S.D. 2014. Resveratrol as a supplement to exercise training: friend or foe? J. Physiol. 592(3): 551–552. doi:10.1113/jphysiol.2013. 267922. PMID:24488074. Chow, H.-H.S., Garland, L.L., Hsu, C.-H., Vining, D.R., Chew, W.M., Miller, J.A., et al. 2010. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev. Res. (Phila), 3(9): 1168–1175. doi:10.1158/1940-6207.CAPR-09-0155. Crandall, J.P., Oram, V., Trandafirescu, G., Reid, M., Kishore, P., Hawkins, M., et al. 2012. Pilot study of resveratrol in older adults with impaired glucose tolerance. J. Gerontol. A Biol. Sci. Med. Sci. 67(12): 1307–1312. doi:10.1093/ gerona/glr235. PMID:22219517. Dolinsky, V.W., Jones, K.E., Sidhu, R.S., Haykowsky, M., Czubryt, M.P., Gordon, T., and Dyck, J.R.B. 2012. Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats. J. Physiol. 590(Pt 11): 2783– 2799. doi:10.1113/jphysiol.2012.230490. Gliemann, L., Schmidt, J.F., Olesen, J., Biensø, R.S., Peronard, S.L., Grandjean, S.U., et al. 2013. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J. Physiol. 591(Pt 20): 5047– 5059. doi:10.1113/jphysiol.2013.258061. Hart, N., Sarga, L., Csende, Z., Koltai, E., Koch, L.G., Britton, S.L., et al. 2013. Resveratrol enhances exercise training responses in rats selectively bred for high running performance. Food Chem Toxicol. 61: 53–59. doi:10.1016/j.fct. 2013.01.051. PMID:23422033. Howells, L.M., Berry, D.P., Elliott, P.J., Jacobsen, E.W., Hoffman, E., Hegarty, B., et al. 2011. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases-safety, pharmacokinetics and pharmacodynamics. Cancer Prev. Res. (Phila), 4: 1419–1425. doi:10. 1158/1940-6207.CAPR-11-0148. la Porte, C., Voduc, N., Zhang, G., Seguin, I., Tardiff, D., Singhal, N., and Cameron, W. 2010. Steady-state pharmacokinetics and tolerability of transresveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin. Pharmacokinet. 49(7): 449–454. doi:10.2165/ 11531820-000000000-00000. PMID:20528005. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., et al. 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1␣. Cell, 127(6): 1109– 1122. doi:10.1016/j.cell.2006.11.013. PMID:17112576. Magyar, K., Halmosi, R., Palfi, A., Feher, G., Czopf, L., Fulop, A., et al. 2012.
1187
Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin. Hemorheol. Microcirc. 50(3): 179–187. doi:10. 3233/CH-2011-1424. PMID:22240353. Malaguti, M., Angeloni, C., and Hrelia, S. 2013. Polyphenols in exercise performance and prevention of exercise-induced muscle damage. Oxidative Medicine and Cellular Longevity 2013, Article ID 825928. 9 pp. doi:10.1155/2013/ 825928. PMID:23983900. Murase, T., Haramizu, S., Ota, N., and Hase, T. 2009. Suppression of the agingassociated decline in physical performance by a combination of resveratrol intake and habitual exercise in senescence-accelerated mice. Biogerontology, 10(4): 423–434. doi:10.1007/s10522-008-9177-z. PMID:18830683. Oga, T., Nishimura, K., Tsukino, M., Hajiro, T., Ikeda, A., and Izumi, T. 2000. The effects of oxitropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. A comparison of three different exercise tests. Am. J. Respir. Crit. Care Med. 161(6): 1897–1901. doi:10.1164/ ajrccm.161.6.9905045. Pollack, R.M., and Crandall, J.P. 2013. Resveratrol: therapeutic potential for improving cardiometabolic health. Am. J. Hypertens. 26(11): 1260–1268. doi:10. 1093/ajh/hpt165. Smoliga, J.M., and Blanchard, O.L. 2013. Recent data do not provide evidence that resveratrol causes ‘mainly negative’ or ‘adverse’ effects on exercise training in humans. J. Physiol. 591(20): 5251–5252. doi:10.1113/jphysiol.2013.262956. PMID:24130323. Smoliga, J.M., Colombo, E.S., and Campen, M.J. 2013. A healthier approach to clinical trials evaluating resveratrol for primary prevention of age-related diseases in healthy populations. Aging, 5(7): 495–506. PMID:24073437. Timmers, S., Konings, E., Bilet, L., Houtkooper, R.H., van de Weijer, T., Goossens, G.H., et al. 2011. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14(5): 612–622. doi:10.1016/j.cmet.2011.10.002. PMID:22055504. Tomé-Carneiro, J., Gonzálvez, M., Larrosa, M., Yáñez-Gascón, M.J., García-Almagro, F.J., Ruiz-Ros, J.A., et al. 2012. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am. J. Cardiol. 110(3): 356–363. doi:10.1016/j.amjcard.2012.03.030. PMID: 22520621. Vang, O., Ahmad, N., Baile, C.A., Baur, J.A., Brown, K., Csiszar, A., et al. 2011. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLOS ONE, 6(6): e19881. doi:10.1371/journal.pone. 0019881. PMID:21698226. Wu, R.-E., Huang, W.-C., Liao, C.-C., Chang, Y.-K., Kan, N.-W., and Huang, C.-C. 2013. Resveratrol protects against physical fatigue and improves exercise performance in mice. Molecules, 18(4): 4689–4702. doi:10.3390/molecules18044689. PMID:23603951.
Published by NRC Research Press
Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
BRIEF COMMUNICATION Effect of resveratrol on exercise capacity: a randomized placebo-controlled crossover pilot study Nha Voduc, Charles la Porte, Caroline Tessier, Ranjeeta Mallick, and D. William Cameron
Abstract: To assess the effect on exercise capacity and tolerability of resveratrol, 13 healthy, sedentary adult volunteers were enrolled in a randomized crossover study comparing resveratrol and placebo over two 4-week periods, with a 2-week time between periods when subjects received no treatment. No significant changes in exercise duration or aerobic capacity (peak oxygen uptake) were observed. Gastrointestinal side effects were more common during resveratrol treatment (77% vs. 15%, p = 0.0048). A small reduction in fasting glucose and small but statistically significant increases in liver enzymes, total cholesterol, and triglycerides were observed, although mean results remained within normal limits. There was no change in complete blood count, inflammatory markers, renal function, or other measures of liver function. Key words: resveratrol, exercise capacity, safety, tolerability. Résumé : Pour évaluer l’effet du resvératrol sur la tolérabilité et la capacité physique, treize adultes sédentaires en bonne santé se portent volontaires dans une étude croisée aléatoire pour comparer le resvératrol a` un placebo au cours de deux périodes de 4 semaines intercalées de 2 semaines lorsque les sujets ne reçoivent aucun traitement. On n’observe pas de différence significative de durée d’effort et de puissance aérobie (consommation d’oxygène de pointe). On souligne des malaises gastrointestinaux plus fréquents durant le traitement au resvératrol (77 % vs 15 %, p = 0,0048). On observe une légère diminution du glucose a` jeun et une légère augmentation significative des enzymes hépatiques, du cholestérol total et des triglycérides, mais les moyennes des résultats s’inscrivent en-deça` des valeurs normales. Il n’y a pas de modification de l’hémogramme, des marqueurs inflammatoires, de la fonction rénale et d’autres variables de la fonction hépatique. [Traduit par la Rédaction] Mots-clés : resvératrol, capacité physique, sécurité, tolérabilité.
Introduction
Materials and methods
Resveratrol is a naturally occurring substance found in certain foods, including grapes and red wine. Preliminary laboratory and animal experiments have suggested that resveratrol could have a broad range of health benefits, including anti-inflammatory, cardioprotective, chemopreventative, and neuroprotective effects (Vang et al. 2011). Recently, human studies have suggested beneficial metabolic effects (Crandall et al. 2012; Timmers et al. 2011) and anti-inflammatory effects (Tomé-Carneiro et al. 2012) with resveratrol supplementation but the majority of health benefits found in animal studies have yet to be replicated in human subjects. Rodents given resveratrol supplements significantly increased their aerobic capacity, resistance to fatigue, exercise time, muscle strength, and muscle fibre oxygen consumption (Lagouge et al. 2006; Murase et al. 2009; Dolinsky et al. 2012; Hart et al. 2013; Wu et al. 2013), although these benefits have not yet been demonstrated in humans (Malaguti et al. 2013). We designed this pilot study to assess the tolerability of resveratrol and the effects of resveratrol supplementation on exercise performance in healthy sedentary adults.
For a comprehensive description of study methods and full study results, please refer to the supplementary material file1. Ethics statement The study protocol and methodology were reviewed and approved by the Ottawa Hospital Research Ethics Board (protocol no. 2008540-01H). The study protocol and risks were discussed with all participants prior to enrolment and written consent was obtained. Design We conducted a randomized, phase II, placebo-controlled, doubleblind parallel 2-arm, 2-period crossover trial, with a 2-week washout period, which is a period of time when subjects received no treatment, and crossover, for assessment of tolerance, safety, and clinical effects of oral resveratrol versus placebo in healthy sedentary adults. Participants This study enrolled healthy, sedentary adults between the ages of 18–65 years. Potential participants were screened (on visit 1)
Received 27 November 2013. Accepted 20 April 2014. N. Voduc. Department of Medicine, Division of Respirology, University of Ottawa at The Ottawa Hospital, General Campus, 501 Smyth Road, Box 211, Ottawa, ON K1H 8L6, Canada. C. la Porte.* Molecular Medicine, Department of Medicine, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. C. Tessier. The Ottawa Hospital Pulmonary Function Lab/Bronchoscopy, The Ottawa Hospital, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada. R. Mallick. Ottawa Hospital Research Institute, The Ottawa Hospital, General Campus, 501 Smyth Road, Office # L1213B, Ottawa, ON K1H 8L6, Canada. D.W. Cameron. Department of Medicine, Division of Infectious Diseases, University of Ottawa at The Ottawa Hospital, General Campus, 501 Smyth Road, Box 228, Ottawa, ON K1H 8L6, Canada. Corresponding author: Nha Voduc (e-mail: [email protected]). *Present address: Janssen-Cilag BV, Dr. Paul Janssenweg 150, Tilburg, the Netherlands. 1Supplementary data are available with the article through the journal Web site at http://nrcresearchpress.com/doi/suppl/10.1139/apnm-2013-0547. Appl. Physiol. Nutr. Metab. 39: 1183–1187 (2014) dx.doi.org/10.1139/apnm-2013-0547
Published at www.nrcresearchpress.com/apnm on 30 April 2014.
1184
with the help of a questionnaire, physical examination, fasting laboratory tests, pulmonary function tests, and an incremental exercise test (visit 1, see supplementary Table S11). Exclusion criteria included the finding of any clinically significant abnormality, including pre-existing medical conditions that could potentially affect exercise capacity or ability to tolerate resveratrol. Participants with a body mass index of less than 20 kg/m2 or greater than 30 kg/m2 were excluded. Only sedentary adults were recruited to avoid any potential interaction between exercise training and resveratrol. All testing was performed at the General campus of the Ottawa Hospital, a tertiary care academic hospital that is affiliated with the University of Ottawa. Intervention The study intervention was resveratrol, administered orally twice daily, during one of two 4-week treatment periods. For the first week, resveratrol (Transmax (Biotivia, Arlington, Va., USA)) was administered at a dose of 500 mg bid. This was increased to 1000 mg bid for the remaining 3 weeks if tolerated by the patient. We had previously confirmed the bioavailability of Transmax in healthy subjects (la Porte et al. 2010). Outcomes The primary outcomes of interest were exercise capacity and tolerability of resveratrol. Assessment of exercise capacity All exercise testing was conducted at the pulmonary function laboratory of the Ottawa Hospital, using SensorMedics Vmax 229 Series metabolic cart. Exercise capacity was assessed via 2 methods: exercise duration on constant load exercise at 75% of maximum workload and peak oxygen uptake (V˙O2peak) attained on incremental exercise testing. V˙O2peak is highly reproducible and is a conventional measure of exercise capacity, although studies in patients with chronic obstructive pulmonary disease have suggested that exercise duration on constant-load exercise may be more responsive to therapeutic intervention (Oga et al. 2000). Because the reproducibility of constant-load exercise duration has not been well established in a healthy patient population, we chose to measure both in our study. During the initial screening (visit 1), subjects underwent an incremental exercise test. This was performed on an electronically braked cycle ergometer (Ergoline – ergometrics 800), using 20 W increments every 2 min. Exercise testing was symptom-limited (the subjects were encouraged to exercise until exhaustion). Seventy-five percent of the peak workload attained during the incremental exercise test was used as the workload for all future constant-load exercise tests. During visit 1, a “practice” constant-load exercise test was also performed. This practice test was used to familiarize the subject with the constantload protocol and reduce learning effects for subsequent tests O the data from the practice test was not analyzed. After visit 1, all subjects underwent 4 exercise testing sessions: 1 at the beginning and end of each treatment period (visits 2, 6, 7, and 11). To minimize variation, all exercise sessions were scheduled at the same time of day for all 4 visits. During each session, both constant-load and incremental testing was conducted, with a1-h rest period in between. Assessment of tolerance During the treatment periods, all subjects underwent weekly assessments and laboratory testing to assess tolerability of resveratrol. During each assessment, subjects were questioned specifically about any new symptoms and adverse events. Laboratory testing included complete blood count, renal function, liver function, electrolytes, urine analysis, prothrombin time, C-reactive protein, and erythrocyte sedimentation rate.
Appl. Physiol. Nutr. Metab. Vol. 39, 2014
Table 1. Baseline demographics, biochemistry, pulmonary function, and exercise performance. Variable
Baseline (mean±SD)
Age (y) Male Female Body mass index (kg/m2) Resting SBP (mm Hg) Resting DBP (mm Hg) FEV1 (% predicted) Total lung capacity (% predicted) Diffusing capacity (% predicted) Glucose (mmol/L) Creatinine (umol/L) ALT (U/L) AST (U/L) GGT (U/L) Cholesterol (mmol/L) Triglycerides (mmol/L) C-Reactive protein (mg/L) Incremental exercise V˙O2peak/kg (mL/(kg·min)) V˙O2peak (% predicted) Peak heart rate (% predicted) Peak ventilation (% predicted) Peak respiratory quotient Anaerobic threshold (% predicted V˙O2max)
42.7±9.4 6 6 25.0±2.3 119±19 69±9 94.3±10.1 97.0±8.8 82.8±6.2 5.3±1.3 82±16 26±8 16±5 17±9 4.5±0.8 1.1±0.4 2.1±2.6 26.3±5.8 76.2±13.1 99.6±4.8 63.9±13.5 1.17±0.07 47.8±8.9
Note: ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; FEV1, forced expiratory volume in the first second of expiration; GGT, gamma-glutamyl transferase; SBP, systolic blood pressure; V˙O2max, maximal oxygen uptake; V˙O2peak, peak oxygen uptake.
Sample size A formal sample size calculation was not possible as there had been no prior studies evaluating the effects of resveratrol on exercise capacity in humans at the time our pilot study was designed. A convenience sample size of 12 participants was chosen for this pilot study. Randomization After eligibility was confirmed and informed consent obtained, all participants were randomly allocated to 1 of the 2 following groups, using a computer-generated variable-block randomization schedule. Allocation occurred after baseline testing on visit 2. Medications were dispensed by the study nurse. •
•
Group A (n = 6): Participants received resveratrol for 4 weeks, followed by no resveratrol for 2 weeks (washout period) and then placebo for twice daily for 4 weeks. Group B (n = 6): Participants received placebo daily for 4 weeks, followed by no placebo for 2 weeks and then resveratrol 4 weeks.
Blinding Physicians, research staff, and participants were blinded to the treatment allocation. The research pharmacist provided the medication/placebo to the research staff based on the randomization schedule. Study medication (resveratrol) and placebo were supplied to the patient in identical-appearing capsules. Statistical methods The baseline characteristics were summarized using the mean ± SD for continuous measurements (Table 1). For assessment of exercise capacity, data from patients who completed all exercise assessments was used. For each subject the difference in each variable (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc.; Table 2) was calculated under both the resveratrol and the placebo. To account for the fact that each patient received both the treatment and placebo, the Published by NRC Research Press
Voduc et al.
1185
Table 2. Comparison of resveratrol and placebo during treatment periods. Period 1 Variable Laboratory data ALT (U/L) AST (U/L) Cholesterol (mmol/L) Creatinine (umol/L) C-Reactive protein (mg/L) GGT (U/L) Glucose (mmol/L) Triglycerides (mmol/L) Exercise data Exercise duration (s) Heart rate (% predicted) Isotime heart rate (beats/min) Isotime RQ Isotime ventilation (L/min) Isotime V˙O2/kg (mL/(kg·min)) RQ Ventilation (% predicted) V˙O2peak/kg (mL/(kg·min)) V˙O2peak (% predicted) Anaerobic threshold (% predicted V˙O2max)
Period 2
Paired t test p value
Treatment
Start
End
Start
End
Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol
29.00 23.67 18.33 12.67 4.40 4.60 77.83 86.50 1.58 2.57 15.00 19.80 5.02 5.57 1.21 0.95
34.50 36.83 15.50 19.83 4.18 5.00 72.33 79.67 0.52 4.58 13.33 17.50 5.48 5.50 0.95 1.24
27.50 30.33 14.17 13.67 4.80 4.50 85.83 70.83 1.68 0.80 17.17 14.50 5.53 5.95 1.27 1.08
27.83 46.50 13.67 23.83 4.90 4.80 82.67 68.67 2.33 0.75 17.00 14.83 5.85 5.35 1.25 1.40
Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol Placebo Resveratrol
737.17 689.67 98.0 96.0 167.83 159.33 1.10 1.13 60.73 64.92 25.65 23.30 1.10 1.12 46.0 62.0 26.52 24.63 74.0 74.0 46.0 45.0
922.67 922.33 97.0 96.0 162.50 158.83 1.09 1.15 60.38 58.47 25.47 22.05 1.09 1.10 56.0 63.0 26.60 24.83 75.0 75.0 49.0 43.0
1006.50 777.33 98.0 95.0 160.17 162.50 1.12 1.10 61.80 61.58 24.47 25.37 1.12 1.12 68.0 59.0 26.92 26.50 81.0 75.0 50.0 51.0
905.17 753.50 97.0 96.0 159.00 163.67 1.09 1.11 68.42 64.47 26.15 25.77 1.06 1.13 64.0 60.0 27.65 26.35 84.0 75.0 48.0 47.0
0.035 0.0016 0.0155 0.9642 0.5556 0.7373 0.0302 0.0132
0.6745 0.2334 0.3415 0.194 0.2102 0.2973 0.0658 0.7358 0.8025 0.7081 0.6192
Note: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; RQ, respiratory quotient; V˙O2max, maximal oxygen uptake; V˙O2peak, peak oxygen uptake.
treatment and placebo differences per variable were compared using a paired t test (Table 2). To assess for a carryover effect, the observations at the beginning of each period for each variable were also compared using a paired t test (supplementary Table S21). For assessment of tolerance, an intent-to-treat approach was used. All analyses were conducted using the entire cohort of participants. The proportion of participants reporting side effects and (or) adverse events were compared between the 2 groups using the Fisher’s exact test. The frequency of each symptom was compared between the 2 treatment arms (supplementary Table S31).
Results
sequently, a thirteenth subject was enrolled to ensure that complete exercise data was available for 12 subjects. Six healthy men and 7 healthy women were enrolled. Mean age was 43 years (range 27–55 years) and mean body mass index was 25.0 kg/m2 (SD 2.3). Baseline patient data are presented in Table 1. Complete laboratory and exercise data for the 12 subjects with complete study data across treatment periods is presented in Table 2. Adverse event data from the subject who “dropped out” was still included in the analysis of tolerance (13 subjects in total). Patient compliance was confirmed with pill counts. Resveratrol and placebo capsules were assayed to confirm content.
Consenting participants were recruited from a list of healthy volunteers at the Clinical Investigation Unit of the Ottawa Hospital. A total of 25 adult volunteers were assessed between 2010 and 2011. Twelve did not meet inclusion criteria and did not undergo randomization (see supplementary Fig. S21 for participant flow diagram). We originally planned to enroll and randomize 12 patients. However, 1 subject developed a skin rash during the second treatment period and dropped out before her final exercise visit. Con-
Exercise responses Resveratrol did not have any significant effect on exercise capacity as reflected by changes in V˙O2peak during incremental exercise testing or exercise duration during constant-load exercise (Table 2). There were also no significant effects on other exercise parameters, such as heart rate, ventilation, peak respiratory quotient, or anaerobic threshold. Published by NRC Research Press
1186
Laboratory investigations Laboratory testing demonstrated small but statistically significant increases in AST, ALT, total cholesterol, and triglycerides at the end of the 4-week treatment period in patients receiving resveratrol (Table 2). Fasting glucose was also reduced by a mean of 0.7 mmol/L. None of these changes were felt to be clinically significant in any of the cases. There were no significant changes in other liver function tests, complete blood count, renal function, electrolytes, prothrombin time, C-reactive protein, or erythrocyte sedimentation rate. Exercise and laboratory test results obtained at the beginning of each treatment period were also compared in order to demonstrate stability of these variables between study periods. There was no significant difference in any of these measurements between periods (supplementary Table S21). Tolerance Overall, 12 of 13 subjects were able to tolerate resveratrol at the full dose of 2 g/day (1000 mg bid). Gastrointestinal complaints (diarrhea, nausea, cramping) were significantly more common with resveratrol than placebo (77% (10 of 13) vs. 15% (2 of 13), p = 0.005), although they were not severe enough to require medical attention or result in discontinuation of the medication in any of the cases (supplementary Table S31). Other adverse events include dermatological complaints (pruritus, rash) (1 subject from the placebo group and 1 subject from the resveratrol group), headache (2 subjects from the placebo group and 1 subject from the resveratrol group), and upper respiratory symptoms (1 subject from the placebo group and none from the resveratrol group). None of these events occurred more frequently during resveratrol treatment (no significant differences were observed). As mentioned above, 1 subject developed a pruritic rash that was resolved following discontinuation of resveratrol (supplementary Table S31).
Discussion We did not find any significant effect of resveratrol on exercise capacity or any other exercise parameters but did find that resveratrol was associated with small changes in laboratory measurements and minor gastrointestinal effects. The major limitations to this study are its small size and relatively short duration. A much larger and (or) longer study may detect a beneficial effect on exercise capacity. When our study was designed, there were no studies evaluating the effects of resveratrol in humans, thus a convenience sample of 12 was used to confirm tolerability. It can also be argued that the duration of the treatment period in our study (4 weeks) may be too short to allow for any beneficial effects on exercise capacity to appear. Given the limited tolerability data available at the time of our study design (2009), the duration of the treatment period our study was limited by our regulatory body, Health Canada, to 4 weeks. The mechanism of benefit of resveratrol on exercise capacity may be an augmentation of effects of exercise training. Many of the previous exercise studies demonstrating an improvement in exercise capacity in animals treated with resveratrol also included an exercise training component (Lagouge et al. 2006; Dolinsky et al. 2012) and it is possible that exercise training is required to obtain a benefit from resveratrol supplementation. A recent study has suggested that resveratrol may actually blunt training effects (Gliemann et al. 2013) although their conclusions have been challenged (Smoliga and Blanchard 2013; Buford and Anton 2014). For this pilot study, we did not include an exercise training component as we first wanted to assess the effects of resveratrol on exercise capacity in isolation, prior to conducting a more complicated study with an exercise training component. We did find that high-dose resveratrol supplementation is associated with gastrointestinal side effects in the majority of subjects. Similar side effects were observed previously at our centre
Appl. Physiol. Nutr. Metab. Vol. 39, 2014
(la Porte et al. 2010) and by other investigators (Chow et al. 2010; Brown et al. 2010; Howells et al. 2011), but the frequency of side effects in the present study was higher than reported in other studies. We do not have a definitive explanation for this. It may be partly due to the higher dose of resveratrol used in our study (for example Brown et al. did not observe gastrointestinal side effects at 1 g of resveratrol/day but did at ≥2.5 g/day). It is possible that the gastrointestinal side effects were related to the formulation of resveratrol we used. It should be emphasized that the side effects we observed were mild. No subject discontinued the study medication because of gastrointestinal symptoms. We also observed statistically significant but small elevations in liver enzymes, triglycerides, and total cholesterol. We felt that the observed elevations in liver enzymes were not clinically significant as the AST and ALT remained within normal limits for our laboratory and were not associated with changes in international normalized ratio or bilirubin. The impact of a longer treatment period on liver function is unknown. We did not find any beneficial effects on lipid profile or anti-inflammatory effect with resveratrol which is in contrast to the literature (Timmers et al. 2011; Tomé-Carneiro et al. 2012). In this study we did observe a small reduction in fasting glucose following resveratrol supplementation. The significance of this reduction is unknown. The treatment period was too short to affect longer term measurements of glucose control. Pollack and Crandall (2013) reported that in subjects with impaired glucose regulation, resveratrol shows modest, consistent benefit. Our study population was different than some of the other resveratrol studies (Timmers et al. 2011; Magyar et al. 2012). We excluded obese subjects as well as those with any significant medical conditions, including diabetes, cardiac disease, and dyslipidemia. Because our subjects did not have any major metabolic derangements, it may not be reasonable to detect a beneficial change in metabolic parameters that are already normal, as suggested by Smoliga et al. (2013). Pollack and Crandall (2013) have suggested that resveratrol’s effects may best observed under conditions of metabolic stress, such as insulin resistance or impaired glucose regulation. Taken together, the lack of effect on exercise performance and the statistically significant increases in triglycerides, cholesterol, and liver enzymes observed in our study would suggest that 4 weeks of 500–1000 mg bid resveratrol supplementation is not useful to improve exercise performance in healthy, nonobese patients. Future studies evaluating the effects of resveratrol on exercise capacity should include a component of exercise training and future studies evaluating the effects of resveratrol on metabolism may wish to focus on patients with pre-existing disease. Other information The trial is registered at ClinicalTrials.gov, no. NCT01615445, http:// clinicaltrials.gov/ct2/show/NCT01615445?term=RESVERATROL+ SUPPLEMENTATION&rank=1. Resveratrol capsules were provided by Biotivia (Biotivia.com). No individuals employed or contracted by the funders or Biotivia played any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Acknowledgements The authors would like to thank Ms. Rosalie Labelle and Ms. Katy Wedgwood for preparation and editing of this manuscript. The study was funded by the Ontario Thoracic Society block term grant (http://www.on.lung.ca/page.aspx?pid=567). Assistance with trial execution was received from the OHRI Clinical Investigation Unit. Salaries were partially supported by the University of Ottawa Department of Medicine. Published by NRC Research Press
Voduc et al.
References Brown, V.A., Patel, K.R., Viskaduraki, M., Crowell, J.A., Perloff, M., Booth, T.D., et al. 2010. Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. Cancer Res. 70(22): 9003–9011. doi:10.1158/ 0008-5472.CAN-10-2364. PMID:20935227. Buford, T.W., and Anton, S.D. 2014. Resveratrol as a supplement to exercise training: friend or foe? J. Physiol. 592(3): 551–552. doi:10.1113/jphysiol.2013. 267922. PMID:24488074. Chow, H.-H.S., Garland, L.L., Hsu, C.-H., Vining, D.R., Chew, W.M., Miller, J.A., et al. 2010. Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study. Cancer Prev. Res. (Phila), 3(9): 1168–1175. doi:10.1158/1940-6207.CAPR-09-0155. Crandall, J.P., Oram, V., Trandafirescu, G., Reid, M., Kishore, P., Hawkins, M., et al. 2012. Pilot study of resveratrol in older adults with impaired glucose tolerance. J. Gerontol. A Biol. Sci. Med. Sci. 67(12): 1307–1312. doi:10.1093/ gerona/glr235. PMID:22219517. Dolinsky, V.W., Jones, K.E., Sidhu, R.S., Haykowsky, M., Czubryt, M.P., Gordon, T., and Dyck, J.R.B. 2012. Improvements in skeletal muscle strength and cardiac function induced by resveratrol during exercise training contribute to enhanced exercise performance in rats. J. Physiol. 590(Pt 11): 2783– 2799. doi:10.1113/jphysiol.2012.230490. Gliemann, L., Schmidt, J.F., Olesen, J., Biensø, R.S., Peronard, S.L., Grandjean, S.U., et al. 2013. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J. Physiol. 591(Pt 20): 5047– 5059. doi:10.1113/jphysiol.2013.258061. Hart, N., Sarga, L., Csende, Z., Koltai, E., Koch, L.G., Britton, S.L., et al. 2013. Resveratrol enhances exercise training responses in rats selectively bred for high running performance. Food Chem Toxicol. 61: 53–59. doi:10.1016/j.fct. 2013.01.051. PMID:23422033. Howells, L.M., Berry, D.P., Elliott, P.J., Jacobsen, E.W., Hoffman, E., Hegarty, B., et al. 2011. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases-safety, pharmacokinetics and pharmacodynamics. Cancer Prev. Res. (Phila), 4: 1419–1425. doi:10. 1158/1940-6207.CAPR-11-0148. la Porte, C., Voduc, N., Zhang, G., Seguin, I., Tardiff, D., Singhal, N., and Cameron, W. 2010. Steady-state pharmacokinetics and tolerability of transresveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy human subjects. Clin. Pharmacokinet. 49(7): 449–454. doi:10.2165/ 11531820-000000000-00000. PMID:20528005. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., et al. 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1␣. Cell, 127(6): 1109– 1122. doi:10.1016/j.cell.2006.11.013. PMID:17112576. Magyar, K., Halmosi, R., Palfi, A., Feher, G., Czopf, L., Fulop, A., et al. 2012.
1187
Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin. Hemorheol. Microcirc. 50(3): 179–187. doi:10. 3233/CH-2011-1424. PMID:22240353. Malaguti, M., Angeloni, C., and Hrelia, S. 2013. Polyphenols in exercise performance and prevention of exercise-induced muscle damage. Oxidative Medicine and Cellular Longevity 2013, Article ID 825928. 9 pp. doi:10.1155/2013/ 825928. PMID:23983900. Murase, T., Haramizu, S., Ota, N., and Hase, T. 2009. Suppression of the agingassociated decline in physical performance by a combination of resveratrol intake and habitual exercise in senescence-accelerated mice. Biogerontology, 10(4): 423–434. doi:10.1007/s10522-008-9177-z. PMID:18830683. Oga, T., Nishimura, K., Tsukino, M., Hajiro, T., Ikeda, A., and Izumi, T. 2000. The effects of oxitropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. A comparison of three different exercise tests. Am. J. Respir. Crit. Care Med. 161(6): 1897–1901. doi:10.1164/ ajrccm.161.6.9905045. Pollack, R.M., and Crandall, J.P. 2013. Resveratrol: therapeutic potential for improving cardiometabolic health. Am. J. Hypertens. 26(11): 1260–1268. doi:10. 1093/ajh/hpt165. Smoliga, J.M., and Blanchard, O.L. 2013. Recent data do not provide evidence that resveratrol causes ‘mainly negative’ or ‘adverse’ effects on exercise training in humans. J. Physiol. 591(20): 5251–5252. doi:10.1113/jphysiol.2013.262956. PMID:24130323. Smoliga, J.M., Colombo, E.S., and Campen, M.J. 2013. A healthier approach to clinical trials evaluating resveratrol for primary prevention of age-related diseases in healthy populations. Aging, 5(7): 495–506. PMID:24073437. Timmers, S., Konings, E., Bilet, L., Houtkooper, R.H., van de Weijer, T., Goossens, G.H., et al. 2011. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 14(5): 612–622. doi:10.1016/j.cmet.2011.10.002. PMID:22055504. Tomé-Carneiro, J., Gonzálvez, M., Larrosa, M., Yáñez-Gascón, M.J., García-Almagro, F.J., Ruiz-Ros, J.A., et al. 2012. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am. J. Cardiol. 110(3): 356–363. doi:10.1016/j.amjcard.2012.03.030. PMID: 22520621. Vang, O., Ahmad, N., Baile, C.A., Baur, J.A., Brown, K., Csiszar, A., et al. 2011. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLOS ONE, 6(6): e19881. doi:10.1371/journal.pone. 0019881. PMID:21698226. Wu, R.-E., Huang, W.-C., Liao, C.-C., Chang, Y.-K., Kan, N.-W., and Huang, C.-C. 2013. Resveratrol protects against physical fatigue and improves exercise performance in mice. Molecules, 18(4): 4689–4702. doi:10.3390/molecules18044689. PMID:23603951.
Published by NRC Research Press
Copyright of Applied Physiology, Nutrition & Metabolism is the property of Canadian Science Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
