A skeptical view on the use of antioxidant supplementation in sport

The Skeptik, 2018, Vol. 4, No. 1, pgs. 1-9

Albena Alexandrova

Department of Physiology and Biochemistry, Coaching Faculty, National Sports Academy "Vassil Levski", 1700, Studentski Grad, Sofia, Bulgaria, e-mail: a_alexandrova_bas@yahoo.com

Oxidative stress induction by exercise

The first assumption that physical exercises can lead to generation of reactive oxygen species (ROS) that cause oxidative modifications of biomolecules occurred in 1978. At this time Dillard et al. demonstrated a 1.8-fold increase in exhaled pentane as a lipid peroxidation marker after 60 minutes of cycling at 25-75% of the maximum oxygen consumption (VO2max). Since then, a number of studies have shown excess generation of ROS and oxidative stress (OS) induction in physical exercise. It is widely accepted that the primary tissue of ROS generation during physical activity is skeletal and heart muscle. At subcellular level numerous sites for ROS production exist: electron transport chains in mitochondria, NAD(P)H oxidase enzymes, xanthine oxidase, phospholipase A2, lipoxygenases, catecholamines and prostanoid metabolism. As well as several secondary sources, such as macrophages (Jackson, 2000) and neutrophils by γ-interferon (IFN-γ), interleukin-1 (IL-1) and tumor necrosis factor (TNF) (Peake and Suzuki, 2004) exist.
ROS are a natural byproduct of the normal metabolism of oxygen. They result from partial reduction of oxygen and include superoxide anion radicals (•O−2), hydrogen peroxide (H2O2) and hydroxyl radicals (•OH). The term ROS includes also other oxygen-containing radicals and molecules such as peroxyl, alkoxyl, and hydroperoxyl radicals, hypochlorous acid, singlet oxygen. Because of their high reactivity ROS are able to modify oxidatively all biological macromolecules impairing the functions of structures they make up.
Increased lipid oxidation, DNA oxidation, and protein oxidation have been reported during, or immediately following exercise (Fisher-Wellman and Bloomer, 2009). The negative consequences of ROS's action in muscles are related to altered contractile function (Reardon and Allen, 2009), decreased maximal force and enhanced fatigue (Baclay and Hansel, 1991), and muscle atrophy (Gumucio and Mendias, 2013). The molecular mechanisms for detrimental effect of ROS could be associated not only with the direct action on muscle structural proteins (Prochniewicz et al., 2008), but also with impairment of mitochondrial enzymes, responsible for energy supply such as succinate dehydrogenase and cytochrome oxidase (Haycock et al., 1996), ATPase pumps for calcium uptake by sarcoplasmic reticulum (Xu et al., 1997; Scherer and Deamer, 1986), ATPase pumps for potassium transport involved in development of action potentials (Sen et al., 1995). In addition the muscle damage could be mediated by ROS-induced gene expression. The activation of NF-κB and FoxO by ROS lead to expression of two specific muscle E3 ubiquitin ligases: atrogin-1 or MAFbx (muscle atrophy F-box) and MuRF-1 (muscle RING-finger protein-1) that participate in degradation of titin, nebulin, troponin, myosin-binding protein C, myosin light chains 1 and 2 and myosin heavy chain (Gumucio and Mendias, 2013). Sriram et al. (2014) demonstrated that OS is able to activate CHOP transcription factor (CCAAT/enhancer-binding protein homologous protein) leading to increase of MuRF1expression and subsequent protein degradation.
The aerobic organisms have developed defense mechanisms against ROS. Cells, including muscle fibers, as well as the extracellular and vascular spaces are equipped with enzymatic and non-enzymatic antioxidants. The enzymatic antioxidant system includes superoxide dismutase, catalase and glutathione peroxidase, and the non-enzymatic antioxidants include glutathione, ascorbic acid, tocopherol, coenzyme Q10 and other low-molecular substances.
However, when ROS generation exceeds the antioxidant defense capacity or antioxidant defense is unable to counteract ROS, oxidative stress occurs.
Thus in front of the athletes and their coaches arise the question whether antioxidant supplementation will improve athletic performance and whether antioxidant supplements should be a part of the nutritional plane. Surveys have indicated that most elite athletes take vitamin supplements (Bojanic et al., 2011) and the most often supplemented antioxidants in sports practice are vitamin C and vitamin E. However the athletes are not very aware with the effect of these vitamins and recommended doses. Some athletes take vitamins in dosages greater than 50-100 times the Recommended Dietary Allowances (Williams, 1989). For instance it has been reported consumption of 10 000 mg of vitamin C daily (Williams, 1984).

Vitamin C

There is a huge amount of data about the protective effect of vitamin C on markers of oxidative stress, induced by exercise (Evans, 2000; Goldfarb et al., 2005; Popovic et al., 2015). Studies on the effect of vitamin C on athletes’ health and performance started in 1952, when Staton reported decreased muscle soreness after 30 days of 100 mg vitamin C supplementation. In regards to exercise-induced muscle damage vitamin C supplementation appears to reduce muscle soreness (Kaminski and Boal, 1992; Bryer and Goldfarb, 2006). In regards to effect of vitamin C supplementation on performance, there was no beneficial effect on either endurance (Gey et al., 1970) or strength (Paulsen et al., 2014) performance. Even in case of vitamin C deficiency it supplementation does not appear to improve the performance (Van de Beek et al., 1990).

Vitamin E

Similar to vitamin C, vitamin E administration has shown protective effect against oxidative stress, induced by exercise leading to muscle cell damage. Decrease in exercise-induced lipid peroxidation was demonstrated in many researches (Dillard et al. 1978; Sumida et al., 1989; Rokitzki et al., 1994a; Takanami et al., 2000; Evans, 2000) in different doses and period of administration. Indeed a relatively recent critical review (Viitala and Newhouse, 2004) aimed to analyze the strength of evidences about the effect of vitamin E on exercise-induced lipid peroxidation, concludes that vitamin E supplementation does not appear to decrease exercise-induced lipid peroxidation in humans. The vitamin E supplementation results in decreased leakage of muscle enzymes in plasma as an indirect marker of muscle damage in response to exercise. Itoh et al. (2000) demonstrated that the intake of 1200 IU vitamin E/day 4 weeks prior to and during 6 successive days of endurance running training (48.3 ±5.7 km/day) reduce the leakage of creatine kinase (CK) and lactate dehydrogenase (LDH) following the days of running. A significant diminution of serum CK increase induced by strenuous exercise, as well as a trend toward decrease in GOT, GPT, and LDH was observed in top-class cyclists after 5 months of vitamin E supplementation (Rokitzki et al., 1994). However, some studies indicated that vitamin E supplementation did not significantly change lipid and protein oxidation and CK values at rest, after exercise to exhaustion, and cycling (Gaeini et al., 2006). Reduction of plasma cytokines (IL-1β and IL-6) after a single session of eccentric exercise (downhill running on an inclined treadmill) preceded by 48-days intake of 800 IU/day vitamin E was reported by Cannon et al., (1991). However the researches do not establish enhancement in exercise performance (Sharman et al., 1971; Talbot and Jamieson, 1977; Shephard, 1983; Tiidus and Houston, 1995; Gerster, 1991; Rokitzki et al., 1994b; Takanami et al., 2000; Gaeini et al., 2006).

Other antioxidants

Other antioxidants as Coenzyme Q 10 (CoQ10), N-acetylcysteine (NAC), beta-carotenes also were tested about their effect on athletes. Several researches demonstrated that administration of CoQ10 has no measurable effect on exercise performance. Braun et al. (1991) examined the effect of CoQ10 intake at dose of 100 mg/day for 8 weeks on bicycle racers. The performance of graded exercise test using cycling ergometer was not affected by the prolonged antioxidant administration and there were no differences in all tested physiological and biochemical parameters between the placebo group and CoQ10 group. Similar results were obtained by Bonetti et al. (2000) after CoQ10 (ubidecarenone) oral treatment for same period (8 weeks). N-acetylcysteine, although inhibits fatigue, did not enhance the performance of sustained maximal efforts in handgrip exercise (Matuszczak et al., 2005). Corn and Barstow (2011) also demonstrated that acute oral dose of NAC extended time to fatigue at 80% Pmax but did not enhance work rates. Only the data about beta-carotene application indicated that it can provide a beneficial influence on race performance. The ingestion of 25000 IU beta-carotene daily of well-trained runners led to significant improvement in 5000 meter race performance (Leblanc, 1998). However, there is not an adequate explanation of the mechanism by which this occurs (Leblanc, 1998).

Combination of antioxidants

There are some investigations about the effect of combined intake of vitamin C and E on endurance (Rokitzki et al., 1994b) and strenuous exercise (Petersen et al., 2001). It has been supposed this combination will be better than either vitamin alone, since vitamin C regenerates vitamin E by reducing vitamin E radicals formed when vitamin E scavenges the oxygen radicals. However, there were no data about enhancement of exercise performance (Paulsen et al., 2014; Morrison et al., 2015). There are also data about application of triple combinations: vitamin C, vitamin E and beta-carotene (Kanter et al., 1993; Scroder et al., 2000); vitamin C, vitamin E and CoQ10 (Nielson et al., 1999), as the response to exercise was not affected by the applied antioxidants.

Why antioxidants do not improve exercise performance?

With development of molecular biology it was discovered that ROS, generated in exercise, are powerful cellular signals, promoting expression of multiple genes involved in training adaptation (Niess and Simon, 2007; Powers et al., 2010). Nowadays is widely accepted that basal and physiological increase of ROS is required for muscle force production, whereas higher levels lead to oxidative damage and decline in performance (Reid, 2001). This is in accordance with hormesis concept whereby a beneficial adaptive effect results from exposure to low continuous or higher intermitted doses of a stressor that is otherwise harmful at large or chronic doses (Ristow, 2014; Yun and Finkel, 2014). Therefore antioxidant supplementation in exercise training, leading to reduction of ROS generation, may hamper the favorable adaptations.
It has been demonstrated that ROS take part in regulation of following processes: mitochondrial biogenesis, angiogenesis, vasodilatation, insulin sensitivity, immune response, antioxidant enzyme expression and growth factor signaling (Grodstein et al., 2013; Ristow, 2014; Yun and Finkel, 2014; Webb et al., 2017).
Gomez-Cabrera et al. (2008) demonstrated that supplementation with vitamin C affected adaptation to endurance exercise training. They found a reduction in the exercise-induced expression of key transcription factors involved in mitochondrial biogenesis (peroxisome proliferator–activated receptor co-activator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (mTFA)) after administration of vitamin C. This reduction resulted in hampered endurance capacity in rats. In addition vitamin C supplementation did not improve V̇O2max associated with training in rats and in humans. The suppression of PGC-1α led also to antioxidant enzymes decrease, since PGC-1 activates NRF2, which induce the antioxidant enzyme expression (St. Pierre et al., 2006). Gomez-Cabrera et al. (2008) found decrease in gene (mRNA) expression of manganese-superoxide dismutase (Mn-SOD) and glutathione peroxidase (GPx) after treatment of rats with high dose of vitamin C (500 mg/kg body wt). Similar results were obtained in humans after 4 weeks of vitamin C (1000 mg/day) and E (400 IU/day) supplementation: the training-induced expression of antioxidant enzyme mRNAs was blocked (Ristow et al., 2009). In the same study was demonstrated that the training-induced expression of ROS-sensitive transcriptional regulators of insulin sensitivity increased only in absence of antioxidants.
Paulsen et al. (2014) reported that vitamin C and E supplementation led to a reduction of phosphorylation of p70S6 kinase and mitogen-activated protein kinases p38 and ERK1/2 that interrupt the cellular and physiological adaptations to strength training in humans.
It should be mentioned that some research did not find effect of high dose antioxidants administration and reported normal adaptations to exercise training in rats (Higashida et al., 2011) and human (Yfanti et al., 2010). The contradictory results and conclusions provoked discussion on the topic (Gomez-Cabrera et al., 2008; Holloszy et al., 2012).
In conclusion, although there is some discrepancy about the effect of antioxidant supplementation on sport performance, more consistently it has been reported that the antioxidants blunt the favorable adaptation to training load (Merry and Ristow, 2016). Therefore athletes, couches and nutritionists involved in compiling sports diets should re-evaluated the antioxidant supplements intake.

REFERENCES

1. Barclay JK, Hansel M. Free radicals may contribute to oxidative skeletal muscle fatigue. Can J Physiol Pharmacol. 1991, 69(2):279-84.
2. Bojanic V., Radović J., Bojanić Z., Lazović M. Hydrosoluble vitamins and sport. Acta Medica Medianae, 2011, 5 (2):68-75.
3. Bonetti A, Solito F, Carmosino G, Bargossi AM, Fiorella PL. Effect of ubidecarenone oral treatment on aerobic power in middle-aged trained subjects. J Sports Med Phys Fitness. 2000, 40(1):51-7.
4. Braun B, Clarkson PM, Freedson PS, Kohl RL. Effects of coenzyme Q10 supplementation on exercise performance, VO2max, and lipid peroxidation in trained cyclists. Int J Sport Nutr. 1991, 1(4):353-65.
5. Bryer SC, Goldfarb AH. Effect of high dose vitamin C supplementation on muscle soreness, damage, function, and oxidative stress to eccentric exercise. International Journal of Sport Nutrition and Exercise Metabolism, 2006, 16(3):270–280.
6. Cannon JG, Meydani SN, Fielding RA, Fiatarone MA, Meydani M, Farhangmehr M, Orencole SF, Blumberg JB, Evans WJ. Acute phase response in exercise. II. Associations between vitamin E, cytokines, and muscle proteolysis. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1991, 260(6):R1235–R1240.
7. Corn SD, Barstow TJ. Effects of oral N-acetylcysteine on fatigue, critical power, and W' in exercising humans. Respir Physiol Neurobiol. 2011, 178(2):261-8. doi: 10.1016/j.resp.2011.06.020. Epub 2011 Jun 29.
8. Corn SD, Barstow TJ. Effects of oral N-acetylcysteine on fatigue, critical power, and W′ in exercising humans. Respiratory Physiology & Neurobiology, 2011, 178(2):261–268.
9. Dillard CJ, Litov RE, Savin WM, Dumelin EE, Tappel AL. Effects of exercise, vitamin E, and ozone on pulmonary function and lipid peroxidation. J Appl Physiol Respir Environ Exerc Physiol. 1978, 45(6):927-32.
10. Evans WJ. Vitamin E, vitamin C, and exercise. Am J Clin Nutr. 2000, 72(2 Suppl):647S-52S.
11. Fisher-Wellman K, Bloomer RJ. Acute exercise and oxidative stress: a 30 year history. Dynamic medicine : 2009, 8:1-25.
12. Gaeini AA, Rahnama N, Hamedinia MR. Effects of vitamin E supplementation on oxidative stress at rest and after exercise to exhaustion in athletic students. J Sports Med Phys Fitness. 2006, 46(3):458-61.
13. Gerster H. Function of vitamin E in physical exercise: a review. Zeitschrift für Ernährungswissenschaft. June 1991, 30(2):89–97. https://doi.org/10.1007/BF01610064
14. Gey GO, Cooper KH, Bottenberg RA. Effect of ascorbic acid on endurance performance and athletic injury. J. Am. Med. Assoc. 1970, 211:105.
15. Goldfarb AH, Patrick SW, Bryer S, You T. Vitamin C supplementation affects oxidative-stress blood markers in response to a 30-minute run at 75% VO2max. International journal of sport nutrition and exercise metabolism, 2005, 15(3):279–90.
16. Gomez-Cabrera MC, Domenech E, Romagnoli M, Arduini A, Borras C, Pallardo FV, Sastre J, Viña J. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr. 2008, 87(1):142-9.
17. Gomez-Cabrera MC, Domenech E, Viña J. Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic Biol Med. 2008, 44(2):126-31. doi: 10.1016/j.freeradbiomed.2007.02.001. Epub 2007 Feb 9.
18. Gomez-Cabrera MC, Ristow M, Viña J. Letter to the Editor. Antioxidant supplements in exersice: worse than useless? Am J Physiol Endocrinol Metab. 2012, 302:E476–E477. doi:10.1152/ajpendo.00567.2011.
19. Grodstein F, O'Brien J, Kang JH, Dushkes R, Cook NR, Okereke O, Manson JE, Glynn RJ, Buring JE, Gaziano M & Sesso HD. Long‐term multivitamin supplementation and cognitive function in men: a randomized trial. Ann Intern Med. 2013, 159:806–814.
20. Gumucio JP, Mendias CL. Atrogin-1, MuRF-1, and sarcopenia. Endocrine. 2013, 43:12–21.
21. Haycock JW, Jones P, Harris JB, Mantle D. Differential susceptibility of human skeletal muscle proteins to free radical induced oxidative damage: a histochemical, immunocytochemical and electron microscopical study in vitro. Acta Neuropathol. 1996, 92(4):331-40.
22. Higashida K, Kim SH, Higuchi M, Holloszy JO & Han DH. Normal adaptations to exercise despite protection against oxidative stress. Am J Physiol Endocrinol Metab. 2011, 301:E779–E784.
23. Holloszy JO, Higashida K, Kim SH, Higuchi M, Han DH. Letters to the Editor: Response to letter to the editor by Gomez-Cabrera et al. Am J Physiol Endocrinol Metab. 2012, 302:E478–E479, doi:10.1152/ajpendo.00596.2011.
24. Itoh H, Ohkuwa T, Yamazaki Y, Shimoda T, Wakayama A, Tamura S, Yamamoto T, Sato Y, Miyamura M.Vitamin E supplementation attenuates leakage of enzymes following 6 successive days of running training. Int J Sports Med. 2000, 21(5):369-74.
25. Jackson MJ. In: Hanninen, O., Packer, L., Sen, C.K. (Eds.), Handbook of Oxidants and Antioxidants in Exercise. Elsevier, Amsterdam, 2000, pp.57-68.
26. Kaminski M, Boal R. An effect of ascorbic acid on delayed-onset muscle soreness. Pain. 1992, 50(3):317-21.
27. Kanter MM, Nolte LA, Holloszy JO. Effects of an antioxidant vitamin mixture on lipid peroxidation at rest and postexercise. Journal of Applied Physiology. 1993, 74:965-969.
28. Leblanc KE. Beta-Carotene and Exercise Performance: Effects on Race Performance, Oxidative Stress, and Maximal Oxygen Consumption. 1998. LSU Historical Dissertations and Theses. 6846. https://digitalcommons.lsu.edu/gradschool_disstheses/6846
29. Matuszczak Y, Farid M, Jones J, Lansdowne S, Smith MA, Taylor AA, Reid MB. Effects of N-acetylcysteine on glutathione oxidation and fatigue during handgrip exercise. Muscle & Nerve, 2005, 32(5):633–638.
30. Merry TL, Ristow M. Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? J Physiol. 2016, 594(18):5135-47. doi: 10.1113/JP270654. Epub 2016 Jan 18.
31. Morrison D, Hughes J, Della Gatta PA, Mason S, Lamon S, Russell AP, Wadley GD. Vitamin C and E supplementation prevents some of the cellular adaptations to endurance-training in humans. Free Radic Biol Med. 2015, 89:852-62. doi: 10.1016/j.freeradbiomed.2015.10.412. Epub 2015 Oct 19.
32. Nielson A.N., Mizuno M., Ratkevicius A., Mohr T., Rohde M., Mortensen S.A., Quistorff B. No effect of antioxidant supplementation in triathletes on maximal oxygen uptake, 31P-NMRS detected muscle energy metabolism and muscle fatigue. Int. J. Sports Med. 1999, 20:154-158.
33. Niess AM, Simon P. Response and adaptation of skeletal muscle to exercise-the role of reactive oxygen species. Front Biosci. 2007, 12:4826-38.
34. Niki E. Interaction of ascorbate and alpha-tocopherol. Annals of the New York Academy of Sciences. 1987, 498:186–99.
35. Paulsen G, Cumming KT, Hamarsland H, Børsheim E, Berntsen S, Raastad T. Can supplementation with vitamin C and E alter physiological adaptations to strength training? BMC Sports Sci Med Rehabil. 2014, 6: 8. Published online 2014 Jul 5. doi:10.1186/2052-1847-6-28. PMCID: PMC4114441
36. Paulsen G, Cumming KT, Holden G, Hallén J, Rønnestad BR, Sveen O, Skaug A, Paur I, Bastani NE, Østgaard HN, Buer C, Midttun M, Freuchen F, Wiig H, Ulseth ET, Garthe I, Blomhoff R, Benestad HB, Raastad T. Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial. J Physiol. 2014, 592(8):1887-901. doi: 10.1113/jphysiol.2013.267419. Epub 2014 Feb 3.
37. Peake J, Suzuki K. Neutrophil activation, antioxidant supplements and exercise-induced oxidative stress. Exerc Immunol Rev. 2004, 10:129-41.
38. Petersen EW, Ostrowski K, Ibfelt T, Richelle M, Offord E, Halkjaer-Kristensen J, Pedersen BK. Effect of vitamin supplementation on cytokine response and on muscle damage after strenuous exercise. Am J Physiol Cell Physiol. 2001, 280(6):C1570-5.
39. Popovic LM, Mitic NR, Miric D, Bisevac B, Miric M, Popovic B. Influence of vitamin C supplementation on oxidative stress and neutrophil inflammatory response in acute and regular exercise. Oxidative medicine and cellular longevity. 2015:295497.
40. Powers SK, Duarte J, Kavazis AN, Talbert EE. Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp Physiol. 2010, 95(1):1-9. doi: 10.1113/expphysiol.2009.050526. Epub 2009 Oct 30. Review.
41. Powers SK, Hamilton K. Antioxidants and exercise. Clinics in sports medicine, 1999, 18(3): 525–36.
42. Prochniewicz E, Spakowicz D, Thomas DD. Changes in actin structural transitions associated with oxidative inhibition of muscle contraction. Biochemistry. 2008, 47(45):11811-7. doi: 10.1021/bi801080x. Epub 2008 Oct 15.
43. Prochniewicz E., Spakowicz D., Thomas DD. Changes in Actin Structural Transitions Associated with Oxidative Inhibition of Muscle Contraction. Biochemistry. 2008, 47:11811–11817.
44. Reardon TF, Allen DG. Time to fatigue is increased in mouse muscle at 37°C: the role of iron and reactive oxygen species. J Physiol. 2009b, 587:4705–4716.
45. Reid M.B. Nitric oxide, reactive oxygen species, and skeletal muscle contraction. Med. Sci. Sports Exerc. 2001, 33:371-376.
46. Ristow M, Zarse K, Oberbach A, Klöting N, Birringer M, Kiehntopf M, Stumvoll M, Kahn CR, Blüher M. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A. 2009, 106(21):8665-70. doi: 10.1073/pnas.0903485106. Epub 2009 May 11.
47. Ristow M. Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat Med. 2014, 20(7):709-11. doi: 10.1038/nm.3624.
48. Rokitzki L, Logemann E, Huber G, Keck E, Keul J. alpha-Tocopherol supplementation in racing cyclists during extreme endurance training. International journal of sport nutrition. 1994, 4(3):253–64.(b)
49. Rokitzki L, Logemann E, Sagredos AN, Murphy M, Wetzel-Roth W, Keul J. Lipid peroxidation and antioxidative vitamins under extreme endurance stress. Acta Physiol Scand. 1994, 151(2):149-58.(a)
50. Scherer NM, Deamer DW. Oxidation of thiols in the Ca2+-ATPase of sarcoplasmic reticulum microsomes. Biochim Biophys Acta. 1986, 862(2):309-17.
51. Schröder H, Navarro E, Mora J, Galiano D, Tramullas A. Effects of alpha-tocopherol, beta-carotene and ascorbic acid on oxidative, hormonal and enzymatic exercise stress markers in habitual training activity of professional basketball players. Eur J Nutr. 2001, 40(4):178-84.
52. Sen CK. Oxidants and antioxidants in exercise. J Appl Physiol (1985). 1995, 79(3):675-86.
53. Sharman IM, Down MG, Sen RN. The effects of vitamin E and training on physiological function and athletic performance in adolescent swimmers. Br J Nutr. 1971, 26(2):265-76.
54. Shephard RJ. Vitamin E and athletic performance. J Sports Med Phys Fitness. 1983, 23(4):461-70.
55. Smith JR, Broxterman RM, Ade CJ, Evans KK, Kurti SP, Hammer SM, Barstow TJ, Harms CA. Acute supplementation of N ‐acetylcysteine does not affect muscle blood flow and oxygenation characteristics during handgrip exercise. Physiological Reports. 2016, 4(7):e12748.
56. Sriram S, Subramanian S, Juvvuna PK, Ge X, Lokireddy S, McFarlane CD, Wahli W, Kambadur R, Sharma M. Myostatin augments muscle-specific ring finger protein-1 expression through an NF-kB independent mechanism in SMAD3 null muscle. Mol Endocrinol. 2014, 28(3):317-30. doi: 10.1210/me.2013-1179. Epub 2014 Jan 17.
57. Staton WM. The Influence of Ascorbic Acid in Minimizing Post-Exercise Muscle Soreness in Young Men. Research Quarterly. American Association for Health, Physical Education and Recreation. 1952, 23(3):356-60.
58. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, Handschin Ch, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of Reactive Oxygen Species and Neurodegeneration by the PGC-1 Transcriptional Coactivators. Cell. 2006, 127(2):397-408.
59. Sumida S, Tanaka K, Kitao H, Nakadomo F. Exercise-induced lipid peroxidation and leakage of enzymes before and after vitamin E supplementation. Int. J. Biochem. 1989, 21(8):835-838.
60. Takanami Y, Iwane H, Kawai Y, Shimomitsu T. Vitamin E supplementation and endurance exercise: are there benefits? Sports medicine (Auckland, N.Z.). 2000, 29(2):73–83.
61. Talbot D, Jamieson J. An examination of the effect of vitamin E on the performance of highly trained swimmers. Can J of Appl Sports Sci. 1977, 2:67–71.
62. Tiidus PM, Houston ME. Vitamin E status and response to exercise training. Sports Med. 1995, 20(1):12-23.
63. Van der Beek EJ, van Dokkum W, Schrijver J, Wesstra A, Kistemaker C, Hermus RJ. Controlled vitamin C restriction and physical performance in volunteers. J. Am. Coll. Nutr., 1990, 9(4):332-339.
64. Viitala P, Newhouse IJ. Vitamin E supplementation, exercise and lipid peroxidation in human participants. Eur J Appl Physiol. 2004, 93(1-2):108-15. Epub 2004 Jul 10.
65. Webb R, Hughes MG, Thomas AW, Morris K. The Ability of Exercise-Associated Oxidative Stress to Trigger Redox-Sensitive Signalling Responses. Antioxidants. 2017, 6(3):63. http://doi.org/10.3390/antiox6030063
66. Williams MH. Dietary supplements and sports performance: introduction and vitamins. Journal of the International Society of Sports Nutrition. 2004, 1(2):1–6.
67. Williams MH. Vitamin and mineral supplements to athletes: do they help? Clin Sports Med. 1984, 3(3):623-37.
68. Williams MH. Vitamin supplementation and athletic performance. Int J Vitam Nutr Res Suppl. 1989, 30:163-91.
69. Xu KY, Zweier JL, Becker LC. Hydroxyl radical inhibits sarcoplasmic reticulum Ca(2+)-ATPase function by direct attack on the ATP binding site. Circ Res. 1997, 80(1):76-81.
70. Yfanti C, Akerström T, Nielsen S, Nielsen AR, Mounier R, Mortensen OH, Lykkesfeldt J, Rose AJ, Fischer CP, Pedersen BK. Antioxidant supplementation does not alter endurance training adaptation. Med Sci Sports Exerc. 2010, 42(7):1388-95. doi: 10.1249/MSS.0b013e3181cd76be.
71. Yun J, Finkel T. Mitohormesis. Cell Metab. 2014, 19(5):757-66. doi: 10.1016/j.cmet.2014.01.011. Epub 2014 Feb 20.