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Created page with "{{DISPLAYTITLE:Vitamin C For Runners}} Vitamin C may be an important supplement for runners. A runner's quads lengthen to slow their body's descent on landing, a type of eccen..."
{{DISPLAYTITLE:Vitamin C For Runners}}
Vitamin C may be an important supplement for runners. A runner's quads lengthen to slow their body's descent on landing, a type of eccentric exercise. This eccentric stress not only causes [[Delayed Onset Muscle Soreness]] (DOMS), but it also causes immediate weakness. If you've ever had problems descending stairs after a marathon, you've had DOMS. The good news is that experiencing DOMS provides a protection from future bouts, something known as the Repeated Bout Effect (RBE), which is where Vitamin C comes in. As well as being an antioxidant, Vitamin C is important in may other ways, including the production of the scaffolding that makes up muscles (collagen.) There is some evidence that Vitamin C may help with the RBE, and without sufficient Vitamin C, the ability to adapt to long runs may be impaired. While Vitamin C has been shown to interfere with the way people adapt to exercise at a biochemical level, that doesn't appear to translate into practical problems. If you take Vitamin C as a supplement, it's best to take it spread evenly through the day rather than a single larger dose.
=The Role of Vitamin C=
Vitamin C is best known for its role as an antioxidant. However, it's not only an antioxidant, but it's also cofactor for 15 different enzymes<ref name="EnglardSeifter1986"/>, including the production of norepinephrine<ref name="LevineDhariwal1991"/>, carnitine<ref name="Rebouche1991b"/>, and collagen<ref name="ProckopKivirikko1995"/>. It also enhances non-heme iron absorption<ref name="HallbergBrune1987"/>. Increased Vitamin C may also boost the amount of Collagen synthesized<ref name="GeesinDarr1988"/><ref name="Sullivan Uschmann Hough Leboy pp. 22500–6"/>. This is especially valuable for runners, as collagen is a key structural protein, including muscle fibers<ref name="KovanenSuominen1984"/> and tendons<ref name="FranchiTrirè2007"/>. Even within the role as an antioxidant there is the possibility that different antioxidants may fulfill different roles. For instance, there is evidence that Vitamin C depleted plasma is susceptible to fat (lipid) oxidation, even when other anti-oxidants are present<ref name="FreiEngland1989"/>. Personally, I suspect that these various roles may result in differing actions of vitamins C in differing circumstances. Vitamin C is concentrated in nearly all cells in the body above plasma levels, such as the brain with 16-18x and muscle with 4-6x, though It's unclear why many tissues concentrate Vitamin C levels well beyond the level needed for the enzymatic actions, sometimes 10-100x higher<ref name="PadayattyLevine2016"/>. There is evidence from animal models that the Vitamin C needs may vary widely, possibly due to genetic differences<ref name="Yew1975"/>. This has been seen in humans, where there is wide variation in susceptibility to scurvy amongst sailors<ref name="Yew1975"/>.
=Vitamin C Requirements=
The recommended intake for vitamins C is focused on preventing deficiency problems, primarily scurvy<ref name="CarrFrei1999"/>. Vitamin C deficiency (scurvy) results in lassitude (fatigue), coiled hair, gum problems, anemia, hemorrhages, tooth loss and other problems<ref name="PadayattyLevine2016"/>. Sometimes the only symptom of vitamins C deficiency is lassitude, even when plasma levels are below 8 uM<ref name="LevineConry-Cantilena1996"/>. Most animals can produce their own Vitamin C, except for humans and other primates, Guinea pigs, fruit bats, and some birds and fish<ref name="PadayattyLevine2016"/>. The optimum dose of Vitamin C for runners is unclear based on the available research.
=Vitamin C Intakes=
Vitamin C is absorbed in the small intestine, reaching peak plasma levels in 2-3 hours, and then to extracellular fluids<ref name="PadayattyLevine2016"/>. Over many days, the level of vitamin C in the plasma stabilizes, as shown below<ref name="LevineConry-Cantilena1996"/>]].
[[File:Vitamin C Plateau.jpg|center|thumb|300px|The fasting plasma Vitamin C levels of a subject given 60mg/day<ref name="LevineConry-Cantilena1996"/>.]]
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Varying doses increase the plasma levels with diminishing returns<ref name="LevineConry-Cantilena1996"/>, giving a sigmoid (s) shaped curve. Plasma Vitamin C levels are well regulated, with even extreme oral doses (3g every 4 hours) results in peak levels of only 220 mmol/L<ref name="LevinePadayatty2011"/><ref name="PadayattySun2004"/> (note that IV Vitamin C produces vastly higher plasma levels.)
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[[File:Vitamin C dose response.jpg|center|thumb|300px|The stable fasting plasma Vitamin C levels reached with varying doses<ref name="LevineConry-Cantilena1996"/>]]
The graphs above are from a single dose, with the measurement in the fasting state, but it's only at low doses of Vitamin C that peak and fasting levels are the same (i.e. 15 mg twice a day is 8.7 mmol/L) <ref name="PadayattyLevine2016"/>. If you look at the graph below you can see that the time course of Vitamin C and the timing of the doses results in different areas under the curve<ref name="PadayattySun2004"/>. Here you can see that while the higher doses of Vitamin C result in similar levels after 20+ hours, the levels following the doses are quite different and much higher for higher doses. Taking Vitamin C regularly though the day would result in higher average levels than a single dose. For instance, 1g/day of Vitamin C is sufficient to saturate fasting plasma levels, but levels may transiently raise higher (250+ mmol/L)<ref name="PolidoriMecocci2004"/>.
[[File:Vitamin C dose response2.jpg|center|thumb|400px|Dose response over the course of a day to different doses of Vitamin C<ref name="PadayattySun2004"/>]]
./
One study found that taking 60mg/day took ~3 weeks to reach stable plateau blood levels, and there were sharp change in blood levels up to 100mg, then far less change from 200mg up to 2,500mg<ref name="LevineConry-Cantilena1996"/>.
=Factors Influencing Vitamin C Needs=
Both smoking and diabetes decrease Vitamin C plasma levels compared with controls, increasing intake needs<ref name="PadayattyLevine2016"/>. Vitamin C can be reversibly or irreversibly oxidized, with irreversible oxidation consuming Vitamin C, resulting in an increased dietary need<ref name="PadayattyLevine2016"/>.
=Distribution of Vitamin C=
Vitamin C is regulated by controlling absorption in the intestine, and the balance of excretion/reabsorption in the kidney<ref name="CorpeTu2010"/>, as well as by recycling Vitamin C after it has functioned as an antioxidant<ref name="Washko Wang Levine pp. 15531–5"/>. Typically, humans only have about 1,500mg of Vitamin C in their body<ref name="HodgesHood1971"/>. Because vitamin C is an anion at physiologic pH, it cannot simply diffuse across the cell membrane to extracellular fluid and must be actively transported<ref name="RivasZúñiga2008"/>, which results in different tissues having different concentrations as shown in the picture below<ref name="PadayattyLevine2016"/>. While the level of vitamin C in skeletal muscle is lower than many other tissues<ref name="Schaus1957"/>, the size of the muscles suggests they main contain 66% of the body's vitamin C<ref name="OmayeSchaus1987"/>. A study of Vitamin C from Kiwi fruit found for intakes between ~50-210mg/day, there was a strong correlation between plasma and muscle Vitamin C levels<ref name="CarrBozonet2013"/>.
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[[File:Vitamin C Distribution.png|center|thumb|500px|The distribution of Vitamin C at 100 mg/day<ref name="PadayattyLevine2016"/>.]]
=Vitamin C, Exercise, and Aerobic Capacity=
There is lots of evidence that Vitamin C changes how the human body responds to exercise, but interpreting the evidence is not straightforward. Many of the studies have found changes in enzyme levels after exercise with Vitamin C compared with placebos, but don't measure exercise outcomes such as [[VO2max|V̇O<sub>2</sub>max]]<ref name="MorrisonHughes2015"/>. I've mostly ignored these studies as they may not reflect real world impacts. In fact, one study of 54 recreationally endurance-trained individuals taking either 100mg Vitamin C plus 235 mg Vitamin E or a placebo found that cellular adaptation to exercise was hampered by the supplements, but no changes in [[VO2max|V̇O<sub>2</sub>max]] or running performance<ref name="PaulsenCumming2014"/>. I've included the studies I've found where the outcomes are measured in real world terms for aerobic capacity (primarily [[VO2max|V̇O<sub>2</sub>max]].)
* There's strong evidence that Vitamin C deficiency results in impaired exercise ability<ref name="Corete-1999"/><ref name="Suboticanec1984"/><ref name="Buzina-1982"/>. The remainder of the studies in this section will look at Vitamin C supplementation at doses beyond those needed for the prevention of clinical deficiency.
* Many studies do not have controls with standardized Vitamin C levels, and at low intake levels small changes in intake make a large difference in plasma levels. Interventions should have controls with low intakes of Vitamin C, as some studies have used controls where the plasma levels of Vitamin C are already near saturation<ref name="PadayattyLevine2016"/>. For instance, in one study the Vitamin C treated group had similar plasma levels to the placebo group, rendering the identical results between the groups a bit meaningless<ref name="YfantiÅkerström2010"/> (at least they measured.)
* 15 amateur athletes split between placebo and 90 days of 500mg Vitamin E, 30mg beta-carotene, and then 1,000mg Vitamin C for the last 15 days<ref name="AguilóTauler2007"/>. There was no measurement of the Vitamin C status in the subjects. The [[VO2max|V̇O2max]] was 57 for the placebo group and 60 for the supplemented. The increase in [[VO2max|V̇O<sub>2</sub>max]] was not significant for either group, but workload at 4 mmol/L of [[Lactate]] was higher in the supplemented group than the placebo (but not at 2 mmol/L). I found this interesting, but inconclusive given the issues of measuring [[Lactate]], and I'd interpret this as showing no impact of Vitamin C on fitness.
* Of 14 Sedentary men ([[VO2max|V̇O<sub>2</sub>max]] < 43), 5 were given 1g/day of Vitamin C while 9 acted as controls<ref name="Gomez-CabreraDomenech2008"/>. All underwent 8 weeks of training, 3 days/week for 40 minutes, ramping up from 65% to 80% of [[VO2max|V̇O<sub>2</sub>max]]. There were no statistically different changes in [[VO2max|V̇O<sub>2</sub>max]], though the average improvement was 22% in the placebo and 10.8% in the supplemented group, mostly due to the lower initial [[VO2max|V̇O<sub>2</sub>max]] in the placebo group. With such a small group, it's possible that a larger study would reveal differences or that the differences would disappear. Interestingly, they also studied rats and found that Vitamin C dramatically reduced their endurance improvement, though again no significant differences in the rats' [[VO2max|V̇O<sub>2</sub>max]]. (The levels of Vitamin C in the supplemented group were ~165 mmol/L and in the control group were ~45 mmol/L.)
* A study that used "antioxidant rich foods" during altitude training found that [[VO2max|V̇O<sub>2</sub>max]] increased in both treated and control groups equally, but hemoglobin concentration increased more in the treated group<ref name="KoivistoPaulsen2018"/>.
* A study of 15 recreationally active men were given 1g/day of Vitamin C (n=8) or a placebo for 4 weeks of high intensity interval training, with no difference in improvement for [[VO2max|V̇O<sub>2</sub>max]], 10K time trial, or running economy<ref name="RobertsBeattie2011"/>.
* 21 active men underwent cycling training 5 days/week for 12 weeks while 11 of them received 500mg Vitamin C and 400 IU of Vitamin E<ref name="YfantiÅkerström2010"/>. There was no statistical difference in improvement in [[VO2max|V̇O<sub>2</sub>max]], maximum power, workload at [[Lactate Threshold]], or muscle [[Glycogen]] content.
=Vitamin C, Exercise, and Muscular Resiliency =
Unlike cycling or swimming, running involves eccentric muscular stress, with the muscles extending under load to absorb the body weight on landing<ref name="K.Groot2002"/><ref name="KollerSumann2006"/>, something that's exacerbated by downhill running<ref name="EstonMickleborough1995"/>. This eccentric stress is one of the causes of muscle soreness after a marathon<ref name="KyröläinenPullinen2000"/>. This damage causes [[Delayed Onset Muscle Soreness]] (DOMS), and it's particularly important to runners because while the soreness is delayed, there is muscular weakness that occurs during the damaging exercise<ref name="MarginsonRowlands2005"/>. This means the soreness you experience after a marathon involves muscular weakness during the race. There are various ways of reducing the muscle damage and treating the soreness from DOMS, but the most important is called "the repeated bout effect" (RBE). The principle of RBE is that performing exercise that causes DOMS and recovering then gives protection from similar exercise in the future<ref name="HowatsonVan Someren2007"/>. There are a number of possible mechanisms behind RBE<ref name="HyldahlChen2017"/>, including neural adaptations, changes in muscle fiber structure, changes in inflammatory response, and extracellular matrix structural remodeling. It's the extracellular matrix structural remodeling that's of interest here, as that remodeling involves collagen formation<ref name="TakagiOgasawara2016"/>, and as noted above, Vitamin C is an important part in collagen formation<ref name="GeesinDarr1988"/><ref name="Sullivan Uschmann Hough Leboy pp. 22500–6"/>. There's one study that suggests that Vitamin C might be important for the Repeated Bout Effect<ref name="HeHockemeyer2015"/> . This study used 1,000mg of Vitamin C and 400 IU Vitamin E per day on 22 moderately trained men and subjected them to two bouts of downhill running (40 min, -10%, 65-70% [[VO2max|V̇O<sub>2</sub>max]].) They found that the supplementation not only reduced DOMS after the first bout, but enhanced the RBE. Obviously, this is only one study, it used Vitamin E in addition to Vitamin C, and didn't measure strength deficits, but it's highly suggestive.
==My Vitamin C Experiment ==
The research above mirrors my personal anecdotal experience. I've been taking Vitamin C in doses around 1g/day for many years as it seems to help my skin condition. I stopped taking Vitamin C for some months in 2018 due to the research suggesting it interferes with enzyme response to exercise. During that time without Vitamin C supplementation, I was also trying to ramp back up my [[Downhill Running]] via [[Treadmill Descent]]s. I believe downhill running was a key component in my training for ultras, allowing me to race 100 miles with little muscle soreness the next day. Unfortunately, I found that 60-90 minutes of downhill running produced severe DOMS, and I couldn't get past that mark. I seemed to be stuck at that level and unable to make progress, where in previous years I'd been able to build up to marathon+ distance downhill runs. After a particularly disappointing all-day, self-supported run on Mount Mitchell in August I revisited the research on Vitamin C more comprehensively and found the study on Vitamin C and the Repeated Bout Effect. Having restarted my Vitamin C intake, and upped it to 500mg 3-5x per day, I found my ability to run downhill returned rapidly. I was able to built up to running marathon distance downhill runs at -10% within a few months, and only #1 on the DOMS scale. So for me at least, Vitamin C may be a critical component to endurance running.
==Addition Eccentric Exercise Research ==
Sadly, most research on eccentric exercise has focused on preventing or treating causes [[Delayed Onset Muscle Soreness]] (DOMS), rather than maximizing the Repeated Bout Effect, or even limiting the immediate reduction on strength. For instance, a study showed that 3g/day of Vitamin C reduced DOMS, but not reduce muscular power<ref name="BryerGoldfarb2006"/>.
=Vitamin C and Tendons?=
To follow.
=VC as pro-oxidant? =
To follow.
=VC and Diabetes? =
To follow.
=Vitamin C, Running, and the Common Cold=
Controlled studies suggest that Vitamin C may reduce the length of the common cold, but not prevent the colds except in those undergoing severe exercise such as a marathon<ref name="HemiläChalker2013"/>.
=Vitamin C, Depression, and Anxiety=
There is some evidence that Vitamin C may be related to depression and anxiety. More details to follow.
=Vitamin C Conversion Factors=
To convert ascorbic acid mg /100 mL to mol/L, multiply by 56.78<ref name="Jacob1990"/>.
=References=
<references>
<ref name="YfantiÅkerström2010">Christina Yfanti, Thorbjörn Åkerström, Søren Nielsen, Anders R. Nielsen, Remi Mounier, Ole H. Mortensen, Jens Lykkesfeldt, Adam J. Rose, Christian P. Fischer, Bente K. Pedersen, Antioxidant Supplementation Does Not Alter Endurance Training Adaptation, Medicine & Science in Sports & Exercise, volume 42, issue 7, 2010, pages 1388–1395, ISSN [http://www.worldcat.org/issn/0195-9131 0195-9131], doi [http://dx.doi.org/10.1249/MSS.0b013e3181cd76be 10.1249/MSS.0b013e3181cd76be]</ref>
<ref name="RobertsBeattie2011">Llion A. Roberts, Kris Beattie, Graeme L. Close, James P. Morton, Vitamin C Consumption Does Not Impair Training-Induced Improvements in Exercise Performance, International Journal of Sports Physiology and Performance, volume 6, issue 1, 2011, pages 58–69, ISSN [http://www.worldcat.org/issn/1555-0265 1555-0265], doi [http://dx.doi.org/10.1123/ijspp.6.1.58 10.1123/ijspp.6.1.58]</ref>
A. E. Koivisto, G. Paulsen, I. Paur, I. Garthe, E. Tønnessen, T. Raastad, N. E. Bastani, J. Hallén, R. Blomhoff, S. K. Bøhn, Antioxidant-rich foods and response to altitude training: A randomized controlled trial in elite endurance athletes, Scandinavian Journal of Medicine & Science in Sports, volume 28, issue 9, 2018, pages 1982–1995, ISSN [http://www.worldcat.org/issn/09057188 09057188], doi [http://dx.doi.org/10.1111/sms.13212 10.1111/sms.13212]</ref>
<ref name="PaulsenCumming2014">Gøran Paulsen, Kristoffer T. Cumming, Geir Holden, Jostein Hallén, Bent Ronny Rønnestad, Ole Sveen, Arne Skaug, Ingvild Paur, Nasser E. Bastani, Hege Nymo Østgaard, Charlotte Buer, Magnus Midttun, Fredrik Freuchen, Håvard Wiig, Elisabeth Tallaksen Ulseth, Ina Garthe, Rune Blomhoff, Haakon B. Benestad, Truls Raastad, Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial, The Journal of Physiology, volume 592, issue 8, 2014, pages 1887–1901, ISSN [http://www.worldcat.org/issn/00223751 00223751], doi [http://dx.doi.org/10.1113/jphysiol.2013.267419 10.1113/jphysiol.2013.267419]</ref>
<ref name="MorrisonHughes2015">Dale Morrison, Jed Hughes, Paul A. Della Gatta, Shaun Mason, Séverine Lamon, Aaron P. Russell, Glenn D. Wadley, Vitamin C and E supplementation prevents some of the cellular adaptations to endurance-training in humans, Free Radical Biology and Medicine, volume 89, 2015, pages 852–862, ISSN [http://www.worldcat.org/issn/08915849 08915849], doi [http://dx.doi.org/10.1016/j.freeradbiomed.2015.10.412 10.1016/j.freeradbiomed.2015.10.412]</ref>
<ref name="Gomez-CabreraDomenech2008">Mari-Carmen Gomez-Cabrera, Elena Domenech, Marco Romagnoli, Alessandro Arduini, Consuelo Borras, Federico V Pallardo, Juan Sastre, Jose Viña, Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance, The American Journal of Clinical Nutrition, volume 87, issue 1, 2008, pages 142–149, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/87.1.142 10.1093/ajcn/87.1.142]</ref>
<ref name="AguilóTauler2007">Antoni Aguiló, Pedro Tauler, Antoni Sureda, Nuria Cases, Josep Tur, Antoni Pons, Antioxidant diet supplementation enhances aerobic performance in amateur sportsmen, Journal of Sports Sciences, volume 25, issue 11, 2007, pages 1203–1210, ISSN [http://www.worldcat.org/issn/0264-0414 0264-0414], doi [http://dx.doi.org/10.1080/02640410600951597 10.1080/02640410600951597]</ref>
<ref name="LevineConry-Cantilena1996">M. Levine, C. Conry-Cantilena, Y. Wang, R. W. Welch, P. W. Washko, K. R. Dhariwal, J. B. Park, A. Lazarev, J. F. Graumlich, J. King, L. R. Cantilena, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance., Proceedings of the National Academy of Sciences, volume 93, issue 8, 1996, pages 3704–3709, ISSN [http://www.worldcat.org/issn/0027-8424 0027-8424], doi [http://dx.doi.org/10.1073/pnas.93.8.3704 10.1073/pnas.93.8.3704]</ref>
<ref name="PadayattyLevine2016">SJ Padayatty, M Levine, Vitamin C: the known and the unknown and Goldilocks, Oral Diseases, volume 22, issue 6, 2016, pages 463–493, ISSN [http://www.worldcat.org/issn/1354523X 1354523X], doi [http://dx.doi.org/10.1111/odi.12446 10.1111/odi.12446]</ref>
<ref name="HodgesHood1971">Robert E. Hodges, James Hood, John E. Canham, Howerde E. Sauberlich, Eugene M. Baker, Clinical manifestations of ascorbic acid deficiency in man, The American Journal of Clinical Nutrition, volume 24, issue 4, 1971, pages 432–443, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/24.4.432 10.1093/ajcn/24.4.432]</ref>
<ref name="LevineConry-Cantilena1996">M. Levine, C. Conry-Cantilena, Y. Wang, R. W. Welch, P. W. Washko, K. R. Dhariwal, J. B. Park, A. Lazarev, J. F. Graumlich, J. King, L. R. Cantilena, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance., Proceedings of the National Academy of Sciences, volume 93, issue 8, 1996, pages 3704–3709, ISSN [http://www.worldcat.org/issn/0027-8424 0027-8424], doi [http://dx.doi.org/10.1073/pnas.93.8.3704 10.1073/pnas.93.8.3704]</ref>
<ref name="EnglardSeifter1986">S Englard, S Seifter, The Biochemical Functions of Ascorbic Acid, Annual Review of Nutrition, volume 6, issue 1, 1986, pages 365–406, ISSN [http://www.worldcat.org/issn/0199-9885 0199-9885], doi [http://dx.doi.org/10.1146/annurev.nu.06.070186.002053 10.1146/annurev.nu.06.070186.002053]</ref>
<ref name="LevineDhariwal1991">M Levine, K R Dhariwal, P W Washko, J D Butler, R W Welch, Y H Wang, P Bergsten, Ascorbic acid and in situ kinetics: a new approach to vitamin requirements, The American Journal of Clinical Nutrition, volume 54, issue 6, 1991, pages 1157S–1162S, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/54.6.1157s 10.1093/ajcn/54.6.1157s]</ref>
<ref name="Rebouche1991b">C J Rebouche, Ascorbic acid and carnitine biosynthesis, The American Journal of Clinical Nutrition, volume 54, issue 6, 1991, pages 1147S–1152S, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/54.6.1147s 10.1093/ajcn/54.6.1147s]</ref>
<ref name="ProckopKivirikko1995">Darwin J. Prockop, Kari I. Kivirikko, Collagens: Molecular Biology, Diseases, and Potentials for Therapy, Annual Review of Biochemistry, volume 64, issue 1, 1995, pages 403–434, ISSN [http://www.worldcat.org/issn/0066-4154 0066-4154], doi [http://dx.doi.org/10.1146/annurev.bi.64.070195.002155 10.1146/annurev.bi.64.070195.002155]</ref>
<ref name="HallbergBrune1987">Leif Hallberg, Mats Brune, Lena Rossander-Hulthén, Is There a Physiological Role of Vitamin C in Iron Absorption?, Annals of the New York Academy of Sciences, volume 498, issue 1 Third Confere, 1987, pages 324–332, ISSN [http://www.worldcat.org/issn/0077-8923 0077-8923], doi [http://dx.doi.org/10.1111/j.1749-6632.1987.tb23771.x 10.1111/j.1749-6632.1987.tb23771.x]</ref>
<ref name="GeesinDarr1988">Jeffrey C. Geesin, Douglas. Darr, Russel. Kaufman, Saood. Murad, Sheldon R. Pinnell, Ascorbic Acid Specifically Increases Type I and Type III Procollagen Messenger RNA Levels in Human Skin Fibroblasts, Journal of Investigative Dermatology, volume 90, issue 4, 1988, pages 420–424, ISSN [http://www.worldcat.org/issn/0022202X 0022202X], doi [http://dx.doi.org/10.1111/1523-1747.ep12460849 10.1111/1523-1747.ep12460849]</ref>
<ref name="Sullivan Uschmann Hough Leboy pp. 22500–6">TA Sullivan, B Uschmann, R Hough, PS Leboy, Ascorbate modulation of chondrocyte gene expression is independent of its role in collagen secretion., The Journal of biological chemistry, volume 269, issue 36, ISSN [http://www.worldcat.org/issn/0021-9258 0021-9258], PMID [http://www.ncbi.nlm.nih.gov/pubmed/8077198 8077198], pages 22500–6</ref>
<ref name="Washko Wang Levine pp. 15531–5">PW Washko, Y Wang, M Levine, Ascorbic acid recycling in human neutrophils., The Journal of biological chemistry, volume 268, issue 21, ISSN [http://www.worldcat.org/issn/0021-9258 0021-9258], PMID [http://www.ncbi.nlm.nih.gov/pubmed/8340380 8340380], pages 15531–5</ref>
<ref name="CorpeTu2010">Christopher P. Corpe, Hongbin Tu, Peter Eck, Jin Wang, Robert Faulhaber-Walter, Jurgen Schnermann, Sam Margolis, Sebastian Padayatty, He Sun, Yaohui Wang, Robert L. Nussbaum, Michael Graham Espey, Mark Levine, Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice, Journal of Clinical Investigation, volume 120, issue 4, 2010, pages 1069–1083, ISSN [http://www.worldcat.org/issn/0021-9738 0021-9738], doi [http://dx.doi.org/10.1172/JCI39191 10.1172/JCI39191]</ref>
<ref name="Schaus1957">Raymond Schaus, The Ascorbic Acid Content of Human Pituitary, Cerebral Cortex, Heart, and Skeletal Muscle and Its Relation to Age, The American Journal of Clinical Nutrition, volume 5, issue 1, 1957, pages 39–41, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/5.1.39 10.1093/ajcn/5.1.39]</ref>
<ref name="OmayeSchaus1987">Stanley T. Omaye, Ellen E. Schaus, Mark A. Kutnink, Wayne C. Hawkes, Measurement of Vitamin C in Blood Components by High-Performance Liquid Chromatography., Annals of the New York Academy of Sciences, volume 498, issue 1 Third Confere, 1987, pages 389–401, ISSN [http://www.worldcat.org/issn/0077-8923 0077-8923], doi [http://dx.doi.org/10.1111/j.1749-6632.1987.tb23776.x 10.1111/j.1749-6632.1987.tb23776.x]</ref>
<ref name="CarrBozonet2013">Anitra C Carr, Stephanie M Bozonet, Juliet M Pullar, Jeremy W Simcock, Margreet CM Vissers, Human skeletal muscle ascorbate is highly responsive to changes in vitamin C intake and plasma concentrations, The American Journal of Clinical Nutrition, volume 97, issue 4, 2013, pages 800–807, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.3945/ajcn.112.053207 10.3945/ajcn.112.053207]</ref>
<ref name="Jacob1990">Robert A. Jacob, Assessment of Human Vitamin C Status, The Journal of Nutrition, volume 120, issue suppl_11, 1990, pages 1480–1485, ISSN [http://www.worldcat.org/issn/0022-3166 0022-3166], doi [http://dx.doi.org/10.1093/jn/120.suppl_11.1480 10.1093/jn/120.suppl_11.1480]</ref>
<ref name="Yew1975">Man-Li S. Yew, BIOLOGICAL VARIATION IN ASCORBIC ACID NEEDS, Annals of the New York Academy of Sciences, volume 258, issue 1 Second Confer, 1975, pages 451–457, ISSN [http://www.worldcat.org/issn/0077-8923 0077-8923], doi [http://dx.doi.org/10.1111/j.1749-6632.1975.tb29303.x 10.1111/j.1749-6632.1975.tb29303.x]</ref>
<ref name="PolidoriMecocci2004">M.Cristina Polidori, Patrizia Mecocci, Mark Levine, Balz Frei, Short-term and long-term vitamin C supplementation in humans dose-dependently increases the resistance of plasma to ex vivo lipid peroxidation, Archives of Biochemistry and Biophysics, volume 423, issue 1, 2004, pages 109–115, ISSN [http://www.worldcat.org/issn/00039861 00039861], doi [http://dx.doi.org/10.1016/j.abb.2003.12.019 10.1016/j.abb.2003.12.019]</ref>
<ref name="FreiEngland1989">B. Frei, L. England, B. N. Ames, Ascorbate is an outstanding antioxidant in human blood plasma., Proceedings of the National Academy of Sciences, volume 86, issue 16, 1989, pages 6377–6381, ISSN [http://www.worldcat.org/issn/0027-8424 0027-8424], doi [http://dx.doi.org/10.1073/pnas.86.16.6377 10.1073/pnas.86.16.6377]</ref>
<ref name="LevinePadayatty2011">Mark Levine, Sebastian J. Padayatty, Michael Graham Espey, Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries, Advances in Nutrition, volume 2, issue 2, 2011, pages 78–88, ISSN [http://www.worldcat.org/issn/2161-8313 2161-8313], doi [http://dx.doi.org/10.3945/an.110.000109 10.3945/an.110.000109]</ref>
<ref name="PadayattySun2004">Sebastian J. Padayatty, He Sun, Yaohui Wang, Hugh D. Riordan, Stephen M. Hewitt, Arie Katz, Robert A. Wesley, Mark Levine, Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use, Annals of Internal Medicine, volume 140, issue 7, 2004, pages 533, ISSN [http://www.worldcat.org/issn/0003-4819 0003-4819], doi [http://dx.doi.org/10.7326/0003-4819-140-7-200404060-00010 10.7326/0003-4819-140-7-200404060-00010]</ref>
<ref name="HemiläChalker2013">Harri Hemilä, Elizabeth Chalker, Vitamin C for preventing and treating the common cold, Cochrane Database of Systematic Reviews, 2013, ISSN [http://www.worldcat.org/issn/14651858 14651858], doi [http://dx.doi.org/10.1002/14651858.CD000980.pub4 10.1002/14651858.CD000980.pub4]</ref>
<ref name="LevineConry-Cantilena1996">M. Levine, C. Conry-Cantilena, Y. Wang, R. W. Welch, P. W. Washko, K. R. Dhariwal, J. B. Park, A. Lazarev, J. F. Graumlich, J. King, L. R. Cantilena, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance., Proceedings of the National Academy of Sciences, volume 93, issue 8, 1996, pages 3704–3709, ISSN [http://www.worldcat.org/issn/0027-8424 0027-8424], doi [http://dx.doi.org/10.1073/pnas.93.8.3704 10.1073/pnas.93.8.3704]</ref>
<ref name="KovanenSuominen1984">V. Kovanen, H. Suominen, E. Heikkinen, Collagen of slow twitch and fast twitch muscle fibres in different types of rat skeletal muscle, European Journal of Applied Physiology and Occupational Physiology, volume 52, issue 2, 1984, pages 235–242, ISSN [http://www.worldcat.org/issn/0301-5548 0301-5548], doi [http://dx.doi.org/10.1007/BF00433399 10.1007/BF00433399]</ref>
<ref name="FranchiTrirè2007">Marco Franchi, Alessandra Trirè, Marilisa Quaranta, Ester Orsini, Victoria Ottani, Collagen Structure of Tendon Relates to Function, The Scientific World JOURNAL, volume 7, 2007, pages 404–420, ISSN [http://www.worldcat.org/issn/1537-744X 1537-744X], doi [http://dx.doi.org/10.1100/tsw.2007.92 10.1100/tsw.2007.92]</ref>
<ref name="CarrFrei1999">Anitra C Carr, Balz Frei, Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans, The American Journal of Clinical Nutrition, volume 69, issue 6, 1999, pages 1086–1107, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/69.6.1086 10.1093/ajcn/69.6.1086]</ref>
<ref name="RivasZúñiga2008">C. I. Rivas, F. A. Zúñiga, A. Salas-Burgos, L. Mardones, V. Ormazabal, J. C. Vera, Vitamin C transporters, Journal of Physiology and Biochemistry, volume 64, issue 4, 2008, pages 357–375, ISSN [http://www.worldcat.org/issn/1138-7548 1138-7548], doi [http://dx.doi.org/10.1007/BF03174092 10.1007/BF03174092]</ref>
<ref name="Corete-1999">Swan, and Corte. "Substrate utilization and work efficiency during submaximal exercise in vitamin C depleted-repleted adults." International journal for vitamin and nutrition research 69.1 (1999): 41-44.</ref>
<ref name="Suboticanec1984">K Suboticanec-Buzina, R Buzina, G Brubacher, J Sapunar, S Christeller, Vitamin C status and physical working capacity in adolescents., International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition, volume 54, issue 1, 1984, ISSN [http://www.worldcat.org/issn/0300-9831 0300-9831], PMID [http://www.ncbi.nlm.nih.gov/pubmed/6735616 6735616], pages 55–60</ref>
<ref name="Buzina-1982">R Buzina, Z Grgić, M Jusić, J Sapunar, N Milanović, G Brubacher, Nutritional status and physical working capacity., Human nutrition. Clinical nutrition, volume 36, issue 6, 1982, ISSN [http://www.worldcat.org/issn/0263-8290 0263-8290], PMID [http://www.ncbi.nlm.nih.gov/pubmed/7161138 7161138], pages 429–38</ref>
<ref name="YfantiÅkerström2010">Christina Yfanti, Thorbjörn Åkerström, Søren Nielsen, Anders R. Nielsen, Remi Mounier, Ole H. Mortensen, Jens Lykkesfeldt, Adam J. Rose, Christian P. Fischer, Bente K. Pedersen, Antioxidant Supplementation Does Not Alter Endurance Training Adaptation, Medicine & Science in Sports & Exercise, volume 42, issue 7, 2010, pages 1388–1395, ISSN [http://www.worldcat.org/issn/0195-9131 0195-9131], doi [http://dx.doi.org/10.1249/MSS.0b013e3181cd76be 10.1249/MSS.0b013e3181cd76be]</ref>
<ref name="HeHockemeyer2015">F. He, J. Hockemeyer, D. Sedlock, Does Combined Antioxidant Vitamin Supplementation Blunt Repeated Bout Effect?, International Journal of Sports Medicine, volume 36, issue 05, 2015, pages 407–413, ISSN [http://www.worldcat.org/issn/0172-4622 0172-4622], doi [http://dx.doi.org/10.1055/s-0034-1395630 10.1055/s-0034-1395630]</ref>
<ref name="K.Groot2002">Bijker K., G. de Groot, Hollander A., Differences in leg muscle activity during running and cycling in humans, European Journal of Applied Physiology, volume 87, issue 6, 2002, pages 556–561, ISSN [http://www.worldcat.org/issn/1439-6319 1439-6319], doi [http://dx.doi.org/10.1007/s00421-002-0663-8 10.1007/s00421-002-0663-8]</ref>
<ref name="KollerSumann2006">A Koller, G Sumann, W Schobersberger, H Hoertnagl, C Haid, N Maffulli, Decrease in eccentric hamstring strength in runners in the Tirol Speed Marathon * COMMENTARY, British Journal of Sports Medicine, volume 40, issue 10, 2006, pages 850–852, ISSN [http://www.worldcat.org/issn/0306-3674 0306-3674], doi [http://dx.doi.org/10.1136/bjsm.2006.028175 10.1136/bjsm.2006.028175]</ref>
<ref name="EstonMickleborough1995">R G Eston, J Mickleborough, V Baltzopoulos, Eccentric activation and muscle damage: biomechanical and physiological considerations during downhill running., British Journal of Sports Medicine, volume 29, issue 2, 1995, pages 89–94, ISSN [http://www.worldcat.org/issn/0306-3674 0306-3674], doi [http://dx.doi.org/10.1136/bjsm.29.2.89 10.1136/bjsm.29.2.89]</ref>
<ref name="KyröläinenPullinen2000">H. Kyröläinen, T. Pullinen, R. Candau, J. Avela, P. Huttunen, P. V. Komi, Effects of marathon running on running economy and kinematics, European Journal of Applied Physiology, volume 82, issue 4, 2000, pages 297–304, ISSN [http://www.worldcat.org/issn/1439-6319 1439-6319], doi [http://dx.doi.org/10.1007/s004210000219 10.1007/s004210000219]</ref>
<ref name="MarginsonRowlands2005">Vicky Marginson, Ann V. Rowlands, Nigel P. Gleeson, Roger G. Eston, Comparison of the symptoms of exercise-induced muscle damage after an initial and repeated bout of plyometric exercise in men and boys, Journal of Applied Physiology, volume 99, issue 3, 2005, pages 1174–1181, ISSN [http://www.worldcat.org/issn/8750-7587 8750-7587], doi [http://dx.doi.org/10.1152/japplphysiol.01193.2004 10.1152/japplphysiol.01193.2004]</ref>
<ref name="HowatsonVan Someren2007">G. Howatson, K. Van Someren, T. Hortobágyi, Repeated Bout Effect after Maximal Eccentric Exercise, International Journal of Sports Medicine, volume 28, issue 7, 2007, pages 557–563, ISSN [http://www.worldcat.org/issn/0172-4622 0172-4622], doi [http://dx.doi.org/10.1055/s-2007-964866 10.1055/s-2007-964866]</ref>
<ref name="HyldahlChen2017">Robert D. Hyldahl, Trevor C. Chen, Kazunori Nosaka, Mechanisms and Mediators of the Skeletal Muscle Repeated Bout Effect, Exercise and Sport Sciences Reviews, volume 45, issue 1, 2017, pages 24–33, ISSN [http://www.worldcat.org/issn/0091-6331 0091-6331], doi [http://dx.doi.org/10.1249/JES.0000000000000095 10.1249/JES.0000000000000095]</ref>
<ref name="TakagiOgasawara2016">Ryo Takagi, Riki Ogasawara, Arata Tsutaki, Koichi Nakazato, Naokata Ishii, Regional adaptation of collagen in skeletal muscle to repeated bouts of strenuous eccentric exercise, Pflügers Archiv - European Journal of Physiology, volume 468, issue 9, 2016, pages 1565–1572, ISSN [http://www.worldcat.org/issn/0031-6768 0031-6768], doi [http://dx.doi.org/10.1007/s00424-016-1860-3 10.1007/s00424-016-1860-3]</ref>
<ref name="BryerGoldfarb2006">S.C. Bryer, A.H. Goldfarb, 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, volume 16, issue 3, 2006, pages 270–280, ISSN [http://www.worldcat.org/issn/1526-484X 1526-484X], doi [http://dx.doi.org/10.1123/ijsnem.16.3.270 10.1123/ijsnem.16.3.270]</ref>
<ref name="KoivistoPaulsen2018">A. E. Koivisto, G. Paulsen, I. Paur, I. Garthe, E. Tønnessen, T. Raastad, N. E. Bastani, J. Hallén, R. Blomhoff, S. K. Bøhn, Antioxidant-rich foods and response to altitude training: A randomized controlled trial in elite endurance athletes, Scandinavian Journal of Medicine & Science in Sports, volume 28, issue 9, 2018, pages 1982–1995, ISSN [http://www.worldcat.org/issn/09057188 09057188], doi [http://dx.doi.org/10.1111/sms.13212 10.1111/sms.13212]</ref>
</references>
Vitamin C may be an important supplement for runners. A runner's quads lengthen to slow their body's descent on landing, a type of eccentric exercise. This eccentric stress not only causes [[Delayed Onset Muscle Soreness]] (DOMS), but it also causes immediate weakness. If you've ever had problems descending stairs after a marathon, you've had DOMS. The good news is that experiencing DOMS provides a protection from future bouts, something known as the Repeated Bout Effect (RBE), which is where Vitamin C comes in. As well as being an antioxidant, Vitamin C is important in may other ways, including the production of the scaffolding that makes up muscles (collagen.) There is some evidence that Vitamin C may help with the RBE, and without sufficient Vitamin C, the ability to adapt to long runs may be impaired. While Vitamin C has been shown to interfere with the way people adapt to exercise at a biochemical level, that doesn't appear to translate into practical problems. If you take Vitamin C as a supplement, it's best to take it spread evenly through the day rather than a single larger dose.
=The Role of Vitamin C=
Vitamin C is best known for its role as an antioxidant. However, it's not only an antioxidant, but it's also cofactor for 15 different enzymes<ref name="EnglardSeifter1986"/>, including the production of norepinephrine<ref name="LevineDhariwal1991"/>, carnitine<ref name="Rebouche1991b"/>, and collagen<ref name="ProckopKivirikko1995"/>. It also enhances non-heme iron absorption<ref name="HallbergBrune1987"/>. Increased Vitamin C may also boost the amount of Collagen synthesized<ref name="GeesinDarr1988"/><ref name="Sullivan Uschmann Hough Leboy pp. 22500–6"/>. This is especially valuable for runners, as collagen is a key structural protein, including muscle fibers<ref name="KovanenSuominen1984"/> and tendons<ref name="FranchiTrirè2007"/>. Even within the role as an antioxidant there is the possibility that different antioxidants may fulfill different roles. For instance, there is evidence that Vitamin C depleted plasma is susceptible to fat (lipid) oxidation, even when other anti-oxidants are present<ref name="FreiEngland1989"/>. Personally, I suspect that these various roles may result in differing actions of vitamins C in differing circumstances. Vitamin C is concentrated in nearly all cells in the body above plasma levels, such as the brain with 16-18x and muscle with 4-6x, though It's unclear why many tissues concentrate Vitamin C levels well beyond the level needed for the enzymatic actions, sometimes 10-100x higher<ref name="PadayattyLevine2016"/>. There is evidence from animal models that the Vitamin C needs may vary widely, possibly due to genetic differences<ref name="Yew1975"/>. This has been seen in humans, where there is wide variation in susceptibility to scurvy amongst sailors<ref name="Yew1975"/>.
=Vitamin C Requirements=
The recommended intake for vitamins C is focused on preventing deficiency problems, primarily scurvy<ref name="CarrFrei1999"/>. Vitamin C deficiency (scurvy) results in lassitude (fatigue), coiled hair, gum problems, anemia, hemorrhages, tooth loss and other problems<ref name="PadayattyLevine2016"/>. Sometimes the only symptom of vitamins C deficiency is lassitude, even when plasma levels are below 8 uM<ref name="LevineConry-Cantilena1996"/>. Most animals can produce their own Vitamin C, except for humans and other primates, Guinea pigs, fruit bats, and some birds and fish<ref name="PadayattyLevine2016"/>. The optimum dose of Vitamin C for runners is unclear based on the available research.
=Vitamin C Intakes=
Vitamin C is absorbed in the small intestine, reaching peak plasma levels in 2-3 hours, and then to extracellular fluids<ref name="PadayattyLevine2016"/>. Over many days, the level of vitamin C in the plasma stabilizes, as shown below<ref name="LevineConry-Cantilena1996"/>]].
[[File:Vitamin C Plateau.jpg|center|thumb|300px|The fasting plasma Vitamin C levels of a subject given 60mg/day<ref name="LevineConry-Cantilena1996"/>.]]
/
Varying doses increase the plasma levels with diminishing returns<ref name="LevineConry-Cantilena1996"/>, giving a sigmoid (s) shaped curve. Plasma Vitamin C levels are well regulated, with even extreme oral doses (3g every 4 hours) results in peak levels of only 220 mmol/L<ref name="LevinePadayatty2011"/><ref name="PadayattySun2004"/> (note that IV Vitamin C produces vastly higher plasma levels.)
/
[[File:Vitamin C dose response.jpg|center|thumb|300px|The stable fasting plasma Vitamin C levels reached with varying doses<ref name="LevineConry-Cantilena1996"/>]]
The graphs above are from a single dose, with the measurement in the fasting state, but it's only at low doses of Vitamin C that peak and fasting levels are the same (i.e. 15 mg twice a day is 8.7 mmol/L) <ref name="PadayattyLevine2016"/>. If you look at the graph below you can see that the time course of Vitamin C and the timing of the doses results in different areas under the curve<ref name="PadayattySun2004"/>. Here you can see that while the higher doses of Vitamin C result in similar levels after 20+ hours, the levels following the doses are quite different and much higher for higher doses. Taking Vitamin C regularly though the day would result in higher average levels than a single dose. For instance, 1g/day of Vitamin C is sufficient to saturate fasting plasma levels, but levels may transiently raise higher (250+ mmol/L)<ref name="PolidoriMecocci2004"/>.
[[File:Vitamin C dose response2.jpg|center|thumb|400px|Dose response over the course of a day to different doses of Vitamin C<ref name="PadayattySun2004"/>]]
./
One study found that taking 60mg/day took ~3 weeks to reach stable plateau blood levels, and there were sharp change in blood levels up to 100mg, then far less change from 200mg up to 2,500mg<ref name="LevineConry-Cantilena1996"/>.
=Factors Influencing Vitamin C Needs=
Both smoking and diabetes decrease Vitamin C plasma levels compared with controls, increasing intake needs<ref name="PadayattyLevine2016"/>. Vitamin C can be reversibly or irreversibly oxidized, with irreversible oxidation consuming Vitamin C, resulting in an increased dietary need<ref name="PadayattyLevine2016"/>.
=Distribution of Vitamin C=
Vitamin C is regulated by controlling absorption in the intestine, and the balance of excretion/reabsorption in the kidney<ref name="CorpeTu2010"/>, as well as by recycling Vitamin C after it has functioned as an antioxidant<ref name="Washko Wang Levine pp. 15531–5"/>. Typically, humans only have about 1,500mg of Vitamin C in their body<ref name="HodgesHood1971"/>. Because vitamin C is an anion at physiologic pH, it cannot simply diffuse across the cell membrane to extracellular fluid and must be actively transported<ref name="RivasZúñiga2008"/>, which results in different tissues having different concentrations as shown in the picture below<ref name="PadayattyLevine2016"/>. While the level of vitamin C in skeletal muscle is lower than many other tissues<ref name="Schaus1957"/>, the size of the muscles suggests they main contain 66% of the body's vitamin C<ref name="OmayeSchaus1987"/>. A study of Vitamin C from Kiwi fruit found for intakes between ~50-210mg/day, there was a strong correlation between plasma and muscle Vitamin C levels<ref name="CarrBozonet2013"/>.
/
[[File:Vitamin C Distribution.png|center|thumb|500px|The distribution of Vitamin C at 100 mg/day<ref name="PadayattyLevine2016"/>.]]
=Vitamin C, Exercise, and Aerobic Capacity=
There is lots of evidence that Vitamin C changes how the human body responds to exercise, but interpreting the evidence is not straightforward. Many of the studies have found changes in enzyme levels after exercise with Vitamin C compared with placebos, but don't measure exercise outcomes such as [[VO2max|V̇O<sub>2</sub>max]]<ref name="MorrisonHughes2015"/>. I've mostly ignored these studies as they may not reflect real world impacts. In fact, one study of 54 recreationally endurance-trained individuals taking either 100mg Vitamin C plus 235 mg Vitamin E or a placebo found that cellular adaptation to exercise was hampered by the supplements, but no changes in [[VO2max|V̇O<sub>2</sub>max]] or running performance<ref name="PaulsenCumming2014"/>. I've included the studies I've found where the outcomes are measured in real world terms for aerobic capacity (primarily [[VO2max|V̇O<sub>2</sub>max]].)
* There's strong evidence that Vitamin C deficiency results in impaired exercise ability<ref name="Corete-1999"/><ref name="Suboticanec1984"/><ref name="Buzina-1982"/>. The remainder of the studies in this section will look at Vitamin C supplementation at doses beyond those needed for the prevention of clinical deficiency.
* Many studies do not have controls with standardized Vitamin C levels, and at low intake levels small changes in intake make a large difference in plasma levels. Interventions should have controls with low intakes of Vitamin C, as some studies have used controls where the plasma levels of Vitamin C are already near saturation<ref name="PadayattyLevine2016"/>. For instance, in one study the Vitamin C treated group had similar plasma levels to the placebo group, rendering the identical results between the groups a bit meaningless<ref name="YfantiÅkerström2010"/> (at least they measured.)
* 15 amateur athletes split between placebo and 90 days of 500mg Vitamin E, 30mg beta-carotene, and then 1,000mg Vitamin C for the last 15 days<ref name="AguilóTauler2007"/>. There was no measurement of the Vitamin C status in the subjects. The [[VO2max|V̇O2max]] was 57 for the placebo group and 60 for the supplemented. The increase in [[VO2max|V̇O<sub>2</sub>max]] was not significant for either group, but workload at 4 mmol/L of [[Lactate]] was higher in the supplemented group than the placebo (but not at 2 mmol/L). I found this interesting, but inconclusive given the issues of measuring [[Lactate]], and I'd interpret this as showing no impact of Vitamin C on fitness.
* Of 14 Sedentary men ([[VO2max|V̇O<sub>2</sub>max]] < 43), 5 were given 1g/day of Vitamin C while 9 acted as controls<ref name="Gomez-CabreraDomenech2008"/>. All underwent 8 weeks of training, 3 days/week for 40 minutes, ramping up from 65% to 80% of [[VO2max|V̇O<sub>2</sub>max]]. There were no statistically different changes in [[VO2max|V̇O<sub>2</sub>max]], though the average improvement was 22% in the placebo and 10.8% in the supplemented group, mostly due to the lower initial [[VO2max|V̇O<sub>2</sub>max]] in the placebo group. With such a small group, it's possible that a larger study would reveal differences or that the differences would disappear. Interestingly, they also studied rats and found that Vitamin C dramatically reduced their endurance improvement, though again no significant differences in the rats' [[VO2max|V̇O<sub>2</sub>max]]. (The levels of Vitamin C in the supplemented group were ~165 mmol/L and in the control group were ~45 mmol/L.)
* A study that used "antioxidant rich foods" during altitude training found that [[VO2max|V̇O<sub>2</sub>max]] increased in both treated and control groups equally, but hemoglobin concentration increased more in the treated group<ref name="KoivistoPaulsen2018"/>.
* A study of 15 recreationally active men were given 1g/day of Vitamin C (n=8) or a placebo for 4 weeks of high intensity interval training, with no difference in improvement for [[VO2max|V̇O<sub>2</sub>max]], 10K time trial, or running economy<ref name="RobertsBeattie2011"/>.
* 21 active men underwent cycling training 5 days/week for 12 weeks while 11 of them received 500mg Vitamin C and 400 IU of Vitamin E<ref name="YfantiÅkerström2010"/>. There was no statistical difference in improvement in [[VO2max|V̇O<sub>2</sub>max]], maximum power, workload at [[Lactate Threshold]], or muscle [[Glycogen]] content.
=Vitamin C, Exercise, and Muscular Resiliency =
Unlike cycling or swimming, running involves eccentric muscular stress, with the muscles extending under load to absorb the body weight on landing<ref name="K.Groot2002"/><ref name="KollerSumann2006"/>, something that's exacerbated by downhill running<ref name="EstonMickleborough1995"/>. This eccentric stress is one of the causes of muscle soreness after a marathon<ref name="KyröläinenPullinen2000"/>. This damage causes [[Delayed Onset Muscle Soreness]] (DOMS), and it's particularly important to runners because while the soreness is delayed, there is muscular weakness that occurs during the damaging exercise<ref name="MarginsonRowlands2005"/>. This means the soreness you experience after a marathon involves muscular weakness during the race. There are various ways of reducing the muscle damage and treating the soreness from DOMS, but the most important is called "the repeated bout effect" (RBE). The principle of RBE is that performing exercise that causes DOMS and recovering then gives protection from similar exercise in the future<ref name="HowatsonVan Someren2007"/>. There are a number of possible mechanisms behind RBE<ref name="HyldahlChen2017"/>, including neural adaptations, changes in muscle fiber structure, changes in inflammatory response, and extracellular matrix structural remodeling. It's the extracellular matrix structural remodeling that's of interest here, as that remodeling involves collagen formation<ref name="TakagiOgasawara2016"/>, and as noted above, Vitamin C is an important part in collagen formation<ref name="GeesinDarr1988"/><ref name="Sullivan Uschmann Hough Leboy pp. 22500–6"/>. There's one study that suggests that Vitamin C might be important for the Repeated Bout Effect<ref name="HeHockemeyer2015"/> . This study used 1,000mg of Vitamin C and 400 IU Vitamin E per day on 22 moderately trained men and subjected them to two bouts of downhill running (40 min, -10%, 65-70% [[VO2max|V̇O<sub>2</sub>max]].) They found that the supplementation not only reduced DOMS after the first bout, but enhanced the RBE. Obviously, this is only one study, it used Vitamin E in addition to Vitamin C, and didn't measure strength deficits, but it's highly suggestive.
==My Vitamin C Experiment ==
The research above mirrors my personal anecdotal experience. I've been taking Vitamin C in doses around 1g/day for many years as it seems to help my skin condition. I stopped taking Vitamin C for some months in 2018 due to the research suggesting it interferes with enzyme response to exercise. During that time without Vitamin C supplementation, I was also trying to ramp back up my [[Downhill Running]] via [[Treadmill Descent]]s. I believe downhill running was a key component in my training for ultras, allowing me to race 100 miles with little muscle soreness the next day. Unfortunately, I found that 60-90 minutes of downhill running produced severe DOMS, and I couldn't get past that mark. I seemed to be stuck at that level and unable to make progress, where in previous years I'd been able to build up to marathon+ distance downhill runs. After a particularly disappointing all-day, self-supported run on Mount Mitchell in August I revisited the research on Vitamin C more comprehensively and found the study on Vitamin C and the Repeated Bout Effect. Having restarted my Vitamin C intake, and upped it to 500mg 3-5x per day, I found my ability to run downhill returned rapidly. I was able to built up to running marathon distance downhill runs at -10% within a few months, and only #1 on the DOMS scale. So for me at least, Vitamin C may be a critical component to endurance running.
==Addition Eccentric Exercise Research ==
Sadly, most research on eccentric exercise has focused on preventing or treating causes [[Delayed Onset Muscle Soreness]] (DOMS), rather than maximizing the Repeated Bout Effect, or even limiting the immediate reduction on strength. For instance, a study showed that 3g/day of Vitamin C reduced DOMS, but not reduce muscular power<ref name="BryerGoldfarb2006"/>.
=Vitamin C and Tendons?=
To follow.
=VC as pro-oxidant? =
To follow.
=VC and Diabetes? =
To follow.
=Vitamin C, Running, and the Common Cold=
Controlled studies suggest that Vitamin C may reduce the length of the common cold, but not prevent the colds except in those undergoing severe exercise such as a marathon<ref name="HemiläChalker2013"/>.
=Vitamin C, Depression, and Anxiety=
There is some evidence that Vitamin C may be related to depression and anxiety. More details to follow.
=Vitamin C Conversion Factors=
To convert ascorbic acid mg /100 mL to mol/L, multiply by 56.78<ref name="Jacob1990"/>.
=References=
<references>
<ref name="YfantiÅkerström2010">Christina Yfanti, Thorbjörn Åkerström, Søren Nielsen, Anders R. Nielsen, Remi Mounier, Ole H. Mortensen, Jens Lykkesfeldt, Adam J. Rose, Christian P. Fischer, Bente K. Pedersen, Antioxidant Supplementation Does Not Alter Endurance Training Adaptation, Medicine & Science in Sports & Exercise, volume 42, issue 7, 2010, pages 1388–1395, ISSN [http://www.worldcat.org/issn/0195-9131 0195-9131], doi [http://dx.doi.org/10.1249/MSS.0b013e3181cd76be 10.1249/MSS.0b013e3181cd76be]</ref>
<ref name="RobertsBeattie2011">Llion A. Roberts, Kris Beattie, Graeme L. Close, James P. Morton, Vitamin C Consumption Does Not Impair Training-Induced Improvements in Exercise Performance, International Journal of Sports Physiology and Performance, volume 6, issue 1, 2011, pages 58–69, ISSN [http://www.worldcat.org/issn/1555-0265 1555-0265], doi [http://dx.doi.org/10.1123/ijspp.6.1.58 10.1123/ijspp.6.1.58]</ref>
A. E. Koivisto, G. Paulsen, I. Paur, I. Garthe, E. Tønnessen, T. Raastad, N. E. Bastani, J. Hallén, R. Blomhoff, S. K. Bøhn, Antioxidant-rich foods and response to altitude training: A randomized controlled trial in elite endurance athletes, Scandinavian Journal of Medicine & Science in Sports, volume 28, issue 9, 2018, pages 1982–1995, ISSN [http://www.worldcat.org/issn/09057188 09057188], doi [http://dx.doi.org/10.1111/sms.13212 10.1111/sms.13212]</ref>
<ref name="PaulsenCumming2014">Gøran Paulsen, Kristoffer T. Cumming, Geir Holden, Jostein Hallén, Bent Ronny Rønnestad, Ole Sveen, Arne Skaug, Ingvild Paur, Nasser E. Bastani, Hege Nymo Østgaard, Charlotte Buer, Magnus Midttun, Fredrik Freuchen, Håvard Wiig, Elisabeth Tallaksen Ulseth, Ina Garthe, Rune Blomhoff, Haakon B. Benestad, Truls Raastad, Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial, The Journal of Physiology, volume 592, issue 8, 2014, pages 1887–1901, ISSN [http://www.worldcat.org/issn/00223751 00223751], doi [http://dx.doi.org/10.1113/jphysiol.2013.267419 10.1113/jphysiol.2013.267419]</ref>
<ref name="MorrisonHughes2015">Dale Morrison, Jed Hughes, Paul A. Della Gatta, Shaun Mason, Séverine Lamon, Aaron P. Russell, Glenn D. Wadley, Vitamin C and E supplementation prevents some of the cellular adaptations to endurance-training in humans, Free Radical Biology and Medicine, volume 89, 2015, pages 852–862, ISSN [http://www.worldcat.org/issn/08915849 08915849], doi [http://dx.doi.org/10.1016/j.freeradbiomed.2015.10.412 10.1016/j.freeradbiomed.2015.10.412]</ref>
<ref name="Gomez-CabreraDomenech2008">Mari-Carmen Gomez-Cabrera, Elena Domenech, Marco Romagnoli, Alessandro Arduini, Consuelo Borras, Federico V Pallardo, Juan Sastre, Jose Viña, Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance, The American Journal of Clinical Nutrition, volume 87, issue 1, 2008, pages 142–149, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/87.1.142 10.1093/ajcn/87.1.142]</ref>
<ref name="AguilóTauler2007">Antoni Aguiló, Pedro Tauler, Antoni Sureda, Nuria Cases, Josep Tur, Antoni Pons, Antioxidant diet supplementation enhances aerobic performance in amateur sportsmen, Journal of Sports Sciences, volume 25, issue 11, 2007, pages 1203–1210, ISSN [http://www.worldcat.org/issn/0264-0414 0264-0414], doi [http://dx.doi.org/10.1080/02640410600951597 10.1080/02640410600951597]</ref>
<ref name="LevineConry-Cantilena1996">M. Levine, C. Conry-Cantilena, Y. Wang, R. W. Welch, P. W. Washko, K. R. Dhariwal, J. B. Park, A. Lazarev, J. F. Graumlich, J. King, L. R. Cantilena, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance., Proceedings of the National Academy of Sciences, volume 93, issue 8, 1996, pages 3704–3709, ISSN [http://www.worldcat.org/issn/0027-8424 0027-8424], doi [http://dx.doi.org/10.1073/pnas.93.8.3704 10.1073/pnas.93.8.3704]</ref>
<ref name="PadayattyLevine2016">SJ Padayatty, M Levine, Vitamin C: the known and the unknown and Goldilocks, Oral Diseases, volume 22, issue 6, 2016, pages 463–493, ISSN [http://www.worldcat.org/issn/1354523X 1354523X], doi [http://dx.doi.org/10.1111/odi.12446 10.1111/odi.12446]</ref>
<ref name="HodgesHood1971">Robert E. Hodges, James Hood, John E. Canham, Howerde E. Sauberlich, Eugene M. Baker, Clinical manifestations of ascorbic acid deficiency in man, The American Journal of Clinical Nutrition, volume 24, issue 4, 1971, pages 432–443, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/24.4.432 10.1093/ajcn/24.4.432]</ref>
<ref name="LevineConry-Cantilena1996">M. Levine, C. Conry-Cantilena, Y. Wang, R. W. Welch, P. W. Washko, K. R. Dhariwal, J. B. Park, A. Lazarev, J. F. Graumlich, J. King, L. R. Cantilena, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance., Proceedings of the National Academy of Sciences, volume 93, issue 8, 1996, pages 3704–3709, ISSN [http://www.worldcat.org/issn/0027-8424 0027-8424], doi [http://dx.doi.org/10.1073/pnas.93.8.3704 10.1073/pnas.93.8.3704]</ref>
<ref name="EnglardSeifter1986">S Englard, S Seifter, The Biochemical Functions of Ascorbic Acid, Annual Review of Nutrition, volume 6, issue 1, 1986, pages 365–406, ISSN [http://www.worldcat.org/issn/0199-9885 0199-9885], doi [http://dx.doi.org/10.1146/annurev.nu.06.070186.002053 10.1146/annurev.nu.06.070186.002053]</ref>
<ref name="LevineDhariwal1991">M Levine, K R Dhariwal, P W Washko, J D Butler, R W Welch, Y H Wang, P Bergsten, Ascorbic acid and in situ kinetics: a new approach to vitamin requirements, The American Journal of Clinical Nutrition, volume 54, issue 6, 1991, pages 1157S–1162S, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/54.6.1157s 10.1093/ajcn/54.6.1157s]</ref>
<ref name="Rebouche1991b">C J Rebouche, Ascorbic acid and carnitine biosynthesis, The American Journal of Clinical Nutrition, volume 54, issue 6, 1991, pages 1147S–1152S, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/54.6.1147s 10.1093/ajcn/54.6.1147s]</ref>
<ref name="ProckopKivirikko1995">Darwin J. Prockop, Kari I. Kivirikko, Collagens: Molecular Biology, Diseases, and Potentials for Therapy, Annual Review of Biochemistry, volume 64, issue 1, 1995, pages 403–434, ISSN [http://www.worldcat.org/issn/0066-4154 0066-4154], doi [http://dx.doi.org/10.1146/annurev.bi.64.070195.002155 10.1146/annurev.bi.64.070195.002155]</ref>
<ref name="HallbergBrune1987">Leif Hallberg, Mats Brune, Lena Rossander-Hulthén, Is There a Physiological Role of Vitamin C in Iron Absorption?, Annals of the New York Academy of Sciences, volume 498, issue 1 Third Confere, 1987, pages 324–332, ISSN [http://www.worldcat.org/issn/0077-8923 0077-8923], doi [http://dx.doi.org/10.1111/j.1749-6632.1987.tb23771.x 10.1111/j.1749-6632.1987.tb23771.x]</ref>
<ref name="GeesinDarr1988">Jeffrey C. Geesin, Douglas. Darr, Russel. Kaufman, Saood. Murad, Sheldon R. Pinnell, Ascorbic Acid Specifically Increases Type I and Type III Procollagen Messenger RNA Levels in Human Skin Fibroblasts, Journal of Investigative Dermatology, volume 90, issue 4, 1988, pages 420–424, ISSN [http://www.worldcat.org/issn/0022202X 0022202X], doi [http://dx.doi.org/10.1111/1523-1747.ep12460849 10.1111/1523-1747.ep12460849]</ref>
<ref name="Sullivan Uschmann Hough Leboy pp. 22500–6">TA Sullivan, B Uschmann, R Hough, PS Leboy, Ascorbate modulation of chondrocyte gene expression is independent of its role in collagen secretion., The Journal of biological chemistry, volume 269, issue 36, ISSN [http://www.worldcat.org/issn/0021-9258 0021-9258], PMID [http://www.ncbi.nlm.nih.gov/pubmed/8077198 8077198], pages 22500–6</ref>
<ref name="Washko Wang Levine pp. 15531–5">PW Washko, Y Wang, M Levine, Ascorbic acid recycling in human neutrophils., The Journal of biological chemistry, volume 268, issue 21, ISSN [http://www.worldcat.org/issn/0021-9258 0021-9258], PMID [http://www.ncbi.nlm.nih.gov/pubmed/8340380 8340380], pages 15531–5</ref>
<ref name="CorpeTu2010">Christopher P. Corpe, Hongbin Tu, Peter Eck, Jin Wang, Robert Faulhaber-Walter, Jurgen Schnermann, Sam Margolis, Sebastian Padayatty, He Sun, Yaohui Wang, Robert L. Nussbaum, Michael Graham Espey, Mark Levine, Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice, Journal of Clinical Investigation, volume 120, issue 4, 2010, pages 1069–1083, ISSN [http://www.worldcat.org/issn/0021-9738 0021-9738], doi [http://dx.doi.org/10.1172/JCI39191 10.1172/JCI39191]</ref>
<ref name="Schaus1957">Raymond Schaus, The Ascorbic Acid Content of Human Pituitary, Cerebral Cortex, Heart, and Skeletal Muscle and Its Relation to Age, The American Journal of Clinical Nutrition, volume 5, issue 1, 1957, pages 39–41, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/5.1.39 10.1093/ajcn/5.1.39]</ref>
<ref name="OmayeSchaus1987">Stanley T. Omaye, Ellen E. Schaus, Mark A. Kutnink, Wayne C. Hawkes, Measurement of Vitamin C in Blood Components by High-Performance Liquid Chromatography., Annals of the New York Academy of Sciences, volume 498, issue 1 Third Confere, 1987, pages 389–401, ISSN [http://www.worldcat.org/issn/0077-8923 0077-8923], doi [http://dx.doi.org/10.1111/j.1749-6632.1987.tb23776.x 10.1111/j.1749-6632.1987.tb23776.x]</ref>
<ref name="CarrBozonet2013">Anitra C Carr, Stephanie M Bozonet, Juliet M Pullar, Jeremy W Simcock, Margreet CM Vissers, Human skeletal muscle ascorbate is highly responsive to changes in vitamin C intake and plasma concentrations, The American Journal of Clinical Nutrition, volume 97, issue 4, 2013, pages 800–807, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.3945/ajcn.112.053207 10.3945/ajcn.112.053207]</ref>
<ref name="Jacob1990">Robert A. Jacob, Assessment of Human Vitamin C Status, The Journal of Nutrition, volume 120, issue suppl_11, 1990, pages 1480–1485, ISSN [http://www.worldcat.org/issn/0022-3166 0022-3166], doi [http://dx.doi.org/10.1093/jn/120.suppl_11.1480 10.1093/jn/120.suppl_11.1480]</ref>
<ref name="Yew1975">Man-Li S. Yew, BIOLOGICAL VARIATION IN ASCORBIC ACID NEEDS, Annals of the New York Academy of Sciences, volume 258, issue 1 Second Confer, 1975, pages 451–457, ISSN [http://www.worldcat.org/issn/0077-8923 0077-8923], doi [http://dx.doi.org/10.1111/j.1749-6632.1975.tb29303.x 10.1111/j.1749-6632.1975.tb29303.x]</ref>
<ref name="PolidoriMecocci2004">M.Cristina Polidori, Patrizia Mecocci, Mark Levine, Balz Frei, Short-term and long-term vitamin C supplementation in humans dose-dependently increases the resistance of plasma to ex vivo lipid peroxidation, Archives of Biochemistry and Biophysics, volume 423, issue 1, 2004, pages 109–115, ISSN [http://www.worldcat.org/issn/00039861 00039861], doi [http://dx.doi.org/10.1016/j.abb.2003.12.019 10.1016/j.abb.2003.12.019]</ref>
<ref name="FreiEngland1989">B. Frei, L. England, B. N. Ames, Ascorbate is an outstanding antioxidant in human blood plasma., Proceedings of the National Academy of Sciences, volume 86, issue 16, 1989, pages 6377–6381, ISSN [http://www.worldcat.org/issn/0027-8424 0027-8424], doi [http://dx.doi.org/10.1073/pnas.86.16.6377 10.1073/pnas.86.16.6377]</ref>
<ref name="LevinePadayatty2011">Mark Levine, Sebastian J. Padayatty, Michael Graham Espey, Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries, Advances in Nutrition, volume 2, issue 2, 2011, pages 78–88, ISSN [http://www.worldcat.org/issn/2161-8313 2161-8313], doi [http://dx.doi.org/10.3945/an.110.000109 10.3945/an.110.000109]</ref>
<ref name="PadayattySun2004">Sebastian J. Padayatty, He Sun, Yaohui Wang, Hugh D. Riordan, Stephen M. Hewitt, Arie Katz, Robert A. Wesley, Mark Levine, Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use, Annals of Internal Medicine, volume 140, issue 7, 2004, pages 533, ISSN [http://www.worldcat.org/issn/0003-4819 0003-4819], doi [http://dx.doi.org/10.7326/0003-4819-140-7-200404060-00010 10.7326/0003-4819-140-7-200404060-00010]</ref>
<ref name="HemiläChalker2013">Harri Hemilä, Elizabeth Chalker, Vitamin C for preventing and treating the common cold, Cochrane Database of Systematic Reviews, 2013, ISSN [http://www.worldcat.org/issn/14651858 14651858], doi [http://dx.doi.org/10.1002/14651858.CD000980.pub4 10.1002/14651858.CD000980.pub4]</ref>
<ref name="LevineConry-Cantilena1996">M. Levine, C. Conry-Cantilena, Y. Wang, R. W. Welch, P. W. Washko, K. R. Dhariwal, J. B. Park, A. Lazarev, J. F. Graumlich, J. King, L. R. Cantilena, Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance., Proceedings of the National Academy of Sciences, volume 93, issue 8, 1996, pages 3704–3709, ISSN [http://www.worldcat.org/issn/0027-8424 0027-8424], doi [http://dx.doi.org/10.1073/pnas.93.8.3704 10.1073/pnas.93.8.3704]</ref>
<ref name="KovanenSuominen1984">V. Kovanen, H. Suominen, E. Heikkinen, Collagen of slow twitch and fast twitch muscle fibres in different types of rat skeletal muscle, European Journal of Applied Physiology and Occupational Physiology, volume 52, issue 2, 1984, pages 235–242, ISSN [http://www.worldcat.org/issn/0301-5548 0301-5548], doi [http://dx.doi.org/10.1007/BF00433399 10.1007/BF00433399]</ref>
<ref name="FranchiTrirè2007">Marco Franchi, Alessandra Trirè, Marilisa Quaranta, Ester Orsini, Victoria Ottani, Collagen Structure of Tendon Relates to Function, The Scientific World JOURNAL, volume 7, 2007, pages 404–420, ISSN [http://www.worldcat.org/issn/1537-744X 1537-744X], doi [http://dx.doi.org/10.1100/tsw.2007.92 10.1100/tsw.2007.92]</ref>
<ref name="CarrFrei1999">Anitra C Carr, Balz Frei, Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans, The American Journal of Clinical Nutrition, volume 69, issue 6, 1999, pages 1086–1107, ISSN [http://www.worldcat.org/issn/0002-9165 0002-9165], doi [http://dx.doi.org/10.1093/ajcn/69.6.1086 10.1093/ajcn/69.6.1086]</ref>
<ref name="RivasZúñiga2008">C. I. Rivas, F. A. Zúñiga, A. Salas-Burgos, L. Mardones, V. Ormazabal, J. C. Vera, Vitamin C transporters, Journal of Physiology and Biochemistry, volume 64, issue 4, 2008, pages 357–375, ISSN [http://www.worldcat.org/issn/1138-7548 1138-7548], doi [http://dx.doi.org/10.1007/BF03174092 10.1007/BF03174092]</ref>
<ref name="Corete-1999">Swan, and Corte. "Substrate utilization and work efficiency during submaximal exercise in vitamin C depleted-repleted adults." International journal for vitamin and nutrition research 69.1 (1999): 41-44.</ref>
<ref name="Suboticanec1984">K Suboticanec-Buzina, R Buzina, G Brubacher, J Sapunar, S Christeller, Vitamin C status and physical working capacity in adolescents., International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition, volume 54, issue 1, 1984, ISSN [http://www.worldcat.org/issn/0300-9831 0300-9831], PMID [http://www.ncbi.nlm.nih.gov/pubmed/6735616 6735616], pages 55–60</ref>
<ref name="Buzina-1982">R Buzina, Z Grgić, M Jusić, J Sapunar, N Milanović, G Brubacher, Nutritional status and physical working capacity., Human nutrition. Clinical nutrition, volume 36, issue 6, 1982, ISSN [http://www.worldcat.org/issn/0263-8290 0263-8290], PMID [http://www.ncbi.nlm.nih.gov/pubmed/7161138 7161138], pages 429–38</ref>
<ref name="YfantiÅkerström2010">Christina Yfanti, Thorbjörn Åkerström, Søren Nielsen, Anders R. Nielsen, Remi Mounier, Ole H. Mortensen, Jens Lykkesfeldt, Adam J. Rose, Christian P. Fischer, Bente K. Pedersen, Antioxidant Supplementation Does Not Alter Endurance Training Adaptation, Medicine & Science in Sports & Exercise, volume 42, issue 7, 2010, pages 1388–1395, ISSN [http://www.worldcat.org/issn/0195-9131 0195-9131], doi [http://dx.doi.org/10.1249/MSS.0b013e3181cd76be 10.1249/MSS.0b013e3181cd76be]</ref>
<ref name="HeHockemeyer2015">F. He, J. Hockemeyer, D. Sedlock, Does Combined Antioxidant Vitamin Supplementation Blunt Repeated Bout Effect?, International Journal of Sports Medicine, volume 36, issue 05, 2015, pages 407–413, ISSN [http://www.worldcat.org/issn/0172-4622 0172-4622], doi [http://dx.doi.org/10.1055/s-0034-1395630 10.1055/s-0034-1395630]</ref>
<ref name="K.Groot2002">Bijker K., G. de Groot, Hollander A., Differences in leg muscle activity during running and cycling in humans, European Journal of Applied Physiology, volume 87, issue 6, 2002, pages 556–561, ISSN [http://www.worldcat.org/issn/1439-6319 1439-6319], doi [http://dx.doi.org/10.1007/s00421-002-0663-8 10.1007/s00421-002-0663-8]</ref>
<ref name="KollerSumann2006">A Koller, G Sumann, W Schobersberger, H Hoertnagl, C Haid, N Maffulli, Decrease in eccentric hamstring strength in runners in the Tirol Speed Marathon * COMMENTARY, British Journal of Sports Medicine, volume 40, issue 10, 2006, pages 850–852, ISSN [http://www.worldcat.org/issn/0306-3674 0306-3674], doi [http://dx.doi.org/10.1136/bjsm.2006.028175 10.1136/bjsm.2006.028175]</ref>
<ref name="EstonMickleborough1995">R G Eston, J Mickleborough, V Baltzopoulos, Eccentric activation and muscle damage: biomechanical and physiological considerations during downhill running., British Journal of Sports Medicine, volume 29, issue 2, 1995, pages 89–94, ISSN [http://www.worldcat.org/issn/0306-3674 0306-3674], doi [http://dx.doi.org/10.1136/bjsm.29.2.89 10.1136/bjsm.29.2.89]</ref>
<ref name="KyröläinenPullinen2000">H. Kyröläinen, T. Pullinen, R. Candau, J. Avela, P. Huttunen, P. V. Komi, Effects of marathon running on running economy and kinematics, European Journal of Applied Physiology, volume 82, issue 4, 2000, pages 297–304, ISSN [http://www.worldcat.org/issn/1439-6319 1439-6319], doi [http://dx.doi.org/10.1007/s004210000219 10.1007/s004210000219]</ref>
<ref name="MarginsonRowlands2005">Vicky Marginson, Ann V. Rowlands, Nigel P. Gleeson, Roger G. Eston, Comparison of the symptoms of exercise-induced muscle damage after an initial and repeated bout of plyometric exercise in men and boys, Journal of Applied Physiology, volume 99, issue 3, 2005, pages 1174–1181, ISSN [http://www.worldcat.org/issn/8750-7587 8750-7587], doi [http://dx.doi.org/10.1152/japplphysiol.01193.2004 10.1152/japplphysiol.01193.2004]</ref>
<ref name="HowatsonVan Someren2007">G. Howatson, K. Van Someren, T. Hortobágyi, Repeated Bout Effect after Maximal Eccentric Exercise, International Journal of Sports Medicine, volume 28, issue 7, 2007, pages 557–563, ISSN [http://www.worldcat.org/issn/0172-4622 0172-4622], doi [http://dx.doi.org/10.1055/s-2007-964866 10.1055/s-2007-964866]</ref>
<ref name="HyldahlChen2017">Robert D. Hyldahl, Trevor C. Chen, Kazunori Nosaka, Mechanisms and Mediators of the Skeletal Muscle Repeated Bout Effect, Exercise and Sport Sciences Reviews, volume 45, issue 1, 2017, pages 24–33, ISSN [http://www.worldcat.org/issn/0091-6331 0091-6331], doi [http://dx.doi.org/10.1249/JES.0000000000000095 10.1249/JES.0000000000000095]</ref>
<ref name="TakagiOgasawara2016">Ryo Takagi, Riki Ogasawara, Arata Tsutaki, Koichi Nakazato, Naokata Ishii, Regional adaptation of collagen in skeletal muscle to repeated bouts of strenuous eccentric exercise, Pflügers Archiv - European Journal of Physiology, volume 468, issue 9, 2016, pages 1565–1572, ISSN [http://www.worldcat.org/issn/0031-6768 0031-6768], doi [http://dx.doi.org/10.1007/s00424-016-1860-3 10.1007/s00424-016-1860-3]</ref>
<ref name="BryerGoldfarb2006">S.C. Bryer, A.H. Goldfarb, 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, volume 16, issue 3, 2006, pages 270–280, ISSN [http://www.worldcat.org/issn/1526-484X 1526-484X], doi [http://dx.doi.org/10.1123/ijsnem.16.3.270 10.1123/ijsnem.16.3.270]</ref>
<ref name="KoivistoPaulsen2018">A. E. Koivisto, G. Paulsen, I. Paur, I. Garthe, E. Tønnessen, T. Raastad, N. E. Bastani, J. Hallén, R. Blomhoff, S. K. Bøhn, Antioxidant-rich foods and response to altitude training: A randomized controlled trial in elite endurance athletes, Scandinavian Journal of Medicine & Science in Sports, volume 28, issue 9, 2018, pages 1982–1995, ISSN [http://www.worldcat.org/issn/09057188 09057188], doi [http://dx.doi.org/10.1111/sms.13212 10.1111/sms.13212]</ref>
</references>