Plausible ergogenic effects of vitamin D on athletic performance and recovery

Vitamin D, a fat-soluble vitamin, was first discovered in cod liver oil [1] and has since been identified as an essential vitamin, acting as a precursor steroid to a host of metabolic and biological processes. Once converted into its biologically-active form, 1,25-dihydroxyvitamin D [2], it regulates the expression of over 900 gene variants [3]. These gene expressions have been shown to have significant impact on a wide variety of health and performance-related variables, such as exercise-induced inflammation, tumour suppressor genes, neurological function, cardiovascular health, glucose metabolism, bone health and skeletal muscle performance [4‐10]. Surprisingly enough, 88.1 % of the world’s population has inadequate vitamin D levels [11]. Deficiency has been shown to be linked to a variety of adverse psychological and health outcomes, such as suicidal thoughts [12], depression [13], cognitive decline and neurological impairment [14], and an increased risk of cancer [15]. Furthermore, individuals with inefficient vitamin D stores have an increased risk of bone disorders like spondyloarthritis [16], rickets [1, 17], and fractures due to higher bone resorption from an overproduction of parathyroid hormone (PTH) [18, 19]. Lastly, deficiency has catabolic effects on muscle tissue [20], causes muscle weakness [21], and impairs cross-bridge formation [22], all of which could impair athletic performance. Due to the increase in enzymatic activity of exercise [23], athletes may be as susceptible, if not more susceptible to becoming vitamin D deficient when compared to the general population. A recent meta-analysis pooling 23 studies with 2313 athletes found that 56 % of athletes had inadequate vitamin D levels [24]. Because of the high prevalence of vitamin D deficiency [25] and its effects on human physiology, this review is aimed to identify the role of vitamin D in athletic performance (for health related aspects of vitamin D, see [11, 18, 26, 27]). This review will cover how vitamin D is metabolized in the body, its potential roles in athletic performance, sources of vitamin D, differences between vitamin D₂ and vitamin D₃, optimal levels of vitamin D for athletes, and strategies to achieve these levels and prevent toxicity by nutrient-nutrient interactions.

Vitamin D travels in the bloodstream bound to vitamin D-binding proteins [28] and undergoes a three-stage process of key enzymatic reactions [Fig. 1]: 25-hydroxylation, 1α-hydroxylation and 24-hydroxylation [18, 29]. The steroid precursor vitamin D₃ first travels to the liver where it is hydroxylated to 25-hydroxyvitamin D [25(OH)D] by 25-hydroxlayse, which is mediated by the cytochrome P450 enzymes, CYP27A1 (in the mitochondria) and CYP2R1 [29]. This 25(OH)D is then hydroxylated by CYP27B1 (1α-hydroxylation) [29]. This final step occurs primarily in the kidney [18], but various other tissues, namely skeletal muscle, have also been shown to express CYP24A1 enzymes, where 25(OH)D becomes the active hormonal form, 1,25-dihydroxyvitamin D [29]. 1,25-dihydroxyvitamin D then interacts with vitamin D receptors (VDR), which are located in almost every tissue in the body [30, 31], and is then transcribed into the cell and binds to vitamin D response elements (VDREs) located in DNA [18]. If 1,25-dihydroxyvitmain D does not interact with VDREs, it is further degraded by CYP24A1 (24-hydroxylase) to the inactive form, calcitroic acid [29].

Vitamin D₃ receptors exist in human skeletal muscle tissue [30, 31], indicating that 1,25-dihydroxyvitamin D has a direct effect on skeletal muscle activity. Research on the muscle effects of vitamin D₃ [32] is limited to diseased populations [20, 33], or healthy untrained adults [34]. Until recently, a few reviews and meta-analyses have shown that increasing serum 25(OH)D levels in a given population have a positive effect on muscle strength, power and mass [33‐35] but the only study that examined the effects in athletes [36], had mixed results. In addition, von Hurst and Beck [36] concluded that the optimal intake and serum concentration of 25(OH)D have yet to be identified in the athletic population.

Testosterone is an endogenous hormone important for muscular adaptations to training. Naturally low testosterone levels in young men have been linked to decreases in protein anabolism, strength, beta-oxidation, and an increase in adipose deposition [57]. Thus, athletes endeavour to optimize natural androgenic production. A recent cross-sectional study done on 2299 older men (62 ± 11 years of age) showed that 25(OH)D levels correlated with testosterone and androgen levels in men [58]. Low testosterone, or hypogonadism, was identified in 18 % of the participants, and these men had significantly lower mean 25(OH)D levels than the rest of the population. Furthermore, only 11.4 % of the sample had sufficient levels of vitamin D.

Additionally a 12-month, double-blind, randomized control trial in 54 non-diabetic males demonstrated that the group receiving 3332 IU/day of vitamin D had a significant increase in circulating 25-hydroxyvitamin D, total testosterone, bioactive testosterone, and free testosterone levels [59]. These findings support the notion that elevating 25(OH)D levels may augment testosterone production in non-diabetic male subjects, which indicates that vitamin D supplementation might have ergogenic potential through the enhancement of endogenous testosterone production. More research is required in order to investigate this potential role of vitamin D and testosterone levels in various study populations [Table 4].

The specific mechanism of action of 25(OH)D on testosterone in men could potentially be related to two processes: inhibited testosterone aromatization and enhanced androgen binding. Evidence for both of these mechanisms comes from animal models. Specifically, higher 25(OH)D levels inhibit gonadal aromatization of testosterone in VDR knockout mice [60]. Secondly, VDR and vitamin D metabolizing enzymes have been located in human and rat testis and have been shown to enhance the affinity of androgen binding receptors [57, 61, 62]. This effect increases the rate at which androgens can bind to testosterone-producing glands resulting in higher concentrations of steroid hormones, leading to an increase in skeletal muscle hypertrophy, strength and power output [63, 64].

Both D₂ and D₃ are capable of increasing plasma 25(OH)D concentration, but vitamin D₃ might be more effective than vitamin D₂ [75, 77, 78]. When compared to vitamin D₃, vitamin D₂ is less stable, less bioavailable with increasing age, and it has been shown in multiple clinical studies that the amount of vitamin D₂ absorbed is significantly lower than with vitamin D₃. Furthermore, vitamin D₂ has a lower affinity to VDRs [54, 75, 77‐79] and a higher rate of deactivation once hydroxylated in the kidney due to side-chain variations [77]. Lastly, an epidemiological study during the winter months in Dunedin, New Zealand investigated the effects of 1000 IU/day of either vitamin D₂ or vitamin D₃ supplementation over a 25-week period in 95 healthy, adult participants (18–50 years old) [78]. The participants who received the vitamin D₂ supplement had a larger decrease in serum 25(OH)D (74 nmol/L to 50 nmol/L) levels than those who took vitamin D₃ (80 nmol/L to 72 nmol/L) [78]. However, both results show that 1000 IU/day of vitamin D was inadequate to increase serum 25(OH)D concentrations and actually caused a decline with both isoforms.

With vitamin D₃ proving more efficacious, the optimal dosage varies depending on the individual and the institution providing the guidelines. The Institute of Medicine (IOM) recommends 400–800 IU/day for children, adults and individuals >70 years of age to maintain serum vitamin D at >50 nmol/L [11, 80, 81]. Alternatively, the Endocrine Society (ES) recommends a slightly higher intake, with dosages of 400–1000 IU/day for infants, 600–1000 IU/day for children, and 1500-2000 IU/day for adults in order to maintain adequate serum vitamin D concentrations of 75 nmol/L [82]. These recommendations correspond with a review in 2004 [83], stating that 70 nmol/L is the lowest desirable serum concentration to prevent adverse health effects. Other recommendations have suggested optimal levels may be 90 to greater than 120 nmol/L [86, 87], based on estimations made from that of levels seen in individuals inhabiting very sunlight-rich environments [84] and/or have shown optimal lower-extremity function [85].

The definitions of hypovitaminosis or hypervitaminosis are more controversial. The IOM defines inadequate stores of 25(OH)D as 30–50 nmol/L, and deficiency as 25(OH)D <30 nmol/L [88], and sets the upper limit of dietary intake of vitamin D to 4000 IU/day [69]. The ES on the other hand, defines vitamin D deficiency at levels of 25(OH)D <50 nmol/L, insufficiency as 25(OH)D between 51 to 74 nmol/L [89], and sets the upper limit of dietary intake of vitamin D to 10,000 IU/day [19]. However, recent reviews have suggested that this is more of a theoretical concern [72, 83, 84, 90]. The optimal vitamin D dosage and level are clearly controversial [88, 91]. Furthermore, the optimal levels needed for athletic performance have not yet been determined. Growing evidence has supported that 600–800 IU/day may not be sufficient for optimal levels of vitamin D, especially for the athletic population [92], since serum 25(OH)D concentrations greater than 100 nmol/L have been proposed to be optimal for lower body skeletal muscle function [85] and low vitamin D levels are linked to increased bone turnover, increasing the risk of stress fractures [93]. It has been shown that it takes roughly 2000 to 5000 IU/day of vitamin D from all available sources in order to optimize bone health by maintaining serum 25(OH)D levels of 75 to 80 nmol/L [84, 85, 94, 95]. Furthermore, this dosage would be unattainable from natural UVB exposure during the months of October to April when residing in latitudes of 42.2 to 52° N [96] which is indicated by the high prevalence of vitamin D deficient indoor and outdoor athletes in a multitude of disciplines [24, 97‐99]. Lastly, studies that have shown to improve athletic prowess utilize dosages higher than 3000 IU/day, but none have yet to reach levels greater than 100 nmol/L. Thus, it remains unclear, but athletes may benefit from 25(OH)D levels ≥100 nmol/L in order to increase skeletal muscle function and reduce the risk of stress fractures.

However, no study to date has looked at the effects of vitamin D supplementation and skeletal muscle function in the athletic population with 25(OH)D levels of ≥100 nmol/L [36]. Additionally, the previous performance intervention studies presented in this review supplemented with dosages far greater than the recommended dosages of 600–2000 IU/day (e.g., 5000 IU/day of D₃) and 1000 IU/day of vitamin D₃ during the winter months is not enough to prevent a decline in serum 25(OH)D stores [78].

Although it has been reported that vitamin D toxicity might occur with dosages of ≥10,000 IU/day for an extended period [71, 84], producing adverse effects like hypercalcemia, the level of vitamin D causing toxicity is unclear [71, 100], and due to ethical reasons, no prospective studies have analyzed the effect of vitamin D intoxication in humans. Recently, an accidental overdose of 2,000,000 IU of vitamin D₃ in two elderly patients did not cause adverse effects and only elevated blood calcium levels slightly [101]. More importantly, adverse effects have only been reported at serum concentrations of 25(OH)D above 200 nmol/L, which would take daily dosages of 40,000 IU or more of vitamin D to achieve [84], and serum concentrations of 25(OH)D of <140 nmol/L have not been correlated with hypercalcemia. 1,25-dihydroxyvitamin D works synergistically with calcium and allows it to be absorbed from the gastrointestinal tract and stimulates mature osteoblasts to produce receptor activator nuclear factor-kB ligand (RANKL) [102]. RANKL in turn stimulates mineralization and bone resorption via osteoclastogenesis. Increased levels of 25(OH)D can accelerate this process, causing a rise in calcium concentration in the blood, a higher absorption rate of calcium by the kidneys, and could potentially lead to kidney stones and/or potential vascular calcification [103].

Any discussion of vitamin D toxicity merits mention of vitamin K. As with calcium, vitamin K works synergistically with vitamin D to regulate bone resorption, activation and distribution [104]. Vitamin K carboxylates the newly-formed ostecalcin proteins that are produced in mature bone cells and are tightly regulated by vitamin D [105]. Once the protein is carboxylated, it interacts with calcium ions in bone tissue [106] and has a significant effect on bone mineralization, formation, the prevention of bone loss, and potentially the stoppage of fractures in women [105, 107‐111]. However, when levels of vitamin K are inadequate, the ostecalcin production is not suppressed [109]. This situation facilitates a build-up of un-carboxylated (inactive) ostecalcin proteins in bone, leading to a potential increase in calcium release from bone and the deposition of calcium into soft tissues (causing arterial calcification) [112, 113]. Thus, vitamin D₃ toxicity might occur only in the absence of sufficient vitamin K stores.

Recommended dosages of vitamin K range from 50 mcg to 1000 mcg [108]. However, these recommendations are controversial since vitamin K stores are rapidly depleted without constant supply [114] and like vitamin D, vitamin K also has two variants: K₁ and K₂. Sources of vitamin K can be found in pharmacological analogues and naturally in the diet. Vitamin K₁, the most abundant form found in an individual’s diet [115], is high in green leafy cruciferous vegetables, fruits, various vegetable oils and beans [114]. Vitamin K₂, the more bioavailable form of vitamin K [114], comes in a variety of fish, offal, meat, dairy products, fermented cheese (e.g., blue cheese), and fermented products like natto (fermented soybeans, a Japanese delicacy) [116].

Both forms play different roles in the body [117], but the IOM has set the recommended dietary intake only for the K₁ isoform (90 mcg/day for women and 120 mcg/day for men), with no upper limit, and has yet to set any dietary recommendation for vitamin K₂ [114]. Specifically, vitamin K₁ has a key role in the carboxylation of various blood clotting proteins, where vitamin K₂ is essential for the carboxylation and activation of osteocalcin and matrix Gla protein (MGP) (an essential protein needed to prevent soft tissue calcification) [118]. More importantly, one of the vitamin K₂ variants, MK-4, is more effective at mitigating osteoclast formation and the negative health effects of vitamin D overdose [114, 115]. Furthermore, 10 mg/day (10,000 mcg) of synthetic vitamin K₁ (phytonadione, sold as Konakion® [119]) has been shown to be beneficial for elite female marathon runners by increasing bone formation and preventing bone loss [120] and mega-doses of 45 mg/day (45,000 mcg) of MK-4 in combination with vitamin D₃ could prevent osteoporosis in postmenopausal women [102, 109]. Thus, although MK-4 might have the greatest effect on carboxylation of osteocalcin, both vitamin K₁ and K₂ interact with each other in order to optimize bone health and are essential to the human body. Further research in athletic populations should focus on the optimal dosage for vitamin D₃ in combination with vitamin K.

In summary, an interesting theme has emerged from animal studies that supraphysiological dosages of vitamin D₃ have potential ergogenic effects on the human metabolic system and lead to multiple physiological enhancements. These dosages could increase aerobic capacity, muscle growth, force and power production, and a decreased recovery time from exercise. These dosages could also improve bone density. However, both deficiency (12.5 to 50 nmol/L) and high levels of vitamin D (>125 nmol/L) can have negative side effects, with the potential for an increased mortality [121]. Thus, maintenance of optimal serum levels between 75 to 100 nmol/L [11, 86] and ensuring adequate amounts of other essential nutrients including vitamin K are consumed, is key to health and performance. Coaches, medical practitioners, and athletic personnel should recommend their patients and athletes to have their plasma 25(OH)D measured, in order to determine if supplementation is needed. Based on the research presented on recovery, force and power production, 4000-5000 IU/day of vitamin D₃ in conjunction with a mixture of 50 mcg/day to 1000 mcg/day of vitamin K₁ and K₂ seems to be a safe dose and has the potential to aid athletic performance. Lastly, no study in the athletic population has increased serum 25(OH)D levels past 100 nmol/L, (the optimal range for skeletal muscle function) using doses of 1000 to 5000 IU/day. Thus, future studies should test the physiological effects of higher dosages (5000 IU to 10,000 IU/day or more) of vitamin D₃ in combination with varying dosages of vitamin K₁ and vitamin K₂ in the athletic population to determine optimal dosages needed to maximize performance.