View source for Vitamin C

{{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"/>]]
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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=
A 2018 review of the research found that Vitamin C studies on animals improved tendon and bone healing, but that the human research at that point was limited<ref name="DePhillipoAman2018"/>. One study found that 200 IU Vitamin E with 500 mg Vitamin C improved ACL healing (1-6 weeks) after ACL surgery, but the differences disappeared by 3 months<ref name="BarkerLeonard2009">. 
=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"/>. (This will be of use if you're digging into the research papers.) 
=References=
<references>
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<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>
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