Nucleotides the 'Next Big Thing' in Ergogenic Supplements? Faster Force-Recovery & Cortisol + CK Modulation in New, Increased Endurance & Immune Effects in Previous Studies

Nucleotides are building blocks of our DNA and RNA and - as preliminary evi- dence suggests - ergogenic supplements for athletes on intense workout routines. In that, "intense" is the key word, 'cause normally our bodies can produce enough nucleotides on their own.

Nucleotides? Yeah, this are the small subunits, of nucleic acids like DNA and RNA. They are essential to nearly all biological processes including DNA and RNA synthesis, coenzyme synthesis, energy metabolism, cellular signaling and protein homeostasis and can be produced by our bodies "on demand" via de novo synthesis. Just like some of the non-essential amino acids which may become essential under certain circumstances, though, our bodies' own nucleotide production facility are often incapable of meeting the needs of rapidly proliferating tissues.

As Sterczala et al. (2015) point out in the introduction to their latest paper in the Journal of Strength and Conditioning Research, a salvage pathway is therefore required to synthesize nucleotides from exogenous sources (Gil. 2002).

If you are overtraining even the best ergogenic won't help you recover!

Never Train Just "To Burn Calories", Folks!

"Cardio" ↔ Overtraining & Muscle Loss?

Is There Such a Thing as "Overtraining"?

2 Alternative Methods to Test for Overtraining

Heart Rate Variability to Test for Overtraining

Overtraining & Self-Inflicted Hypothyroidism

As such, dietary nucleotides are necessary to maintain immune function, tissue growth and cellular repair. Sounds familiar? Yeah, all of those functions are affected by exercise, which can (at least temporarily) significantly increase one's nucleotide demands to levels that cannot be supplied by endogenous (=the body's own) synthesis, alone. A recent study which shows that the blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis even suggest that this may be one of the reasons old muscle won't grow (Kirby. 2015). Consequently, there has been a growing interest in the potentiaL implications of exogenous nucleotide supplementation on exercise-induced immune
responses.

"Aside from increases in salivary immunoglobulins, McNaughton et al. (2006 & 2007) have observed a decreased cortisol response to exercise, which would partially explain the reduced immunosuppression. Animal models have observed similarly attenuated cortisol responses to stressful stimuli (Palermo. 2013, Tahmasebi-Kohyani. 2012). Given the roles of cortisol in gluconeogenesis and glycogenolysis, a reduced cortisol response may indicate a reduction in the metabolic stress of the exercise bout as a result of nucleotide supplementation. In the days following stressful exercise, [chronically (!) | see red box to learn why this is important] elevated cortisol levels could impair recovery, as cortisol can increase protein degradation and inhibit protein synthesis (Hickson. 1993; Kraemer. 2005)" (Sterczala. 2015). 

So, while we don't want to block the cortisol response to exercise altogether (here's why), Sterczala et al. are right: Attenuating or controlling it may quite beneficial. Especially if this attenuation occurs in the days after the exercise-stressor, when you want your cortisol levels to return to normal. Unfortunately, Ostojic et al. (2012 & 2013) and McNaughton et al. (2006 & 2007) who have already demonstrated the beneficial effects of nucleotide supplementation following acute exercise, did not control for the immune and cortisol response during the recovery period after the exercise stimulus. In addition, their studies involved cycling and running exercises which are, as Sterczala et al. rightly point out, "quite different in terms of muscle recruitment and metabolic demands when compared to heavy resistance exercise" (Sterczala. 2015). Therefore, the effects of nucleotide supplementation on the response patterns to resistance exercise are currently unknown and thus the perfect research object for a new study - Sterczala et al.'s new study.

Only the cortisol, not the GH, IGF-1 or testosterone response to exercise correlate w/ increased lean mass gains  in response to 12w of resistance training (West. 2012).

The acute cortisol response to exercise is not your enemy! In fact, the seminal study by West et al. (2012) which investigated the associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort of young men after weight training shows: Neither the increases in testosterone, nor the growth hormone or IGF-1 excursions right after the workout is associated with lean mass gains in response to a standardized 12-week resistance training regimen. The cortisol excursions right after the workout, on the other hand, are statistically significantly associated with increases in lean mass. So, make no mistake: We don't want to blunt cortisol altogether. If anything, we want to control it - especially on the days after an intense workout.

Said study used a double blinded, cross-over, within subject design, with ten young men and ten women participating in the acute heavy resistance exercise protocol (AHREP) following a loading period with either a nucleotide supplement or placebo supplementation phase.

Do you remember that protease supple- mentation (e.g. 1,000mg Bromelain) has recently been shown to have ergogenic effects in athletes, too? 

"The nuBound® (Nu Science Laboratories, Inc., Boston, MA [the sponsor of the study]) supplement contains dietary nucleotides, which are extracted from yeast (saccharomyces cerevisiae). During the supplement treatment cycle, subjects took two capsules of nuBound® daily, one upon waking, and one following exercise. The two capsules (1000mg) contained 278mg of dietary nucleotides, 375mg amino acids (l-glutamine, l-methionine, l-lysine), riboflavin (4.5mg), folate (400mcg), biotin (188mg) and pantothenic acid (12mcg). Other ingredients included fructo-oligosaccharides (chicory root), inositol and sodium citrate.

During the placebo cycle, subjects followed a dosing schedule identical to the supplement cycle. The placebo capsules were identical in size, shape and color to the nucleotide supplement but contained only lactose and magnesium stearate. During the first treatment cycle, subjects recorded their daily dietary intake on a diet log. The log was then used to help subjects replicate their diet during the second treatment cycle. Subjects also replicated their activity protocol during the study for each cycle" (Sterczala. 2015)."

Each cycle (placebo - PL; nucleiotides - NT) began with a two week loading phase in which subjects took the supplement while maintaining their normal exercise routines. At the beginning of the third week, an acute heavy resistance exercise protocol (AHREP) was completed. To assess the effects on recovery, subjects reported to the laboratory 24, 48 and 72 hrs following the AHREP for additional blood draws and performance testing. Before and after the the acute heavy resistance exercise protocol (AHREP), and at 24, 48, and 72 hrs thereafter, blood samples were analyzed for cortisol, myeloperoxidase, and absolute neutrophil, lymphocyte and monocyte counts. Creatine kinase was analyzed pre-AHREP and at 24, 48, and 72 hrs post-AHREP. Performance measures, including peak back squat isometric force and peak countermovement jump power were also analyzed.

Figure 1: Effects of nucleotide (NT) and placebo supplement (PL) preload for two weeks on cortisol (~stress) and creatine kinase (~muscle damage) response to exercise (Sterczala. 2015).

As you can see in Figure 1 the nucleotide supplementation resulted in significant (P ≤ 0.05) decreases in observed cortisol and MPO acutely following the AHREP, as well as significantly lower CK values at 24 hrs post. The AHREP significantly affected leukocyte counts, however, no treatment effects were observed (which is in contrast to previous studies, but in view of the disconnect between this markers and practically relevant immune outcomes, like the susceptibility to infection, irrelevant).

Figure 2: While the improved cortisol and CK are nice to see, only the accelerated force recovery in the isometric back-squat test may actually be practically relevant for athletes (Sterczala. 2015).

What is significantly more important than any of these markers of muscle stress, muscle damage or immune function is the fact that the the nucleotide supplement increased the peak force in the back squat isometric force test (albeit not the power during counter-movement jumps) immediately post AHREP and at 24 hrs and 48 hrs (see Figure 2). After all, changes like these, and not improvements in markers of whatever are what really matters for athletes.

With Ostojic's 2013 study we do have initial evidence that nucleotide supplements will also have practically relevant ergogenic effects - in this case increases in maximal (to exhaustion) running endurance.

Bottom line: One question you may rightly be asking now is whether the changes Sterczala, et al. observed are actually practically relevant. To answer this question we'd need additional (longer-term) independent (non-sponsored) studies to investigate strength and size gains, directly. Still, the accelerated recovery of maximal isometric force, in the study at hand, and the increased time to exhaustion in Ostojic's 2013 study, in which the researchers investigated the effects of sublingual nucleotides on running in young, physically active men, we cannot negate, that there is evidence to support the notion that nucleotide supplements may be more than another supplemental non-starter that affects the response to exercise without increasing meaningful outcomes like endurance or recovery (proven), strength or hypertrophy (evidence is still lacking).

Personally, I would still wait before I spend money on nucleotide supplements. And this is why: (A) The aforementioned long-term studies with really relevant study outcomes, like increases in VO2max or time trial performance in endurance and increases in muscle size and strength in strength athletes have not yet been conducted. And (B) even though I am not suggesting that the study results were doctored, I would be more inclined to buy and / or recommend nucleotide supplements if the existing studies had not all been sponsored by Nu Science Labs, the makers of the nuBound nucleotide supplement | Comment on Facebook!

References:

• Gil, A. "Modulation of the immune response mediated by dietary nucleotides." European Journal of Clinical Nutrition 56 (2002): S1-4.
• Hickson, et al. "Exercise and inhibition of glucocorticoid-induced muscle atrophy." Exercise and sport sciences reviews 21.1 (1993): 135-168.
• Kraemer, William J., and Nicholas A. Ratamess. "Hormonal responses and adaptations to resistance exercise and training." Sports Medicine 35.4 (2005): 339-361.
• Kirby, et al. "Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis." Journal of Applied Physiology 119.4 (2015).
• Mc Naughton, L., D. J. Bentley, and P. Koeppel. "The effects of a nucleotide supplement on salivary IgA and cortisol after moderate endurance exercise." Journal of sports medicine and physical fitness 46.1 (2006): 84.
• Mc Naughton, Lars, David Bentley, and Peter Koeppel. "The effects of a nucleotide supplement on the immune and metabolic response to short term, high intensity exercise performance in trained male subjects." Journal of sports medicine and physical fitness 47.1 (2007): 112.
• Ostojic, Sergej M., and Milos Obrenovic. "Sublingual nucleotides and immune response to exercise." J. Int. Soc. Sports Nutr 9 (2012): 31.
• Ostojic, Sergej M., Kemal Idrizovic, and Marko D. Stojanovic. "Sublingual Nucleotides Prolong Run Time to Exhaustion in Young Physically Active Men." Nutrients 5.11 (2013): 4776-4785.
• Palermo, Francesco Alessandro, et al. "Effects of dietary nucleotides on acute stress response and cannabinoid receptor 1 mRNAs in sole, Solea solea." Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 164.3 (2013): 477-482.
• Sterczala, et al. " The Physiological Effects of Nucleotide Supplementation on Resistance Exercise Stress in Men and Women." Journal of Strength and Conditioning Research (2015): Publish Ahead of Print.
• West, Daniel WD, and Stuart M. Phillips. "Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training." European journal of applied physiology 112.7 (2012): 2693-2702.

On Short Notice: Nucleotide Supplementation Increases Performance & Fortifies Immune Response. Plus: Oleic Acid Increases, SFA Lowers E2, Testosterone & DHT Binding

Are nucleotides a useful supplements for intensity maniacs and can olive oil reduce your free testosterone levels?

If you have been visiting the SuppVersity for a while now, you were probably surprised to see that the "Short News" (aka "On Short Notice") are back. The reason, I changed my mind and reintroduced this assembly of short news items is that I realized that there is an intemediate category of news and infos between the very short Facebook news that (a) disappear in the oblivion of the SuppVersity Facebook Wall, (b) don't allow me to post graphics that would illustrate the study results and (c) still take some time to write and the detailed analysis in the "original" SuppVersity articles.

So, if you disagree and can give me a good reason why I should not post news compilations like the one at hand more regularly, speak now or forever hold your peace ;-)

Nucliotide supplementation counters immune suppressive effects of exercise

(Ostojic. 2013) - I think I mentioned a similar study a couple of weeks ago in the SuppVersity Facebook News, but since this most recent investigation into the ergogenic effects of the small organic nitrogen-based combinations of a five-carbon sugar and a phosphate group that

• form the building blocks of nucleic acids, such as DNA and RNA, and 
• participate in cellular signaling and metabolism

deals with in young, healthy, fit men and their response to the provision of a supplement that looks similar to something you are probably goint to see on the market pretty soon, I thought it may be interesting enough to make it into this "news" article-format.

Figure 1: Illustration of the molecular structure of nuleotides (Sadava. 2000)

The supplement we are talking about is a combination of different nucleotides, i.e. cytidine 5′-monophosphate, uridine 5′-monophosphate, guanosine 5′-mono-phosphate and adenosine 5′-mono-phosphate from partially purified (90%) germinated barley seeds extracted during sporulation and the reason it's worth knowing what was in it, because it was able to ...

• Want a quick performance fix? Use sodium bicarbonate | learn more

  significantly increase time to exhaustion (+7%)
• ramp up serum levels of immunoglobulin A and
• elevate the NKC cytotoxic activity

in the blood of the 14 recreationally active participants (age 22; BMI 24kg/m²; body fat 11%) who participated in a standardized incremental exercise test on the treadmill ("Run till you drop") after taking 50mg/day of this product for 2 weeks.

Oleic Acid Increases E2, Testosterone & DHT Binding

Not from Greece, the land of olive oil and eve's cheese, but from Spain comes a study that links Oleic acid, the mono-unsaturated fat from Olive oil to increases in SHBG. The researchers from the Universitat Autònoma de Barcelona analyzed the lab reports and nutrition data of a total of 315 men and observed that

"SHBG serum levels were significantly higher in subjects using olive oil for cooking in comparison with subjects using sunflower oil. The SHBG levels correlated positively with MUFA (p < 0.001) and negatively with saturated fatty acids (p = 0.003)." (Sáez-López. 2013)

Based on multiple regression analysis of the data, the scientists calculated that the amount of MUFA in the subjects' diets accounted for 20.4% of SHBG variance. Despite the fact that this means that your MUFA intake determines "only" 20% your SHBG levels, the data in Figure 1 (left), clearly indicates that these 20% show pretty significant correlations with important health markers.

Figure 2: Correlation between SHBG levels and BMI, MUFA intake (in % total fat) and fasting blood glucose - left; correlation between phospholipid MUFA and SFA content and SHBG - right (Sáez-López. 2013)

In order to elucidate the underlying mechanisms, the scientists conduced an additional in-vitro study, in the course of which Sáez-López were able to confirm that oleoyl-CoA, a metabolite that's produced, when oleic acid is metabolized, downregulates PPAR-γ in the liver (HepG2 cells).

As a SuppVersity veteran, you'll know that any reduction in PPAR-gamma in the adipose tissue will result in a decreased propensity of fat storage (read up on it). In the liver, PPAR-gamma is  responsible for the production of SHBG, as well. In view of the fact that SHBG binds and deactivates* androgens and estrogens (*this is not essentially correct for all tissues!), your MUFA intake could thus be one of the set-screws that determine the level of unbound sex-steroids in your blood.

With 60-80% olive oil is one of the best sources of oleic acid and this is not a reason to stop consuming it - irrespective of T-binding (read more)

Bottom Line: Based on the currently available evidence it appears as if nucleotide supplements could have a future as immune and performance booster for intense training athletes.

Despite the fact that it is unlikely that there will be any side effects, (a) the increased immune activity, which could be a problem for people with auto-immune disease and (b) the non-existence of scientific evidence to support their long-time efficacy (and safety), I would wait and see how things develop before investing significant amounts of money in supplemental RNA / DNA precursor.

Something very similar is true for results of the Sáez-López study that investigated the "SHBG raising" effects of oleic acid. In view of the negative association between SHBG levels BMI and fasting blood glucose, which have, by the way, been observed in previous studies: Phillips & Gerald, for example, observed a significant negative correlation between SHBG and the waist / hip ratio in 55 obese men aged 21 to 70 (Philips. 1993). And while SHBG binds testosterone the small change will not render all your testosterone useless, so that you don't have to be afraid of sudden olive oil induced anti-virility effects ;-)

References:

• Ostojic, Sergej M., Kemal Idrizovic, and Marko D. Stojanovic. "Sublingual Nucleotides Prolong Run Time to Exhaustion in Young Physically Active Men." Nutrients 5.11 (2013): 4776-4785.
• Phillips, Gerald B. "Relationship between serum sex hormones and the glucose-insulin-lipid defect in men with obesity." Metabolism 42.1 (1993): 116-120.
• Sadava, D. et al. Life: The Science of Biology, 9th ed. 2009
• Sáez‐López, Cristina, et al. "Oleic acid increases hepatic sex hormone binding globulin production in men." Molecular nutrition & food research (2013).