Post-Workout Chlorogenic Acid / Caffeine Supplementation - For Good or For Worse? Plus: Glycogen Synthesis & Why A Post-Workout May Be a Better Idea Than You'd Think

"Done,... where is my post-workout coffee?" - Post workout caffeine / chlorogenic acid - good or bad idea?

I know it's kind of late to post an article like this months after the ISSN conference, but I recently hit on an overview of the poster presentations and noticed that I did actually miss a couple of interesting studies. Don't worry, I won't be addressing a couple of them in the weeks to come in some detail.

Not all are really news-worthy, but aside from today's item on caffeine and chlorogenic acid, there were also posters on nutrient timing, different forms of protein, commercially available supplements and other stuff that's all classic "SuppVersity fodder"?

Chlorogenic acid? Isn't that Ozzy's green coffee bean stuff? You are correct, but could actually read about it here at the SuppVersityway before it was on Dr. Oz. Plus, I still believe that there is something wrong with the corresponding study and do still have to meet someone who has successfully lost weight by just adding some GCB to the diet, which is effectively what Ozzy and the study promised | learn more

Caffeine and chlorogenic acid? Right, that sounds like green coffee bean extract, but in the case of Jason R Beam et al.'s study, we are dealing with an artificial stack of

• 5mg/kg body weight of caffeine plus 75 g of dextrose (CAF), 
• 5 mg/kg body weight of chlorogenic acid plus 75 g of dextrose (CGA), or 
• 5 mg/body weight of dextrose plus 75 g dextrose (PLA)

the 10 moderately to highly trained study participants consumed after 30-minutes of  high intensity cycling at 60% of peak power output (~90% HR max).

Figure 1:

As you can see in Figure 1, we do see quite extra-ordinary effects of the administration of both caffeine and chlorogenic acid on post-workout glucose metabolism. The changes in the area under the cure (2h AUC) do yet overestimate the real-world difference between the glucose curves (not shown), which have a slightly higher spike immediately after the ingestion.

"Ok, no caffeine after a workout - right!?"

In the case of caffeine that was to be expected, it has after all been shown to decrease the insulin-induced glucose uptake (Graham. 2001). The fact that the glycemic response was - within the statistically probable margins - still identical, is simply the result that the stimulation of glucose uptake and hepatic, as well as muscular glucose storage is not really necessary as long at the glycogen stores are low. Accordingly, a 2004 study by Battram et al. was unable to show any effect of caffeine ingestion on proglycogen and macroglycogen resynthesis after a workout (Battram. 2004).

Figure 2: Skeletal muscle glycogen content (mmol/kg dw) immediately after exercise 0. 1, 4h after cycling to volitional fatigue (70% Vo2Peak) w/ or w/out coingestion of 8mg/kg BW (+ 1g/kg glucose) after the workout - left; corresponding levels of pCAMK and p-Akt (arbitrary units) 1h and 4h after the workout, right (Pederson. 2009).

As you can see in Figure 2 the net amount of glucose that ends up in the musculature after exhaustive (if you don't deplete the stores this effect won't be there) exercise was in fact favorably affected by the congestion of 8mg/kg caffeine and 1g/kg glucose in with caffeine in the 7 endurance-trained cyclists and triathletes in a study by Pedersen et al. from 2009. The exact underlying mechanisms of this beneficial effects, as well as dose response relationships do yet still have to be determined, but Pederson et al. speculate that it may a result of the increased activation of p-AKT:

You think you've heard about p-Akt before, but are not sure where? Well, chances are it was here at the SuppVersity, yet probably in a different context, i.e. as part of the Intermittent Thoughts on Building Muscle | read more

"The increase [in p-AKT] tended to be higher after the ingestion of caffeine with CHO after both 1 and4hof recovery, but failed to reach statistical significance. Akt seems to regulate glucose uptake by phosphorylating and inhibiting the Rab-GTPase-activating protein AS160. Thus it is tempting to speculate on the role of Akt in glucose transport given that the Akt substrate AS160 has been identified as an important regulator of GLUT4 traffic.

We have recently shown that AS160 is phosphorylated in human skeletal muscle after endurance exercise with concomitant phosphorylation of Akt (7), providing correlative evidence to suggest AS160 is an exercise-responsive protein with a role in glucose uptake." (Pederson. 2009)

If we discard potential negative effects of the caffeine-induced CNS activation on post-exercise nervous system recovery, and take into account that the elevated glucose + insulin AUC Beam observed in the experiments for his dissertation and ISSN conference poster are negligible, the preliminary bottom line for post-workout caffeine intake would be: "If glycogen resynthesis is what you are looking for, do it!"

"What about the effects of chlorogenic acid. Shouldn't the exact opposite happen?"

Now that we've searched for explanations of the effects of caffeine on post-workout glycemia we are still left with the astonishing increase in the two-hour glucose area under the curve, i.e. total glycemia, Beam observed in the glucose + chlorogenic arm of his study.

Figure 3: Insulin (AUC) for each subject during the placebo, caffeine, and chlorogenic acid trials (Beam. 2013)

If you take a closer look at the data to the right, you won't get a mechanistic explanation of the underyling reasons, but you will at least get an idea of what statistical significance means and why we are talking about it in almost every study analysis, even if it does not equate physiological significance.

In this particular case the 2 outliers, subject 1 and subject 6 do not simply "ruin" the statistical significance, they are actually the (almost) only reason that insulin response is not virtually identical to the placebo trial.

As far as potential negative consequences of the post-workout consumption of cholorgenic acid goes, you do thus not have to be worried, whether it is actually a good idea to use a supplement that's meant to increase the activity of AMPK in a phase, when the latter is already maximized, is however questionable. In the best case, the additional benefits will be minimal, in the worst case it  CGA will ruin the glucose repartitioning effects of the workout by increasing AMPK and thus glucose uptake in the fat cells (Alonso-Castro. 2008).

If you actually have problems with insulin resistance / glucose uptake (which is not the case for 90%+ of the people who buy corresponding supps), I suggest you check out this list of useful anti-diabetes agents.

Bottom line: I would assume that you will not have expected that, but based on the results of the study at hand and the review of previous literature the effects of caffeine and chlorogenic acid on post-workout glycemia are most likely negligible.

If you still insist on supplementing with one or the other immediately after a workout, though, there would be a rationale to use caffeine. The use of chlorogenic acid, green coffee bean extracts or any other highly advertised and for physical culturist 100% useless "nutrient repartitioning agents", would be at least non-sensical, in view of the potential negative effect on the true nutrient repartitioning effects, even potentially downright counterproductive.

References:

• Alonso-Castro, A. J., Miranda-Torres, A. C., González-Chávez, M. M., & Salazar-Olivo, L. A. (2008). Cecropia obtusifolia Bertol and its active compound, chlorogenic acid, stimulate 2-NBD glucose uptake in both insulin-sensitive and insulin-resistant 3T3 adipocytes. Journal of ethnopharmacology, 120(3), 458-464. 
• Beam, J. (2013). The effect of post-exercise caffeine and chlorogenic acid supplementation on blood glucose disposal and insulin sensitivity.
• Battram, D. S., Shearer, J., Robinson, D., & Graham, T. E. (2004). Caffeine ingestion does not impede the resynthesis of proglycogen and macroglycogen after prolonged exercise and carbohydrate supplementation in humans. Journal of Applied Physiology, 96(3), 943-950.
• Pedersen, D. J., Lessard, S. J., Coffey, V. G., Churchley, E. G., Wootton, A. M., Ng, T., ... & Hawley, J. A. (2008). High rates of muscle glycogen resynthesis after exhaustive exercise when carbohydrate is coingested with caffeine. Journal of Applied Physiology, 105(1), 7-13.

Creatine Before or After the Workout? Finally the Answer is Here! Study Says: Better Take it After for Mass & Strength

The old "creatine = water retention" myth is - at least for the majority of athletes - just that: a myth and a result of the old practice of "loading" with copious amounts of creatine and even more high GI carbs. And it is certainly not a problem that's specific to cheap and effective creatine monohydrate.

In case someone of you ever asked me, whether he or she should take his or her creatine before or after a workout I will probably have answered something like: "I don't think it will make much of a difference, but I personally would suggest you split the dosage".

Now that Jose Antonio and Victoria Ciccone (the first of whom many will probably know from his old radio show on BB.com, the countless articles he wrote, his job as an editor or whatever else), published a paper in the Journal of the International Society of Sports Nutrition, it appears my new answer to the said question would be: "It looks like it's better to take your creatine after a workout." My previous suggestion to take 50% before and 50% after, on the other hand, has not yet been falsified. So maybe I will have to go back on the revised advice again and re-revise it, so to say. And you know what? That's not a problem! That's science. Any "truth" in science is only true until it has been falsified and I do already have my doubts about the universality of this new "truth" about creatine (see bottom line).

So, if after is the way to go? How do we know?

What Antonio and Ciccone did was to recruit 19 male recreational bodybuilders (mean ± SD: age, 23.1 ±2.9 years; height, 166.0 ± 23.2  cm;  body  weight,  80.2  ±  10.4  kg) with training experience of  >1 year who were obliged to stop taking any form of workout supplement or dietary aid at least 4 weeks before the study began.

The Pharmacokinetics of creatine Part I & Part II

"Subjects were randomly assigned to one of two groups: a PRE-SUPP or POST-SUPP group. The PRE-SUPP group consumed 5 grams of creatine monohydrate immediately prior to training. The POST-SUPP group consumed the same amount of creatine immediately after training. Following pre-testing data collection, participants began a periodized four-week resistance training program that was self-administered. On off-training days, subjects consumed creatine at their convenience. The total treatment duration was four weeks." (Antonio. 2013)

All subjects participated in the same standardized periodized, split-routine bodybuilding training regimen that was "geared primarily for skeletal muscle hypertrophy" (Antonio. 2013).

• training frequency: 5x per week
• total number training sessions: 20 
• training duration: ~ 60 min per session

As you can see in the overview in figure 1 the training protocol used a block periodization with a change in the rep scheme after each cycle (=4 workouts, one body part is worked in the respective rep range once) and a pretty high training density, i.e. 5 workouts in a row + 2 days off.

Figure 1: Outline of the training schedule; created based on the description on the original study (Antonio. 2013)

Certainly not exactly a beginner program, but with ~60min per workout it's feasible to train like this for someone who is not getting all too stressed up in his everyday life and has the training experience to handle the CNS load.

That's the study you've been waiting for, right?

With experienced trainees, the requirements of not ingesting any other supplements (including amino acids) that would probably thwart the results, standardized strength tests, as well as random 24h dietary recalls every week, obligatory training logs and BodPod body fat measurements, this is the kind of study of which I would love to see at least once a week - not every 6 months.

Figure 2: Changes in body composition and 1-RM bench press strength, left; nutrient composition in grams/day, right (Antonio. 2013)

The results, however, point towards the main reason studies like these are rare. The chance to measure significant effects in trained individuals are much lower than they are in the average couch potato who grows and drops fat like a maniac, at the very moment he is shooed around in the gym.

In the bodybuilders in the study at hand only the changes in fat free mass and the bench press power did reach statistical significance and the superiority of the post-workout supplementation is "possible" and "likely", but by no means certain. Still, Antonio and Ciccone feel that

Additional tip: Supercharge creatine with baking soda (learn more)

"[t]he use of recreational bodybuilders in the current investigation is advantageous because it is difficult for highly trained individuals to experience an increase in FFM or muscular strength in the time frame allotted for this study." (Antonio. 2013)

Moreover, they point out that "of the 19 subjects that completed the study, 16-21% were non-responders regarding muscular strength and FFM." That's irrespective of the nutrient intake, by the was which was similar between the groups and had with 1.9g of protein per kg body weight per day more than enough protein to support muscle growth.

So is it effective or not?

For an optimal ratio of lean to fat mass loss on a diet it takes "only" twice the RDA of protein.

With respect to the effectiveness of the creatine supplement, the high protein intake could, as Antonio and Ciccone speculate even have been a disadvantage as this could mean that the subjects "could already have a high amount of creatine stored intramuscularly and this may have blunted the results" (Antonio. 2013).

How's that? Well, not only as a result from the minimal amount of creatine in beef, but also due to our bodies ability to produce creatine from L-arginine, glycine, and L-methionine - all of which the trainees should have gotten plenty in their diet.

If we also assume that some of the guys have been "on" creatine before, 4 weeks is not enough to deplete the stores if you don't resort to guanidinoproprionic acid (GPA) to deliberately deplete them (learn more about GPA).

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Bottom line: The benefits may have been subtle, but in view of the fact that we do not have evidence to the contrary you better make sure you take your creatine after your workouts from now on, or all the work you're putting into your workouts is going to be lost... just kiddin', I personally still believe that it does not matter. Creatine uptake is slightly higher with some insulin floating around and the degradation is lower when it does not reside too long in the acidic millieu of the stomach etc. So, without any more specific information on whether or not the subjects consumed their creatine with a meal before or after the workout and whether there were carbs, fiber and whatever in that meal, it's really premature to say whether or not (a) the timing really makes a difference and (b) whether post-workout supplementation is the only way to go.

References:

• Antonio J, Ciccone V. The effects of pre versus post workout supplementation of creatine monohydrate on body composition and strength. J Int Soc Sports Nutr. 2013 Aug 6;10(1):36. [Epub ahead of print]

Peri-Workout Hydro-Whey Supplementation: Tried & Proven Muscle Builder Will Also Increase Tendon Size & Strength

Squats are by no means the only exercise that requires strong muscles and tendons.

In a way you could argue that today's SuppVersity article serves two purposes. Firstly, it provides direct evidence for my outrageous claim that the VPX Shotgun + Synthesize study from Saturday's installment of On Short Notice has little to no practical value, because the use of 2x17g of maltodextrin as a control has little to do with the real-world supplementation regimen the potential consumers of respective products are ingesting. I mean, you can safely assume that people who are willing to spend the money on expensive peri-workout kitchen sink supplements will - just like most of you - be ingesting a whey (or other fast acting) protein source after their workouts, anyways.

It goes without saying that it would not have needed a new study to prove this point, so that informing you about another observation Farup et al. made in their most recent study is not just the second, but actually the main purpose of today's SuppVersity article.

A new whey to build tendons of steel

The training protocol: The subjects completed 33 training sessions during the 12 weeks of training. The training program was primarily designed to induce hypertrophy and to a lesser extent maximal muscle strength highlighted by a large number of sets and repetitions and by moderate high intensity. Training frequency was three times per week with a progressive increase in volume and intensity throughout the 12 weeks.

The resistance training exercise consisted of isolated knee extensions in a Technogym knee extensor machine. All repetitions were performed by lifting the load with the concentric leg (while extending the

eccentric leg unloaded). Then, with aid from a training supervisor, an additional load was released onto the weight stack and then lowered with the eccentric leg.

Both the eccentric and concentric leg training program consisted of isotonic knee extensions (TUT 2-0-2s; rest between sets 2min) and applied the following progression in volume and intensity: 6 x 10-15RM (sessions 1–4), 8 x 10-15RM (S 5–10), 10 x 10-15RM (S 11–20), 12¥6–10 RM (S 21–28), and 8 x 6-10RM (S 29–33).

The actual paper is going to be published in one of the future issues of The Scandinavian Journal of Medicine & Science in Sports and deals with the outcomes of a 12-week double-blinded resistance training intervention in the course of which the 22 male subjects (healthy, young, recreationally active height 181.5+/- 1.5 cm, weight 78.1 1.8 kg, age 23.9 +/-0.8 years, fat% 16.0+/- 0.9%) consumed either

• a high leucine whey protein hydrolysate + carbohydrate group (WHD; 19.5 g whey protein hydrolysate +19.5 g) or 
• an isoenergetic carbohydrate only supplement for the placebo group (PLA, 36g of carbohydrates)

Regardless of supplementary intake, all subjects performed eccentric training with one leg and concentric training with the other.

"This within-subject design was used to minimize the potential differences in the hypertrophy response that are inherent with group designs (e.g. initial training status, habitual nutritional intake,and/or hormonal status). Eccentric leg was randomly chosen to be either the dominant (preferred kicking leg) or the nondominant leg to exclude any potential pre-training difference between the two." (Farup. 2013)

Overall, we are thus comparing not two, but rather four different training modalities, namely eccentric+WHD, eccentric+PLA, concentric+WHD and concentric+PLA.

Maximal standardization, reliable measuring methods

In the two weeks before commencing the training program, magnetic resonance image (MRI) scans of both thighs and patellar tendons and isometric strength test were taken. In conjunction with the before and after tests that were standardized up to the time of the day, pre- and post-training, "to control for potential effects of diurnal rhythm" (Farup. 2013)

The training sessions were closely supervised and monitored by qualified training instructors to ensure proper execution and loading. The same goes for the ingestion of the supplements, 19.5 g whey protein hydrolysate +19.5 g of carbohydrate (both equal to 4% solution) and the placebo drink consisting of 39 g of carbohydrate, which were handed to the trainees at the beginning of the training sessions and were to be consumed before and after the training (50/50).

Even the intake of additional plain water was standardized, so that the subjects would not ingest and fluids 1 1/2 h prior to and 1 h after completion of an exercise session, "to ensure and standardize the conditions for digestion/absorption and within the range typically applied" (Farup. 2013)

The only methodologically lapse was the absence of dietary control. While the subjects of previous studies in which the participants were advised to "maintain their normal habitual dietary intake throughout the study" (Farup. 2013), did not register any differences in habitual total energy or protein intake (Andersen. 2005; Hartman. 2007; Hulmi. 2009; Erskine. 2012) and the accuracy of food logs is generally questionable, this is kind of awkward in view of the lengths to which the scientists went to exclude any other confounding factors.

Enough of the prelude, what about the results?

So, while we cannot exclude that the subjects in any of the two groups may have skewed the overall results by consuming an additional steak on top of their regular diets, it is quite unlikely that these counfounding factors would have been group specific, so that the overall effects on quadriceps cross-sectional area I plotted in figure 1 are unquestionably reliable.

Figure 1: Relative changes in quadriceps and patella tendon CSA in concentrically and eccentrically trained leg of the subjects in the whey protein hydrolysate and placebo groups (Farup. 2013)

The same obviously goes for the strength increases and the initially mentioned increase in patella tendon CSA. All good and reliable evidence supporting the current "standard" in periworkout supplementation.

Apropos, in conjunction with the recent revelations about the unique glucose-sensitizing effects of the short-chain peptides in whey hydrolysate, it may even be worth to consider adding a "hyrolysate" to the current recommendation to ingest 30g of whey protein in the vicinity of your workouts. Convincing evidence from studies that were specifically designed to elicit the marginal benefits of replacing a regular whey protein with the less tasty (you won't notice that with the tons of flavoring agents, though) and still more expensive "pre-digested" form of whey is yet - at least as far as I know - still missing.

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Bottom line: Actually, I already mentioned the most important findings of the study at hand in the introduction:

Figure 2: Whether the effects observed in the study are "hydrolysate specific" and related to the amino acid or peptide composition of the supplement that was used in the study at hand cannot be said without a "regular" whey control. The same goes for the general superiority or inferiority of hydrolysates vs. whey isolates or concentrates.

(a) Whey proteins alone will amplify the effects of regular strength training to a degree that is hard to surpass by the more expensive "advanced muscle builders" - no wonder the producers are reluctant to use anything but an isocaloric carbohydrate supplement as their yardstick. (b) Increases in tendon CSA are a novel benefit to be added to the comprehensive list of benefits of a supplement I suspect most of you are using anyway.

Whether the hydrolyzed whey proteins are actually worth the extra bucks is yet still not 100% certain. As previously mentioned, the number of practically relevant direct comparisons is still scarce. We know that they create a more rapid increase of the amino acid levels in the blood, that they are more insulinogenic and we that some of the short peptides have favorable physiological effects (learn more). A long-term study comparing the muscle and (that's new) tendon building effects of the three commonly available varieties of whey, i.e. concentrate, isolate and hydrolysate, has not yet been conducted. But don't worry, as soon as the pertinent data is going to be available, you'll find all the information you need, as well as the practical implications of the results right here, at the SuppVersity - your #1 source for the latest on exercise, nutrition and supplementation research on the Internet.

References:

• Farup J, Rahbek SK, Vendelbo MH, Matzon A, Hindhede J, Bejder A, Ringgard S, Vissing K. Whey protein hydrolysate augments tendon and muscle hypertrophy independent of resistance exercise contraction mode. Scand J Med Sci Sports. 2013 May 7.

Short-Term Supplementation with Bovine Colostrum Does Not Improve Immune Variables in Well-Trained Athletes. Localized Effect on Intestinal Health Yet Possible.

Just in case you wonder that there were no news yesterday. Blogger was down, so it took me some time to be able to tell all of you, who followed my advice and tuned in to yesterday's episode of Carl Lenore's Super Human Radio: "Amino Acids for Super Humans" and heard Carl and me talk about his use of bovine colostrums as part of his peri-workout supplementation regimen that my concerns over the digestibility of the (mostly) immunomodulating long-chain peptides in colostrum (the milk mammals produce in the last days / first days after pregnancy), appear to be legit. At least the results of a recents study (Carol. 2011), which failed to produce any (systemic) immunomodulatory effects in well-trained athletes, would confirm my assumption that these longer amino acid chains are not able to overcome the tight gut junctions, which are genetically designed to "close" (the further tightening of the junctions is also known as "closure") within the first days after a mammal is born.

Figure 1: Two samples of human breast milk, which has a very different immunoglobulin composition than cows milk and colostrum, cf. Hurley. 2011 (image taken by Wikipedia user Azoreg)

That being said, the results of the aforementioned study that has been published in International Journal of Sports Nutrition and Exercise Metabolism do not come as a surprise for me: After 10 days of supplementation with either colostrums or skim milk powder, the 9 professional male athletes did show absolutely identical immune reactions to high intensity endurance exercise in a carbohydrate depleted state (the glycogen-depletion would augment the immunosuppressive effect of intense exercise beyond what would be seen under normal = glycogen-sufficient circumstances):

Plasma cortisol levels increased over time, reaching the highest level directly after exercise, and were still elevated ~22 hr after exercise compared with baseline values (p < .001). Neutrophil cell count was increased after exercise and dropped below starting values 22 hr after exercise (time effect p < .001). Circulating immunoglobulins did not change over time. A significant time effect was seen for interleukin (IL)-6, IL-10, IL-1-receptor agonist, and C-reactive protein, with levels being higher directly after exercise (p < .05). Other cytokines (interferon-γ, IL-1a, IL-8, tumor necrosis factor-a) did not show a time effect. No differences were seen between colostrum and skim-milk powder in any of the investigated variables.

The lack of systemic effects, i.e. effects on the body as a whole, due to the inability of the long chain peptides to cross the intestinal wall, on the other hand, does not preclude beneficial "side effects" within the gut, itself. Recent studies such as Moller et al. (Moller. 2011), for example showed direct beneficial effects of the "synergistic action of various milk bioactives" on dendritic cell (messengers between the innate and adaptive immunity) cytokine response within the gut. Further evidence for the localized effect of colostrum comes from a 2010 study by Marchbank (Marchbank. 2010) found that colostrum supplementation actually decreased or rather maintained gut permeability, which was otherwise reduced after exhaustive exercise:

Intestinal permeability in the placebo arm increased 2.5-fold following exercise (0.38 ± 0.012 baseline, to 0.92 ± 0.014, P < 0.01), whereas colostrum truncated rise by 80% (0.38 ± 0.012 baseline to 0.49 ± 0.017) following exercise.

These colostrum-specific results corroborate various studies on the effects of hydrolyzed milk peptides on insulin sensitivity, blood pressure and much more, indicate that there is much more to milk and milk products than the sum of their proteins, carbohydrates, fats, minerals and vitamins would suggest. Whether it always has to be colostrum, which is expensive and hard to come by, or raw, unpasteurized milk from the grass-fed cows of your local farmer would not suffice remains to be seen, though.

Triphasic Nutrient Supplement W/ Caffeine, Aminos, Carbs, Creatine & All the Usual Suspects Allows For Higher Training Volume, Lowers Cortisol & Dampens Muscle Damage

Do you really need the whole pre-, intra-, post workout supp-arsenal to benefit from your workouts?

Finally, another workout supplementation study! Yeah, I know you are already suffering the side-effects of withdrawl, but it's just a couple of lines and you will feel relieve - thanks to Stephen P. Bird and his colleagues from the Charles Sturt University in Bathurst, Australia, whose latest paper is about to be published in one of the upcoming issues of Nutrition Research (Bird. 2013). And as if that was not already enough, the participants were strength trained athletes, the  physical activity and diet were standardized according to pre-recorded habits and the supplementation protocol was extensive! With pre-, intra- and post-workout supplements it was exactly what many people today seem to believe was necessary to see any gains

... but is that true? Do you really need all that stuff?

The Australian researchers probably had a similar question in their minds, when they recruited their 15 strength-trained male field and court sport athletes (mean age 21.7years; 1-RM squat 133.0kg, bench press, 94.7 and 3.1 ± 0.3 years of strength training experience) and randomized them to ingest either a placebo supplement or a supplement "stack" consisting of 15g of Musashi Reactivate Hardcore before, 30g of Musashi Elevator during and 50g of Musashi SPORTS after the workout.

Table 1: Ingredient profile of the "tri-phasic" peri-workout supplement;  the placebo contained an aspartame based flavor that matched the taste of the active supplement (based on data from Bird. 2013)

In view of the fact that this probably sounds similarly "Chinese" to you as to me, I've provided you with a tabular overview of the ingredient profile of what the scientists call a "triphasic multinutrient supplement". Basically nothing you would not find in the line-up of every major supplement company: Some carbs, EAAs, creatine, beta alanine and AAKG, caffeine and b-vitamins (not listed in table 1) before workout, carbs, EAAs and creatine intra-workout and the obligatory protein- (whey/casein mix), carb-combination garnished with some creatine and glutamine after the workout. Add in some salt, magnesium and potassium and you can even at the as of late obligatory "contains electrolytes" blend and you are good to go.

Acute effects = stat. significant, long-term physiological significance = ?

Caffeine (pre, only), creatine, EAAs, whey (post, only) and even beta alanine and AAKG, the additional carbhydrates, ... all that should do something right? Yep, you are of course right it should. After all people are paying with their hard-earned money for it!

Figure 1: Serum markers glucose, AST, CRP, CK, cortisol and testosterone before, during, right after, 30min after and 24h after the workouts with the active (SUPP) or placebo beverage (PLA); data expressed relative to group-specific pre-values (Bird. 2013)

That being said, the data in figure 1 provides at least initial relieve. There are statistically significant effects for almost all measured hormonal parameters,  if we compare the supplemented with the non-supplemented trials in this double-blind, placebo (PLA)-controlled, crossover study.

Figure 2: Supplement & blood draws (top); overview of the exercises, set x rep scheme and equipment used in the lower body workout (Bird. 2013)

The study design allowed for a 7-day washout before the "crossing" took place and those participants who had been randomized to the supplement group after an obligatory 28-day washout to clear all previously used supplements (and what not ;-) from the system had to perform the test workout (4 sets of 8 to 15 repetitions for 5 lower-body exercises; see figure 2) with/without the "triphasic nutrient supplement" on top of their 33.6 ± 1.8 kcal/kg body mass diet (macros: 3.8g/kg, 1.5g/kg carbs and protein, respectively.

The supplement, or rather the supplements, had to be ingested 15 minutes preexercise, in small, regular doses during the exercise, and the whole 300ml of their post-workout drink right after the workout. and thus according to the manufacturers suggestions.

Aside from the hormonal and inflammatory response (see figure 1) to the workout the scientists also measured the muscular performance and perceptual response during the workouts:

Figure 3: Perceptual measures of exertion & muscle soreness (Bird. 2013)

• the total training volume was higher for SUPP (15 836 ± 518 kg⋅repetitions) compared with PLA (14 390 ± 491 kg⋅repetitions) (P <.05;d = 0.70); 
• countermovement jump peak power (CMJ) did not differ between groups at any timepoint (P> .05;d= 0.05-0.18); in the SUPP group there was however a trend (P= .08;d= 0.32) for increased countermovement jump peak power was yet observed on the third of the four tests 30min after the workout (exact timing see figure 2, top)

• the global rate of perceived exertion (RPE) did increase after the workout in both groups, and was higher 30min after the supplement trial (P < .01; d= 0.89)
• the perceptual responses for muscle soreness was elevated and did not differ between treatments
  after the workouts

However, even for the statistical significant inter-group difference in msucle perceived exertion, the overall effect size is pretty small. It is therefore by no means "obvious", whether the 10% lower perceived exertion during the placebo trial which is probably a direct result of the +10% increase in total training volume, anyways, is of physiological relevance.

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So what do we make of these results? On the one hand it is unquestionably true, that the peri-workout supplementation (I refuse to keep using the hilarious sciency expression "triphasic") did increase the total workout volume, It is also true that it did lower the cortisol increase and produced lower areas under the curve for creatine kinase, but it also lowered the testosterone response to the workout (that the post-workout increase in testosterone is not a legitimate predictor of muscle growth is something you should now, after countless articles on the matter, be aware of; read more about testosterone).

Whey is more insulinogenic than white bread and creatine could make you fatt True for the 1st, remotely possible for the 2nd! And still both simply work....

Much ado about nothing? No, not really. While the hormonal changes are more or less irrelevant an increase in total volue that does not entail greater muscle damage could in fact make a difference that's not just statistically, but also physiologically significant.

What I do yet doubt is that the same results could not have been achieved with a cup of oatmeal, water and protein powder 1h before the workout, a coffee right before the workout and 3-5g of creatine, two bananas and a regular whey protein afterward. All you would have to buy then is a pouch of whey and a 500g jar of creatine monohydrate, which will last you for months. Both SuppVersity supplement staples, as you know and actually among the few supps with physiologically significant effects almost every trainee can benefit from... and did I mention that they are dirt cheap and can be combined with real foods?

References:

• Bird SP, Mabon T, Pryde M, Feebrey S, Cannon J. Triphasic multinutrient supplementation during acute resistance exercise improves session volume load and reduces muscle damage in strength-trained athletes. Nutrition Research. April 2013 [EPub ahead of print].

Instant Coffee, Glycemia & Caffeine Powered Post-Workout Glycogen Repletion. Fish Oil, Arachidonic Acid Release & Prostaglandin Modulation. Adipocyte Sizes & Yoyo Dieting

Judged by the way they are looking at each other they don't care about their differential glucose / insulin response too coffee, but if you do, I suggest you scroll down and read the pertaining news item.

7.3% and 21.4%, those are the SuppVersity figures of the week. Figures that stand for the 2011 youth- and 2010 adult obesity rates in Colorado and they represent the nationwide "optimum" - at least according to CDC data from the respective years. Now, it was already hard to find US states with obesity rates below the nationwide average of 13% (youths) and 27.6% (adults). What is yet even harder or rather impossible is to dig up studies which try to elucidate why Colorado is the "leanest" of the 50 US states. Non-exhausting physical activity, for example, would be a candidate, but according to Wyatt et al. the "[e]ven in Colorado, one of the leanest states, very low levels of physical activity are seen in much of the population." (Wyatt. 2005).

Wouldn't it be worth taking some time to try to elucidate what the citizens in Colorado may be doing, their fellow Americans in Mississippi (highest adult obesity rate of 34.5%) or Alabama (highest youth obesity rates of 17%) ain't doing? Are they maybe having more or less fish oil or drinking only half the amount of caffeine? I don't know, but based on today's installment of "On Short Notice", you should be able to answer whether or not it is likely that factors like these could make a difference ;-)

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Coffee, Sex and Your Physique (Gavrieli. 2013) -- The latter two, i.e. sex and your physique are what determines your postprandial glucose and insulin concentrations after escalating dosages of caffeinated coffee. That's at least what Anna Gavrieli from the Harokopio University in Athens and her colleagues from overseas write in a soon-to-be-published paper.

To examine the effects of different amounts of coffee on blood glucose and insulin concentrations in the postprandial phase (after a meal) the scientist recruited thirty-three volunteers [16♀/17♂, 16 normal-weight and 17 overweight/obese, 27.3 ± 7.2 (19–44) y] who came to the lab fasted and obviously without having  had a "wake up coffee" early in the morning. When they arrived, the subjects received a standardized meal, i.e. a slice white bread, 5 g of butter and 10 g of white sugar, providing 142 kcal (6.5% of energy from proteins, 62.5% from carbohydrates and 31.0% from lipids) along with 200 mL of water or instant coffee containing either 3 or 6 mg of caffeine/kg body weight on three different occasions.

Figure 1: Usual and experimental caffeine intake in the subjects (left); effects on glucose metabolism after standardized "breakfast" (=sugar binge) + water or different dosages of instant coffee (Gavrieli. 2013)

As you can see in figure 1, the blood samples the scientists obtained before, immediately after and in regular intervals over the remaining 3 hours after the ingestion of the "breakfast" do support the hypothesis that men and women, light and heavy weights react very differently to the ingestion of 200-500mg.

So what's the verdict then? Is coffee the way to go?

Post workout caffeine supplementation?! Just like dieting, working out is one of the confounding factors which render results like the one at hand valid only in certain scenarios. Against that background it is not surprising that a 2008 study by Pedersen et al., the results of which I have plotted for you in the figure above (Pedderson. 2013), found statistically significant improvements in glycogen resynthesis w/ 8mg/kg caffeine being coingested with 4mg/kg glucose after a workout. Whether this will yield real world benefits is obviously another story ;-)

While coffee delayed the rise of insulin in response to the standardized meal and the fall of glucose concentrations from its maximum levels in the entire study sample, the glucose incremental area under the curve (IAUC) was not just different between the interventions (with both coffee amounts inducing a greater area compared to water, p = 0.009), but also varied according to the sex and body weight of the subjects:

"Secondary, subgroup analysis at the nominal level showed that this might be more evident among females (PIAUC = .05) and overweight/obese participants (PIAUC = .03). Furthermore, coffee, mainly the 6 mg dose, could be lowering insulin concentrations the first 30 min after its consumption compared to water in men and overweight/obese participants." (Gavrieli. 2013)

So what do we make of these results, now? Well, first of all, even if your breakfast does not deserve the name food, having a single regular sized cup of coffee is unlikely to to any harm. Reversing the ratio of breakfast to coffee on the other hand and having a "Sex & The City" breakfast with a croissant and a large cup of breakfast will have you run the risk of having high blood sugar afterwards (esp. if you drink that 400mg+ pot of coffee with tons of sugar).

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The tissue incorporation of regular triglyceride based fish oils is inferior to their phospholipid bound brethren. Want to learn more? Check out my article on that matter from June 2012 (learn more)

3g of fish oil modulate the eicasonoid production from omega-6 fatty acids in young men (Zulyniak. 2013) -- 2g of EPA and 1g of DHA that was the dosage the 10 young healthy males (23.4 ± 1.7 years) had to consume on every day of the 3-months supplementation period in Zulyniak et al.'s experiment which was designed to "better understand the potential health benefits of fish oil supplementation in young healthy males" (Zulyniak. 2013).

What the researchers observed were the expected decreases in serum triglycerides (-38%), a significant increase in the proportion of HDL-c relative to total cholesterol, as well as - and this is the actual news - an increase in eicosanoids production, namely prostaglandin-F2α (P < 0.0001) and thromboxane-B2 (P = 0.0296), after fish oil supplementation.

The latter two are products of omega-6 metabolism and confirm the replacement of arachidonic acid (AA, the long-chain omega-6 fatty acid and the quasi-analogon to DHA) in the cell membranes of the erythrocytes by EPA and DHA. This process must have triggered the increase in PGF2α and TXB2 production of which the scientists state that

On a side note: The results of this study don't change my opinion as far as the usefulness, let alone necessity of fish oil supplementation in healthy, athletic, fish eating SuppVersity readers is concerned. I don't see any.

"[...]previous work by both Boughton-Smith et al. and Scott et al. suggest that PGE2, PGF2α, TXB2, and 6-keto-PGF1α are the primary products of the COX2 pathway when AA is in abundance. Furthermore, Scott and colleagues suggested that with chronic elevation of AA, PGF2α and TXB2 production is more likely to be up-regulated due to their vasoconstrictive qualities, which would prevent the efflux of AA and other more-damaging eicosanoids from cells into circulation." (Zulyniak. 2013)

Whether this is actually a good thing does yet appear at least somewhat questionable to me and even Zulyniak et al. have to admit that future research was necessary to confirm "the production of eicosanoids capable of regulating vasoconstriction" and thus "substantiate this hypothesis" (Zulyniak. 2013). As you can see, we are still learning new stuff about things of which every disciple of Dr Oz believes he already knew everything.

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Study supports hypothesis that regression in adipocyte size during weight loss could be reason for fat loss plateaus and "walls" (Verhoef. 2013) -- As a seasoned SuppVersity veteran, you are probably aware of the possible influence the size of your fat cells could have on weight loss success, failure or stagnation (learn more).

In a previous post on the Yoyo effect, I already discussed some aspects of adipocyte morphology - including the way lower body fat tends to be more stubborn than upper body fat (read more)

A recent study from the Maastricht University does now offer further support for my previously expressed hypothesis that the reduction of adipocyte size that comes with profound weight loss in then formerly obese individuals could be at the heart of the weight loss plateaus and over-pronounced metabolic downregulation formerly obese individuals experience at way higher body fat levels than someone who has never been obese in his / her whole life. Verhoef et al. put a group of twenty-eight overweight (BMI 28-35kg/m²) healthy subjects on a very low energy diet for 2 months. The 500kcal/day period (50g carbs, 52g protein, 7g fat + multi-mineral supplement delivering the RDA of all nutrients) was followed by a 10-month period of weight maintenance.

Over the course of the low energy diet intervention period, the adipocyte size decreased by -16.7%, the body fat level, on the other hand dropped by only 4.7%. Still, the leptin levels plummeted from 20.3 to 13.1 µg/L and did not return to baseline in the course of the "weight maintenance" phase.

Figure 2: Relative changes (compared to baseline) in body composition, adipocyte volume and leptin after the dieting intervention and the miserable weight maintenance phase (Verhoef. 2013)

In how far the suppressed leptin levels were actually responsible for the fact that the "weight maintenance" phase turned out to be a very dirty, fat only bulking phase cannot be said, but we know from previous studies, that the process of shrinking in itself

"has been reported to generate cellular stress and the more [the adipocytes] shrink, the higher will be the resistance against increasing mitochondrial beta-oxidation via HADHsc [hydroxyacyl-Coenzyme A dehydrogenase] during follow-up." (Verhoef. 2013)

And as if that was not enough the slight increase in ATGL (lipolytic protein) and HADHsc in the "weight maintenance" phase are, as the scientists point out, indicative of the appearance of newly differentiated adipocytes that are are metabolically active contribute to an "improved physiological status", but could potentially make future weight loss (esp. the aesthetic one) even more difficult.

"Empty" adipocytes <> lower leptin <> more glucose-to-fat conversion <> rapid fat gain

If CLA worked in humans as it does in rodents, it could solve the "small adipocyte" problem (learn why)

Moreover, the glycolyctic and thus potentially glucose-to-fat conversion promoting enzyme Aldolase-C did not just distinguish the successful weight maintainers (low Aldolase-C) from the yoyo dieters (high Aldolase-C), it also correlated with the leptin production of the fat cells, of which we know from previous studies that it is in turn negatively correlated to their size (Skurk. 2007)... too complicated?

Ok, let's express it the other way around. The "emptier" your adipocytes are (=smaller size), the less leptin they will produce and the more likely they are to convert glucose to fat and stash that away in their empty "tummies".

Suggested read for those who want to dig further into the purported underlying effects of weight regain: Maclean PS, Bergouignan A, Cornier MA, Jackman MR. Biology's response to dieting: the impetus for weight regain. Am J Physiol Regul Integr Comp Physiol. 2011 Sep;301(3):R581-600.

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That's it for an allegedly too lengthy installment of "On Short Notice"... about as much a misnomer as the "weight maintenance" phase in the Verhoef study, I guess. Maybe some of today's Facebook news can make up for that? In the end news like

Want to make HIIT a hit for you? Not a problem, the SuppVersity holds all the information you need. Start out with the respective two post article series and descend into the archives, where you are going to find more about HIIT, how it compares to LISS and which different regimen have shown some promise in peer-reviewed research (learn more)

• High fat dieting reduces the beneficial effects of resistant starch - Reduction in abdominal obesity with 42% fat diet = zero (read more)
• HIIT hits home in 8 young, untrained men - 12 HIIT sessions lead to increased V02 kinetics (read more)
• Ice slurries are the new energy gels - Scientists observe significant increases in cycling performance (read more)
• Physical therapy as effective as surgery for a meniscal tear and osteoarthritis - Unfortunately patients are too lazy and the revenue for the doctors too small to be used more often (read more)
• Evolution is to blame for inflammatory disease - At least that's what the latest "paleo" research would suggest (read more)

are eventually the reason that the saturdaily short news are always so lengthy. The really short stuff is already on Facebook ;-)

References:

• Gavrieli A, et al. Gender and body mass index modify the effect of increasing amounts of caffeinated coffee on postprandial glucose and insulin concentrations; a randomized, controlled, clinical trial. Metabolism.2013 [ahead of print]
• Pedersen DJ, Lessard SJ, Coffey VG, Churchley EG, Wootton AM, Ng T, Watt MJ, Hawley JA. High rates of muscle glycogen resynthesis after exhaustive exercise when carbohydrate is coingested with caffeine. J Appl Physiol. 2008 Jul;105(1):7-13.
• Verhoef SP, Camps SG, Bouwman FG, Mariman EC, Westerterp KR. Physiological response of adipocytes to weight loss and maintenance. PLoS One. 2013;8(3):e58011.
• Wyatt HR, Peters JC, Reed GW, Barry M, Hill JO. A Colorado statewide survey of walking and its relation to excessive weight. Med Sci Sports Exerc. 2005 May;37(5):724-30.
• Zulyniak MA, et al. Fish oil supplementation alters circulating eicosanoid concentrations in young healthy men. Metabolism. 2013 [ahead of print]

Leucine Inhibits Nitric Oxide & Beneficial Effects of Cardio Training on Glucose Management. Plus: No Increase in Protein Synthesis W/ Protein After Eccentric Workouts?

Pre-, Post and Intra-workout supplements are a multi-million dollar business. But are the products at least half as effective as the shiny advertisements claim?

Let me guess, the actual reason you want to read this article is the shocking claim that everybody's darling, the "pro-anabolic amino acid" leucine may, in addition to having beneficial effects on the phosphorylation of mTOR and the subsequent increase in skeletal muscle protein synthesis, also have negative effects. Right? Ok, I will add a link that takes you right to my elaborations on two recent studies from the São Paulo University and the China Agricultural University and allows you to skip past the information about another recent study.

A study from the Department of Public Health at the Aarhus University and a study that raises the question, whether its results are indicate that eccentric training is potent enough to maximize the protein anabolic response to an extend that the additional provision of dietary protein will not lead to further increases in markers of protein synthesis.

You can learn more about protein intake at the SuppVersity

Protein Timing DOES Matter!

5x More Than the FDA Allows!

Protein requ. of athletes

High EAA protein for fat loss

Fast vs. slow protein

Less Fat, More Muscle!

Before we draw any conclusions, I guess we should first take a look at what Stine Klejs Rahbek and her colleagues actually did: To investigate the effects of leucine-rich whey protein hydrolysate and carbohydrate (WPH+CHO) versus isocaloric carbohydrate (CHO) supplementation on the Akt-mTOR and the AktFOXO signaling axis, during recovery from muscle-damaging exercise and to evaluate whether their hypothesis that WPH+CHO would accentuate signaling for protein synthesis and attenuate signaling for protein degradation, compared to isocaloric CHO, the researchers recruited twenty-four young healthy recreationally active men who had not participated in systematic resistance training or eccentric dominated activities for lower extremity muscles within 6 months prior to inclusion in the study.

The study itself was conducted in a double blinded, isocaloric placebo-controlled fashion in regards to dietary supplementation. Following inclusion, subjects were randomly allocated into either

• a whey protein hydrolysate+carbohydrate group (WPH+CHO, n = 12) or
• isocaloric carbohydrate placebo group (CHO, n = 12)

On the exercise trial day, subjects reported to the laboratory at 07.30 am in a fasted state. Before the eccentric exercise protocol was initiated, muscle soreness was evaluated using a visual analog scale, a blood sample was collected and knee extensor muscle contractile function was evaluated. Subsequently, a unilateral eccentric exercise protocol for was completed, lasting approximately 30 min (see below).

Figure 1: Timeline of interventions and measurements on the four study days are shown. A muscle biopsy was sampled 14 days prior to the exercise trial (i.e. to establish basal level). The protocol for days 1 and 2 was identical (Rahbeck. 2015).

Immediately after the exercise bout, the subjects ingested either a WPH+CHO or a CHO supplement, according to the group they were assigned, and then rested for 3 h. At 3-h post-exercise, a biopsy was obtained from both the exercise and the non-exercise control leg. Before leaving the laboratory, the subjects ingested the second drink (1.00 pm) and received a third drink to ingest 3 h later (4.00 pm).

"On days 1 and 2 (24 and 48 h following exercise, respectively), the subjects were instructed to ingest three supplements at absolute time points similar to day 0, with the fist drink always ingested after the functional tests and biopsy sampling. Biopsy sampling from both the ECC and the CON leg on days 1 and 2 were performed under conditions similar to the pre-exercise biopsy, i.e., the subjects fasted overnight and rested in the supine position for 45 min prior to biopsy sampling. The biopsy sampling on days 1 and 2 was timed to correspond to 24 and 48 h following exercise termination. Assessments on indices of muscle damage (muscle force, muscle soreness and plasma muscle creatine kinase) were repeated at 24, 48, 72, 96, and 168 h after overnight fasting." (Rahbeck. 2015)

All Subjects were instructed to refrain from physical activity such as exercise, stair case walking and other types of strenuous activity in the hours/ days between post-exercise assessments of indices of muscle damage to ensure that all measured effects made actually reflected the effects of the exercise + supplementation intervention.

Figure 2: Effects of eccentric training + supplementation on markers of protein anabolism (left, green) and catabolism (right, red) as measured in the trained leg (Rahbeck. 2015).

Speaking of effects: If you look at the data in Figure 2, you will realize that the eccentric training led to significant decreases in muscle force (by 23–27 % at 24 h post-exercise), which were followed by gradual, although not full recovery at 168 h post-exercise, with no differences between supplement groups. Furthermore, the phosphorylation of mTOR, p70S6K and rpS6 (=the activity of these protein anabolic proteins) increased and phosphorylation of FOXO1 and FOXO3 (=the activity of these catabolic proteins) decreased in the ECC leg, again with no differences between supplement groups.

Eccentric training impairs glucose sensitivity in healthy men (Asp. 1995).

Speaking of eccentric training, you are aware that this form of allegedly highly anabolic (this is scientifically not proven) training will induce a transient decrease in insulin sensitivity (Kirwan. 1992; Asp. 1995), right? So carb binging after an eccentric workout is probably worse than doing the same at any other time for healthy men and women with a decent baseline insulin sensitivity.

If this is not your first visit to the SuppVersity you will yet know that these observations are not sufficient to warrant the previous voiced hypothesis that the exercise induced increase in protein synthesis in response to eccentric exercises realizes as long as you are training "hard enough", because mTOR, p-p70S6K & co are no reliable measure of the actual amount of protein that's transported into the muscle after the workout.

Don't freak out about the Rahbeck study, take a look at the latest studies leucine science!

Instead of freaking out that your protein supplements may be useless, you may thus rather discard this study as interesting, but inconclusive and take a closer look at the latest evidence that leucine, when consumed in excess and isolation could have side effects you may want to avoid.

• Leucine + endurance exercise - no perfect match? In their latest study, scientist from the São Paulo University were able to show that "leucine supplementation did not potentiate the effects of endurance training on protein turnover, and it also reduced its positive effects on glucose homeostasis" (Costa Junior. 2015) - in rodents.
  
  In view of the fact that the interactions between endurance exercise, leucine supplementation and glucose metabolism have not previously been studies, the scientists analyzed the effects of endurance exercise training plus leucine supplementation on protein turnover and glucose homeostasis in healthy mice.
  

  

  Figure 3: Changes in body composition (left), changes in the expression of the catabolic ubiquitin-proteasome protiens (middle) and effects on glucose disappearance index aka effective glucose uptake after the swimming workout (right | Costa Junior. 2015).

  The results you see in Figure 3 tell you three things: (a) Leucine did not have the previously described minor minor beneficial effects on body composition (increases in lean mass are compensated by increases in fat mass); (b) it did not ameliorate the protein turnover during exercise and (c) it did actively blunt the real world increase in glucose uptake after the endurance workout in spite of the fact that changes in marker proteins like AMPK (not shown)would suggest otherwise.
  
  Reason to panic? No, the effects are not pronounced enough. In view of the fact that the benefits of isolated leucine supplementation and "spiking" other supplements with extra leucine are totally overblown, anyway. This may be the final straw that brakes the leucine guzzling camel's neck for those of you who's primary goal is to use exercise to improve their glucose tolerance.
• Leucine an "anti-pump", "anti-heart health" supplement? While they are a bit removed from human in vivo studies, the claims made by Yang et al. in their latest paper in Amino Acids are a bit frightening.
  
  Based on the observation that increased concentrations of l-leucine in the plasma occur in obese humans and other animals with vascular dysfunction, the scientists argue that the unique inhibitory effect of leucine on NO synthesis from l-arginine in endothelial cells may be part of why the increase in serum BCAA that's brought about by a failure to metabolize the branch-chained amino acids in the obese could negatively modulate cardiovascular homeostasis in insulin resistance.
  

  

  Figure 4: This is how leucine messes with NO synthesis. It increases the production of glutamine:fructose- 6-phosphate aminotransferase (GFAT) which then shuts down NO synthesis (Yang. 2015).

  "Results of recent studies indicate that l-leucine is an activator of glutamine:fructose- 6-phosphate aminotransferase (GFAT), which is the fist and a rate-controlling enzyme in the synthesis of glucosamine (an inhibitor of endothelial NO synthesis). Through stimulating the mammalian target of rapamycin signaling pathway and thus protein synthesis, l-leucine may enhance GFAT protein expression, thereby inhibiting NO synthesis in endothelial cells" (Yang. 2015).

  Yang et al. propose that reducing circulating levels of l-leucine or endothelial GFAT activity may provide a potentially novel strategy for preventing and/or treating cardiovascular disease in obese and diabetic subjects and highlight:
  

  "Such means may include dietary supplementation with either α-ketoglutarate to enhance the catabolism of l-leucine in the small intestine and other tissues or with N-ethyll-glutamine to inhibit GFAT activity in endothelial cells" (Yang. 2015).

  If the scientists (reasonable) assumptions are accurate, anything that prevents the leucine-induced activation of GFAT, be it nutritional supplements or pharmaceutical drugs, may in fact contribute to improved cardiovascular function by enhancing vascular NO synthesis. For the average trainee that's not really relevant, but if you look at the composition of contemporary N.O. boosters this revelation may explain why the "old" NO Xplode with arginine, caffeine & co worked significantly better than its BCAA-laden successors. 

Study Says "BCCAs, Don't Build Muscle!" I Say "True, But They Seem to Create an Anabolic Potential." | more

Bottom line: None of the studies presented in this research summary indicates that you have to stop taking the respective supplements. Specifically the use of protein supplements after resistance training workouts is a tried and proven way of augmenting muscle growth - irrespective of the questionably conclusions Stine Klejs Rahbek draw based solely on markers of protein synthesis and in the absence of measuring the influx of protein into the muscle after the standardized eccentric exercise protocol.

Similarly, the results Yang et al. and Costa Junior et al. present in their papers prove that the incredible hype surrounding leucine is misplaced. They do not, however, provide bullet proof evidence of side effects that are severe enough to flush your leucine and BCAA supplements down the toilette | Comment on Facebook!

References:

• Asp, Sven, Jens R. Daugaard, and Erik A. Richter. "Eccentric exercise decreases glucose transporter GLUT4 protein in human skeletal muscle." The Journal of physiology 482.Pt 3 (1995): 705-712.
• Costa Junior, et al. "Leucine supplementation does not affect protein turnover and impairs the benefiial effects of endurance training on glucose homeostasis in healthy mice." Amino Acids (2015): Ahead of Print.
• Kirwan, J. P., et al. "Eccentric exercise induces transient insulin resistance in healthy individuals." J Appl Physiol 72.6 (1992): 2197-202.
• Rahbek, Stine Klejs, et al. "No differential effects of divergent isocaloric supplements on signaling for muscle protein turnover during recovery from muscle-damaging eccentric exercise." Amino Acids (2015): 1-12.
• Yang, Ying, et al. "l-Leucine and NO-mediated cardiovascular function." Amino acids (2015): 1-13.