Measuring Overtraining; Phosphatidic Acid to Potentiate the mTOR Effects of Leucine? Plus: Built-in Serm in Menopausal HRT Blocks Breast Cancer, Creatine Bumps Up Performance Not Body Weight, Estrogen Timing & Brain NDMA Toxicity

Weight-supported sports such as cycling precipitate overtraining

"20%", that's the SuppVersity figure of the week. It tailors directly to the first item in today's installment of On Short Notice and denotes the amount of professional athletes who exhibit symptoms of overtraining syndrome at any given time in their career.

"The prevalence varies by sport and is thought to be highest in endurance sports requiring high volume intense training, such as swimming, triathlon, road cycling, rowing and, to a lesser extent, distance running."  (MacKinnon. 2000)

What all those sports (except for distance running) have in common are long training hours on 6 days per week for several months without appreciable time off. Notably, the chances of overtraining also increase, when the equipment supports your body mass. With weight-bearing activities, such as distance running, on the other hand, the risk of musculoskeletal injury limits training volume and therefore reduces the chance of "running" (literally) into overtraining.

Overall, there is however no group of athletes that is immune to training too long, too hard and without appropriate recovery times. And yes, this goes for power sports, such as weight lifting and judo, as well (cf. Callister. 1990, Fry. 1994)!

Identifying overtraining by psychomotoric evaluation  

When you come to think of it, it does actually stand to reason: Static and dynamic tasks for finger, hand, and arm movements, as they are assessed during a  series of tests to assess motor performance are a way better yardstick to determine the stress (over-)load on the central nervous system (CNS), than simply looking at "how much ya bench". Why? The nasty, creepy and easy to overlook form of overtraining happens largely in your head and your nerves, it's not muscular. Your skeletal muscle can be fully rested, while your central nervous system is at the verge of collapsing.

What does the motor-skill test measure? (1) steadiness (one or both hands) - assesses hand unrest, tremor; (2) inserting long pins (one or both hands) - assesses rate of arm and hand movements, precision of arm-hand movements, manual and digital dexterity; (3) tapping (one or both hands) - assesses wrist-finger speed

Usually the latter goes hand in hand with other not exactly exercise related stress symptoms such as nervousness, and the inability to cope with the imposed stress and piling-up difficulties. Therefore Paul et al. required that all the one-hundred 18-25y athletes (M=65, F=35; university to international level) from various athletic backgrounds, i.e.

• hockey (14%), volleyball (14%), basketball (13%), handball (12%), football (6%), cricket (2%),
• cycling (13%),  running (11%), kabaddi (8%),  swimming  (5%),  gymnastics (1%), and sprinting (1%)

to fill out a "classic" Training Stress Scale (TSS) questionnaire as well. The TSS is a 19-item scale to check the symptoms of acute overtraining which includes a subset of questions designed to assess  the ability of bouncing back mentally after setbacks and mistakes (REB).

Figure 1: Motor performance (steadiness error duration; inserting long pins task duration; tap hits) in 100 athletes grouped into low (LS), medium (MSG), and high (HSG) groups according to their scores on the TSS test (calculated based on Paul. 2012)

As you can see in figure 1 the results of the motor performance test did not just correlate with the data from the stress test questionnaire, they also depict a very good picture of the state of the nervous system, with highly significant difference between the highly stressed and almost certainly overtrained athletes (green) and their lightly stressed peers (figure 1, blue; stress data was assessed by the aformentioned TSS test).

Professional athletes rarely end up  like Christian Bale in the Machinist but as I discussed at length in a previous post, overtraining was one of the two pillars of the crazy regimen the actor used to starve himself into a state that hardly allowed him to perform in front of the camera.

Aside from the high correlation and the confirmation of the hypothesis that psychomotoric tests could prove a valid tool to access the training status of athletes and ambitious gymrats, the investigation yielded the following main results:

• The athletes with lowest training stress symptoms showed the highest reboundability (resilience) from their mistakes. 
• Increased intensity of training stress symptoms indicates attention deficit leading to poor psychomotor performance.
• Along with physical training, psychological training has to be considered as one of the eminent aspects of overall development of an athlete.

In order to maximize athletic performance, it is therefore more or less obligatory to "carefully and timely diagnose for any signs and symptoms for physical and psychological distress" (Paul. 2012). Needless to say that the combination of the TSS and psychomotor performance test offers a way to do just that - to monitor, control and optimize the training routine.

Phosphatidic acid a novel 'mTOR potentiator' for superior gains?

I somehow forget this one in the last installment of On Short Notice, but before the first supplements are going to hit the market (two of the authors have already filed a patent back in 2011 that hasbeen  published in June 2012; see De Ferra. 2012), I thought I'd briefly discuss the results of a recently published study on the potential ergogenic and muscle building effects of phosphatidic acid (PA) by Hoffman et al. (Hoffman. 2012).

The study that was published online in the Journal of the International Society of Sports Nutrition evaluated the effects of an 8-week resistance training on 16 resistance-trained men who had been randomly assigned to consume either 750 mg of PA or a placebo.

Figure 2: Effect of 8 weeks of strength training + post-wporkout amino acid supplementation with and without  750mg phosphatidic acid  per day (left) and ratio of beneficial, trivial and negative effects of supplementation on the respective outcome parameters (Hoffman. 2012)

As the data in figure 2 goes to show you, the supplementation regimen had beneficial effects almost all of the (except for the pennation angle, btw. where greater the angles of pennation, means translates to a smaller amount of effective force transmitted to the tendon), however not a single statistical significant difference was observed. And while the scientists assessment that the overwhelmingly beneficial effect of PA supplementation on lean mass gains is "very likely beneficial", this does not change that the 750mg of PA did not add to allegedly highly beneficial effects of the workout regimen.

Figure 3: Training protocol and amino acid content (in g/100g) of the post-workout supplement (identical in both groups).

Since all particpants had taken part in identical 4-day per week, split routine resistance training programs for 8-weeks (70% of their 1-repetition maximum (1-RM) for all exercises;  90-s rest period was required between each set, for all exercises; for the exercises check out figure 3) and were advised to consume a standardized post-workout protein formula (containing 36-g amino acid and collagen protein blend) mixed in a 500 ml commercial sports drink within 30 minutes post-exercise, the supplemental confounding factors were pretty tightly controlled. If anything but the consumption of the PA supplement would have been responsible for the inter-group differences this would therefore have to be related to

• the non-supervised training sessions at the subjects respective local gyms (training logs regardless of whether they are evaluated by "certified personnel", or not, can obviously be faked), and
• the absence of a prescribed nutritional regimen (the participants kept 3-day food-logs and were advised to stay on their habitual diet; no significant differences in total intake ~3,200kcal/day; according to Hoffman et al. likewise not statistical significant, but wrt to the the changes in body composition maybe noteworthy, were the -17% lower carb and +18.2% higher protein intake in the active = PA arm of the study)

Both the missing supervision, as well as the absence of a fixed nutritional protocol would however pertain to both groups and are thus likely to average out. Plus, they actually make the study more realistic. After all, you are interested in what happens if the average strength trainee (in this case young men with a mean age of ~23years, at least 1 year of training experience and a BMI of 27.7kg/m²) and not to 10 identical clones, don't you?

"So this stuff is not useful, right?"

Figure 4: Exogenous phosphatidic acid is metabolized to lysophosphatidic acid (LPA) in the body and LPA has been shown to work synergistically w/ leucine to increase mTORC1 activity (in vitro data from Winter. 2010).

Despite the "likely" and "very likely beneficial" effects on lower body power and lean body mass, of which only the latter could maybe have reached statistical significance with a larger number of participants (with only 20 subjects, i.e. 10 per group differences need to be more pronounced to reach statistical significance). It should be quite obvious that PA is probably not the next creatine.

Maybe the increased mTORC1 expression Winter et al. have observed upon co-incubation of leucine with LPA are not pronounced enough (figure 4). Or simply not necessary with enough leucine and insulin in the blood stream. After all, the Winter study also showed that basically identical effects were observed when the cells were incubated with leucine + insulin, instead of LPA + insulin (data not shown in figure 4).

So even if oral PA acts just like in-vitro LPA synergistically with leucine to activate the mTOR pathway (Fang. 2001; Winter. 2010; figure 4), the real world benefits in the study at hand are probably about as significant as the hypothetical 500g increase in net protein retention I discussed in he protein timing news earlier this week. Whether this may change with higher and/or more frequent doses in future studies remains to be seen, though. It does at least not appear to be impossible...

Additional news

• 'Built-in SERM' could help making post-menopausal estrogen replacement breast cancer proof At least this is what the results of a recent rodent trial that was conducted by researchers from the Division of Endocrinology at the Department of Medicine of the University of Virginia Health System in Charlottesville would suggest. Even in the absence of a progestin, which does have some ameliorative effects on the pro-carcinogenic effects of estrogen, the addition of the tissue-specific selective estrogen receptor modulator bazedoxifene (BZA) to the allegedly questionable, yet still widely prescribed conjugated equine estrogen (CEE) blocked the CEE- and, in a second control study, even the more potent E₂-stimulated ductal and terminal end bud growth of mammary gland and the corresponding estrogen-responsive gene expression (Song. 2012). 

• 

  Just like any athlete, man or woman who is interested in increasing his / her athletic performance, German Olympic lifter Julia Rohde could benefit from taking regular creatine monohydrate without necessarily running the risk of having to compete in a higher weight class (img sportzentrum-flora.de)

  5g creatine monohydrate (CM) per day helps soccer players to improve their game - or, more precisely, the time they needed to complete a standardized sprint running and dribbling test. And while you will probably not be surprised that CM supplementation did not affect the accuracy of their shots, you may very well be surprised that it did neither induce greater weight gain or any other changes in body composition (Mohebbi. 2012).
  
  The latter may also be interesting for athletes competing in sports where increased muscle mass can become an issue. After all, the results Mohebbi et al. present in the latest issue of the Middle-East Journal of Scientific Research would suggest that unless your training is geared towards increased muscle gain (which is obviously shouldn't be if that would be an issue for you) regular creatine, i.e. not the sugar laden 'cell-volumizers', can help you increase your performance in the absence of the (again, only for certain people) disadvantageous weight gain.
• Whether estrogen will save your brain cells or actually exacerbate the damaging effect of NMDA exposure depends on timing I guess you will all have heard of the protective effects of estrogen against N-methyl-d-aspartate (NMDA) toxicity. Now, a group of researchers from the University of Catania and the University of Rome Sapienza,both obviously in Italy, found that only pretreatment with estrogen will provide these beneficial effects, while the co-incubation or subsequent administration of estrogen will only potentiate the NMDA-induced cell death (Spampinato. 2012)

Have a nice weekend, everyone! As far as the On Short Notice items go, that's it for today. If you want more, just check out the SuppVersity Facebook Wall. I must forewarn you, though, since I am pretty busy this weekend, I am not sure if there will be another installment of the Athlete's Triad Series, tomorrow. If that's not the case, you will however get a regular news item, so don't worry you won't get bored ;-)

References:

• Callister R, Callister RG, Fleck SJ, Dudley GA. Physiological and performance responses to overtraining in elite judo athletes. Med. Sci. Sports Exerc. 1990; 22: 816–24.
• Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J: Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science 2001, 294:1942–1945.  
• De Ferra L, Heuer M, Hagerman S, Purpura S, Jäger R. Method for increasing muscle mass and strength. Filed November 23, 2011. US 2012/0141448 A1. Published on June 7, 2012.
• Fry AC, Kraemer WJ, van Borselen F et al. Performance decrements with high-intensity resistance exercise overtraining. Med. Sci. Sports Exerc. 1994; 26: 1165–73. 
• MacKinnon LT. Special feature for the Olympics: effects of exercise on the immune system: overtraining effects on immunity and performance in athletes. Immunol Cell Biol. 2000 Oct;78(5):502-9.
• Mohebbi H, Rahnama N, Moghadassi M, Ranjbar K. Effect of Creatine Supplementation on Sprint and Skill Performance in Young Soccer Players. Middle-East Journal of Scientific Research. 2012; 12 (3): 397-401.
• Paul M, Khenna N, Sandhu JS. Psychomotor analysis of athletes under overtraining stresss. Serb J Sports Sci. 2012;6(3): 95-10.
• Song Y, Santen RJ, Wang JP, Yue W. Effects of the Conjugated Equine Estrogen/ Bazedoxifene Tissue-Selective Estrogen Complex (TSEC) on Mammary Gland and Breast Cancer in Mice. Endocrinology. 2012 Oct 15.
• Spampinato SF, Merlo S, Molinaro G, Battaglia G, Bruno V, Nicoletti F, Sortino MA. Dual Effect of 17β-Estradiol on NMDA-Induced Neuronal Death: Involvement of Metabotropic Glutamate Receptor 1. Endocrinology. 2012 Oct 17.
• Winter JN, Fox TE, Kester M, Jefferson LS, Kimball SR: Phosphatidic acid mediates activation of mTORC1 through the ERK signaling pathway. Am J Physiol Cell Physiol 2010, 299:C335–C344.

Phosphatidic Acid: A Rising Star on the Supplement Stage? +100% Lean Mass & Size Gains + Trend for Improved Fat Loss in Experienced Trainees w/ 750mg of PA Per Day

Let's face it, you cannot expect a supplement to build muscle on it's own but if there was a completely natural agent that promotes lean mass and strength gains by +100% that would be awesome, right? Well, what if phosphatidic acid was this agent?

It's actually quite unfortunate that the there is this big pond between me and the US, otherwise I would have left no stone unturned to make it to the ISSN conference past week. And if I had been there in person, there would have been one poster I would probably have scrutinized for hours the one on a recently conducted human trial from the The University of Tampa and the School of Physical Education and Sport in São Paulo (Joy. 2013). The study is in fact a follow up on a "likely underpowered" previous experiment, in the course of which the use of Phosphatidic Acid, or 1,2-diacyl-sn-glycero-3-phosphate, a phospholipid that makes up only a small percentage of the natural phospholipid pool and does not only act as a constituent of all cell membranes, but also as an intermediate in the biosynthesis of triacylglycerols and other phospholipids, has been shown to significantly augment the training induced increases in strength and lean mass gains.

"Strength & lean mass? Now, we're talking!"

Now that I got your full attention let's briefly take a look at the protocol, the intricate details of which - I must forewarn you - I am not yet familiar with, simply because a corresponding paper has not yet been published. Based on the summary that came with the poster, I can tell you, though, that we are dealing with something looking very similar to what some of you may be actually doing in the gym:

• total length of the study: 8 weeks
• training sessions per: 2x hypertrophy oriented, 1x strength

The subjects were 28 resistance trained men (21 ± 3 years of age, bodyweight of 76 ± 9 kg, and height of 176 cm ± 9 cm) and thus likewise representative of the main target group of Mediator™, which was the 750mg phosphatidic acid supplement from Chemi Nutra the scientists used in their study.

The changes in body composition were evaluated by DEXA scans, which were corroborated by measurement the circumference of the rectus femoris, the development of the one-repetition max strength (1RM) and the anaerobic power of the participants prior and following the 8 week training intervention.

Figure 1: Significant effects of the addition of PA (750mg/day) on muscle size, mass and strength (Joy. 2013)

The most significant changes Joy et al. observed in their study are summarized in figure 1. As you can see there was a significant group x time effect

• for CSA, in which the EXP group increased (+1.01 cm², ES = 0.92) to a greater extent than the CON group (+0.61 cm², ES = 0.52)
• for LBM, in which the EXP group (+2.4 kg, ES = 0.42) doubled the effects of resistance training alone (CON +1.2 kg, ES = 0.26), and
• for leg press 1RM, in which the EXP group increased to a greater extent (+52.0 kg, ES = 1.2) than the CON group (+32.5 kg, ES = 0.78)

Moreover, the scientists observed "a trend group x time effect (p=0.06) for fat loss, in which the EXP group decreased body fat to a greater extent than the CON group (-1.3kg vs. -0.5kg)." (Joy. 2013)

"Ok, where are the 'on the other hands'? "

I see, as a "healthy skeptic" you are rightly asking yourself about the potential downsides. I mean, greater mass and strength gains and fat loss? Sounds like a dream come true... well, human research in this area is still in it's infancy, but according to poster #2 the scientists presented at the ISSN, ill health effects don't appear to be among the downsides, as there were

"[...] no differences at baseline in blood chemistry and hematology between the CON and EXP supplemented groups [...] no differences were observed in urinalysis values between the groups" (Dudeck. 2013)

Furthermore, the underlying mechanism, i.e. the potent stimulation of the mTOR pathway, was confirmed in an in-vitro analysis with human muscle cells (Gundermann. 2013) and the oral bioavailability was confirmed and quantified in study #3 (Purpura. 2013).

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Table 1: Training protocol and amino acid content (in g/100g) of the post- workout supplement in the previous study (learn more).

So is PA the proven magic bullet we all have been looking for? No, certainly not - there is no "magic bullet", not even real gear works like the literal magic bullet, but it is certainly one of the most exciting supplements on the horizon.

Before you get all too psyched up, you should however keep in mind that the study at hand used a realistic training protocol and strength trained individuals, but it did not use what every trainee uses to boost his mTOR response after a workout: whey protein! In a conversation with one of the authors, I found out that the subjects ingested a collagen protein (amino acid composition see table from a previous study on the right) the researchers picked to isolate the effects of PA on mTOR independent of the mTOR boosting effects of leucine. Yet although it goes without saying that the results could well have been different and the impressive results would lose their significance, only a follow up study will tell whether this is going to be the case or not.

References:

• Dudeck JE, Joy JM, Lowery RP, De Souza EO, Jäger R, McCleary SA, Wilson SMC, Purpura M, Wilson JM. Safety of Soy-Derived Phosphatidic Acid Supplementation in Healthy Young Males.Poster presentation at the ISSN Conference 2013.
• Joy JM, Lowery RP, Dudeck JE, De Souza EO, Jäger R, McCleary SA, Wilson SMC, Purpura M, Wilson JM. Phosphatidic Acid Supplementation Increases Skeletal Muscle Hypertrophy and Strength. Poster presentation at the ISSN Conference 2013.
• Purpura M, Jäger R, Joy JM, Lowery RP, Moore JD, Wilson JM. Effect of Oral Administration of Soy-Derived Phosphatidic Acid on Concentrations of Phosphatidic Acid and lyso-Phosphatidic Acid Molecular Species in Human Plasma Poster presentation at the ISSN Conference 2013.