Chronic High Dose BCAA Supplementation Reduces Endurance Performance by 43% Plus: How Ammonia, Glutamine, Arginine & Low Carb Could be Involved

Tired, exhausted, had to cut your workout short today? Is it the flu, or just too much BCAAs?

When some is good and more is better, even more is not necessarily going to be 'betterer' - and that's not simply due to the fact that there is no comparative to an adjective that's already in the comparative. Therefore it is actually not surprising that a team of researchers from the Department of Food and Experimental Nutrition at the Faculty of Pharmaceutical Sciences, the Department of Nutrition at the School of Public Health and the Department of Physiology and Biophysics at the Institute of Biomedical Sciences of the University of Sã o Paulo in Brazil has just published the results of a study (Falavigna. 2013) which demonstrates that there is an upper limit to the benefits of BCAA supplementation. What I guess will be surprising at least for some not so regular SuppVersity visitors, is that there is more than just a saturation effect: Too much BCAAs can actually have ergolytic (= anti-ergogenic) effects - at least under certain circumstances.

Another chapter in the book of good things that turn against you, when taken in excess

In their latest paper that has just been published in nutrients, Gina Falavigna and her colleagues analyzed effects of chronic BCAA supplementation on exercise performance in male Wistar rats. Based on previous animal and human data and the still widely supported, though actually experimentally non-validated (cf. Meeusen. 2007) theory that BCAAs would work their non-hypertrophy specific, endurance enhancing magic via the blockade of exercise induced 5-HT (serotonin) accumulation in the brain, the researchers speculated that ...

"[...] chronic BCAA supplementation (through the diet, using different BCAA  concentrations) would increase performance in rats subjected to a swimming exhaustion  test." (Falavigna. 2013)

To verify this hypothesis, Flavigna et al. randomized their rats to three different groups receiving either the standard AIN-93M diet for the maintenance of adult rodents (control group) or the same diet with additional additional 3.57% (group S1) and 4.76% (group S2) BCAAs at a ~2:1:1 ratio of lecine : valine : isoleucine (the BCAAs were manufactured by the Brazilian branch of Ajinomoto). The rodents in the S1 and S2 groups did thus receive 50% and 100% more branched-chain amino acids than the rodents in the control group which had to contend themselves with the BCAAs in the casein fraction of their diets (see figure 1, right). In order to assure that the diets would be isocaloric, an amount of starch equivalent to the amoung of BCCAs that had been added to the chow was removed from the supplemented diets.

Overall, the study lasted for six weeks. During this time the rodents were subjected to a 1h/day weight bearing swimming protocol five times a week. In the first two weeks, the rats were ...

"[...] adapted to the water medium and exercised with increasing overloads attached to the tail until an overload corresponding to 5% of total body weight was reached. This final overload was used until the end of the training protocol [...] The overloads were corrected weekly according to the variations in animal weight.  The efficiency of the training protocol was assessed on the basis of maximum activity of the enzyme citrate synthase in the soleus muscle, with a group of sedentary animals being used as the control for this parameter." (Falavigna. 2013)

Neither the overall amount of food nor the body weight gain of the rodents in the control, and the two exercise groups showed any statistically significant difference. The latter cannot be said about the exercise performance, as well as the accumulation of ammonia, though (see figure 1):

Figure 1: Exercise duration and plasma ammonia levels during / after swmming test (left) and macronutrient composition of the experimental diets (right; based on Falavigna.. 2013)

While the rodents in the +50% BCAA group (S1) do show the expected increase in endurance (+37%) their peers in the high dose (+100%) BCAA group (S2) experienced an even more pronounced drop in endurance performance (-43% vs. control), which went hand in hand with a profound increase in blood ammonia (+34%).

"Ammonia is a ubiquitous metabolic product producing multiple effects on physiological and biochemical systems. Its concentration in several body compartments is elevated during exercise, predominantly by the increased activity of the purine nucleotide cycle in skeletal muscle. Depending on the intensity and duration of exercise, muscle ammonia may be elevated to the extent that it leaks (diffuses) from muscle to blood, and thereby can be carried to other organs. The direction of movement of ammonia or the ammonium ion is dependent on concentration and pH gradients between tissues. As such, ammonia can also cross the blood-brain barrier, although the rate of diffusion of ammonia from blood to brain during exercise is unknown. It seems reasonable to assume that exhaustive exercise may induce a state of acute ammonia toxicity which, although transient and reversible relative to disease states, may be severe enough in critical regions of the central nervous system (CNS) to affect continuing coordinated activity. Regional differences in brain ammonia content, detoxification capacity, and specific sensitivity may account for the variability of precipitating factors and latency of response in CNS-mediated dysfunction arising from an exercise" stimulus, e.g., motor incoordination, ataxia and stupor. There have been numerous suggestions that elevated ammonia is associated with, or perhaps is responsible for, exercise fatigue, although evidence for this relies extensively on temporal relationships." (Falvigna. 2013; my emphasis)

Mark the last words of the previously cited paragraph: "[E]vidence for [the role of ammonia] in exercise fatigue relies extensively on temporal relationships". It is thus - as for now - a solely corollary, not yet a causative association, of which I do however feel that it would be very likely to turn into a causal one if someone actually measured the influx of ammonia into the brain during a workout.

Wait, ammonia? But ain't it more likely that the BCAAs block the uptake of tryptophan?

What's for sure is that another hypothesis, which relates to the blockade of tryptophan uptake can be ruled out as an underlying reason of the differences. After all the scientists who argue that ...

"[t]he increased synthesis of serotonin during exercise may be related to the development of central fatigue, because this neurotransmitter has several physiological functions, since it operates by  mood, lethargy, individual behavior, regulation of sleep, body temperature and blood  pressure, appetite suppression and changes in perceived exertion." (Falavigna. 2013)

...actually measure the 5-HT levels and observed no differences between the dietary groups. Overall, the study results to thus clearly indicate that both, medium nor high dose "chronic BCAA supplementation was not effective in improving the main parameters indicative of central fatigue" (Falavigna. 2013) - well, at least as long as we still stick to the hypothesis that the latter is induced by the accumulation of 5-HT in the brain.

Forget about tryptophan and serotonin, focus on ammonia

The fact that neither the high, nor medium dose of BCAAs did exert any effects on the serotonin levels in the brain does yet not explain why the medium dose supplementation regimen produced ergogenic, while the high dose regimen induced ergolytic effects.

The occurrence of direct toxic effects due to (too) high amounts of branched-chain amino acids can be ruled out based on previous studies in which the administration of more than 10g/kg body weight of BCAAs (the human equivalent would be 130g+ per day), as well as dosages of 2.5g/kg body weight chronically did not entail any toxic side effects (Shimomura.  2004). The same is true for other confounding variables, such as the citrate synthase activity, a measure of the general efficiency of the training protocol, bood glucose, insulin,free fatty acids, and lactate levels, as well as liver and muscle glycogen content, which were virtually identical in both groups. This leaves us with the increase in plasma ammonia as our 'last resort' to explain the -58% shorter swimming time in the high (S2) vs. medium (S1) dose BCAA group (-43% lower vs. non-supplemented control).

Figure 2: The reduced performance of the high BCAA group could well be related to peripheral and/or central ammonia build-up as a results of increased BCAA oxidation, camparably low glutamine intakes and the rate-limited enzymantic conversion and recycling of gluatmine (illustration originally from Earrante. 2003). Studies by Snow (2000) and Carvalho-Peixoto (2007) suggest: Both carbohydrate & glutamine supplements could help.

Based on what we know about the mammalian body, the increased build-up of ammonia in the high BCAA group could be a result of the unfortunate combination of temporary energy shortage and learned wastefulness' in a situation, where the otherwise sparse BCAAs are available in abundance. Furthermore, with a glutamine content of only 9-13% in the casein fraction of their diets (Swails. 1992), the rodents in the high BCAA group did ingest more than 2.6-3.8 times more BCAAs than glutamine; a fact which may have contributed to a temporary glutamine deficiency as a result of its increased use in the detoxification of the ammonia that's generated when the BCAAs are oxidized. The resulting peripheral and possibly central ammonia build-up (see figure 2) could then have begun to intoxicate liver and brains of the rodents and thus hampered gluconeogensis (normal levels stimulate, high levels of ammonia hamper gluconeogensis; cf. Fritz. 1988) and induced central fatigue (Wagenmakers. 1990; Nybo. 2004) -- and that not despite, but rather due to the chronic "high dose" BCAA supplementation (HED ~50g/day).

So do I have to drop my BCAAs now or what? Whether these results are relevant for you will probably depend on a whole host of parameters, which include

• the type, intensity and duration of exercise you do, 
• the ratio of BCAAs to glutamine in your diet,
• the amount of arginine, which acts as a substrate for the urea cycle and is therefore necessary to for the excretion of ammonia by the kindeys (Schaefer. 2002),
• the amount of carbohydrates in your diet (with more = less amino acid oxidation = lower ammonia and very low carb = you are in trouble; e.g. Czarnowski. 1995; Snow. 2000; Carvalho-Peixoto. 2007), 

... and those factors I will probably have forgotten to mention now. Unless you don't forget that you can neither lifve from BCCAs and protein alone, but accept the neflglected truth that too much protein is about as bad a too little protein, you can file this post under "show your stupid friends" and get back out, when they complain about feeling sick, bloated and fat "despite" eating a BCAA supplemented high protein, low carb (and often even low fat) diets.

References:

• Carvalho-Peixoto J, Alves RC, Cameron LC. Glutamine and carbohydrate supplements reduce ammonemia increase during endurance field exercise. Appl Physiol Nutr Metab. 2007 Dec;32(6):1186-90.
• Errante LD, Petroff OA. Acute effects of gabapentin and pregabalin on rat forebrain cellular GABA, glutamate, and glutamine concentrations. Seizure. 2003 Jul;12(5):300-6.
• Falavigna G, de Araú jo Junior JA, Rogero MM, de Oliveira Pires IS, rio Graç a Pedrosa R, Martins Junior E, Alves de Castro I, Tirapegui J. Effects of Diets Supplemented with Branched-Chain Amino Acids on the Performance and Fatigue Mechanisms of Rats Submitted to Prolonged Physical Exercise. Nutrients 2013. 4; 1767-1780.
• Fritz S, Bohnensack R. Stimulation of alanine metabolism in rat liver by ammonia. Biomed Biochim Acta. 1988;47(12):923-32.
• Meeusen R, Watson P. Amino acids and the brain: do they play a role in "central fatigue"? Int J Sport Nutr Exerc Metab. 2007 Aug;17 Suppl:S37-46.
• Nybo L, Dalsgaard MK, Steensberg A, Møller K, Secher NH. Cerebral ammonia uptake and accumulation during prolonged exercise in humans. J Physiol. 2005 Feb 15;563(Pt 1):285-90. Epub 2004 Dec 20. 
• Schaefer A, Piquard F, Geny B, Doutreleau S, Lampert E, Mettauer B, Lonsdorfer J. L-arginine reduces exercise-induced increase in plasma lactate and ammonia. Int J Sports Med. 2002 Aug;23(6):403-7.
• Shimomura, Y.; Murakami, T.; Nakai, N.; Nagasaki, M.; Harris, R.A. Exercise promotes BCAA catabolism:  Effects  of BCAA supplementation on skeletal muscle during exercise.  J. Nutr.  2004, 134, 1583S–1587S.
• Snow RJ, Carey MF, Stathis CG, Febbraio MA, Hargreaves M. Effect of carbohydrate ingestion on ammonia metabolism during exercise in humans. J Appl Physiol. 2000 May;88(5):1576-80.
• Swails WS, Bell SJ, Borlase BC, Forse RA, Blackburn GL. Glutamine content of whole proteins: implications for enteral formulas. Nutr Clin Pract. 1992 Apr;7(2):77-80.
• Wagenmakers AJ, Coakley JH, Edwards RH. Metabolism of branched-chain amino acids and ammonia during exercise: clues from McArdle's disease. Int J Sports Med. 1990 May;11 Suppl 2:S101-13.

Fiber Up Your Foods, Omega-3 Preload For Female Fat Loss, 50+ Ways to Treat Constipation, Serotonergic Peptides in Milk, Weight Cycling & Reduced Metabolic Rates, Exercise & 102% Weight Loss From Fat - Plus: More Short News

Inulin enriched foods are good for your gut, your waistline and your pancreas (anti-diabesity effect) and what's more inulin is also on the list of anti-constipation agents,

100g that's this week's SuppVersity figure of the week and that despite the fact that it is the amount of fat you are going to gain within one year when your metabolic rate is 100kcal below where it should be (Piaggi. 2013)... Where it should be? Yeah, ok I know that's idiotic, but if you read today's news-item about the down-regulation of the metabolic rate due to YoYo-dieting the picture that emerges is that of yet another vicious cycle that leads directly into a weight spiral that knows but one direction: upwards!

Another one of today's news-items does however hint at a solution: Just lose 102% fat! What? I see I got you interested. So what are you waiting for? Lot's of good stuff today. So much in fact that let's spend no time and get right to the news-business ;-)

"Fiber up" you foods with prebiotics (inulin in particular)

Pretty obvious that these Spanish Christmas confections take a toll on your HbA1c ;-)

(Capriles. 2013; Garcia-Garcia. 2013) -- You've read about the benefits of "feeding the good guys" a couple of days ago. Now, aside from being a substrate for the purportedly beneficial gut bacteria fiber also changes the feel, taste and most importantly digestive properties of foods. A couple of recently published studies confirm that this can have pretty profound and in most cases highly desirable consequences.

Garcia-Garcia, for example, added some inulin (5%) to Turon, a traditional Spanish sweet treat that's made of toasted almonds, honey and sugar and fed 30g of the Christmas nougat-type confection to 32 healthy, normal-weight volunteers.

While the subjects in the "regular" Turon group had a slight but significant increase in HbA1c (long-term measure of blood glucose management) the blood glucose management of the 17 subjects in the active group did not budge. And while most subjects (64%, specifically those who conumed Turon as a Christmas snack on a regular basis) preferred the "classic" variety, at least 24% did actually like the inulin Turon better (Garcia-Garcia. 2013)

Gluten will interact with PPARs & gut bacteria and can thus precipitate insulin resistance (read more).

In a similar study, scientists were able to show that the addition of prebiotic inulin-type fructans to gluten-free bread (4 g of fructans per 50 g bread serving size) did

"[...] provide structure and gas retention during baking, thus improving GFB quality by yielding better specific volume, softer crumb, improved crust and crumb browning with enhanced sensory acceptance" (Capriles. 2013)

 and decreased the glycemic index and glycemic load of the gluten-free bread by 34% (from 71 to 48) and 33% (from 12 to 8), respectively.

Omega-3 loading improves weight loss in obese women

(Munro. 2013) -- According to a recently published study, a 4-week preload with 6 × 1 g capsules per day LC ω-3PUFA (fish oil) each comprising 70 mg EPA and 270 mg DHA, increased the amount of weight the female (and only the female!) participants of a very low calorie weight loss intervention lost in the subsequent 8-weeks.

Despite being statistically significant, the 1.4% increase in bod weight loss is yet not so pronounced that anyone whose been dieint with LC-PUFA preload in the past should now be fretting about having missed out on this great chance of getting ripped. If you are a man, the protocol would have been useless, anyways.

Constipated? Review offers three types of "solutions" - in some cases a literal sense

(Gelinas. 2013) -- If you are one out of five, chances are you belong to the 20% of the world's population who suffer from constipation on a regular base. If that's the case, you may want to consider one of the following "treatment" strategies, Pierre Galinas mentions in his latest review of the literature:

• 

  Table 1: Relative laxative potential of 50 food ingredients for the prevention of constipation

  Bulking agents  - They soften the stool by binding water; examples are psyllium seed husk, wheat bran, methylcellulose, calcium polycarbophil; are considered "mild" and are not habit forming, but may cause abdominal pain and bloating because of gas formation
• Osmotic agents - They also soften the stool but ba a dfferent mechanism than the bulk fiber, they create an osmotic gradient, which will distend the intestines and stimulates a contractile response; examples are lactulose, sorbitol, mannitol, polyethylene glycol (PEG), magnesium hydroxide (milk of magnesia), sodium phosphate; side effects are gas, and the offensive taste (of some)
• Softeners and lubricants  - They  lubricate (oil) and soften (detergent) the stool; examples are sodium docusate and various mineral oils; pretty milk
• Stimulants - Just like the stims in a fat burner get you going, these get your colon going; examples are epson salts (magnesium sulphate heptahydrate), bisacodyl, sodium picosulphate, sodium sulphate, magnesium oxide, phenolphthalein; they taste offensive, but don't produce gas
• Herbal teas - Provide water and can increase bowel frequency; examples are anthracenes derivatives (senna; aloe; cascara, Frangula bark); unfortunately they taste offensive and work almost immediately; moreover tolerance builds up pretty fast

As you can see there are different ways to get going with the bulk agent aka an increase in fiber intake being the only healthy long-term solution.

Even unhappy cows produce "Happy Milk"

"Mutant Milk" is homogenized milk a potential threat to your health (learn more)?

(Nongonierma. 2013) -- Three days ago a paper by Alice Nongonierma and her colleagues was published ahead of print on the website of the Journal of Food & Function. In the said paper, the researchers describe an experiment, in the course of which they were able to proof that hydrolyzed milk proteins contain a peptides that "behave as serotonin 2C (5-HT2c) receptor agonists" (Nongenierma. 2013). According to the scientists, the bioactive peptides have a relatively low molecular mass (< 1 kDa) and are hydrophobic in nature. With the 5-HT2c receptor being more than just a pharmacological target for the treatment of depression and anxiety, but also a trigger of neurogenesis (growth of new neurons) in the hippocampus (Millan. 2005), this certainly is good news for all the milk junkies out there - or could the serotonine-like effects make you fat?

Magic anti-diabetic mushrooms

(Su. 2013) -- Not what you are thinking now, folks! That's Traditional Chinese Medicine. After all, mushrooms such as Coriolus versicolor and Grifola frondosa have been used in TCM for centuries now. As a recent study by Scientsts from Kang Jien BioTech confirms rightly, so. Extracts from both mushroom had potent inhibitory effects on the carbohydrate digesting enzymes α-amylase and α-glucosidase. With Coriolus being a better inhibitor of the former and Grifola a more potent inhibitor of the latter enzymes.

How this relates to glucose control? Easy: If you don't disentangle the complex carbs your body cannot access their sugar content and if you do it only very slowly even "high" GI starches suddenly turn into low GI foods.

Weight cycling does not forestall future weight loss, but it makes it harder

Geoffrey Cannon's "Dieting Makes You Fat" was first published in 1983 but is that true? Does dieting always make you fatter and would it be better so simply surrender   (learn more)?

(Bosy-Westphal. 2013) -- While the ups and downs in body weight so many dieters are experiencing on a regular basis do not, as it was long suspected, ruin your body composition. A paper that has been published roughly a week ago in the International Journal of Obesitysuggests that another often touted downside, namely the long-term creeping down-regulation of the basal energy expenditure is unfortunately very real.

According to the analysis of the researchers from the Christian-Albrecht University in Kiel, Germany, the 27 "weight regainers" (after ~30% of loss) showed a reduced REE adjusted for changes in organ and tissue masses after weight loss that was not present in the 20 previously weight stable, yet likewise overweight / obese subjects in the control group of the researchers' 13-week dietary intervention study.

It is however not sure, whether this actually is a result of previous weight cycling or vice versa; meaning that the people with the ups and downs in body weight are the ones whose metabolism shuts down the easiest. The study at hand was obviously not able to exclude this possibility.

More than 100% weight loss from fat? How is that supposed to work?

(Hall. 2013) -- Actually this study was published late in the year 2013, that it still made it to On Short Notice has two reasons. Reason #1 is that it was an Epub way ahead of print. Reason #2 is that the figures the author reports appear to be pretty nonsensical. I mean how on earth can the projection K.. Hall from the National Institute of Health in Bethesda made based on data from the Biggest Loser camp yield a net weight loss of 24kg of which more than 100% (102% to be precise) came from the exuberant body fat stores of the (>70kg for the average participant) of the "big losers"?

For the researchers who worked with the Biggest Losers the highly successful TV show was a fluke. Having a TV station pay for their "research" certainly is something extraordinary and against and the study at hand is only the latest publication based on data from the Biggest Loser camp (read up on a previous news item)

The answer is actually pretty straight forward and underlines the efficacy of exercise as a weight loss tool that won't leave you skinny fat, but lean and more muscular. After all, the initially counter-intuitive +2% extra came from the increase in lean mass the Big Losers experienced despite being on a 1,300kcal-1,600kcal diet and working out at a "vigorous intensity" for 3.1h and 1.1h per day in phase 1 and phase 2 of the boot-camp intervention (the simulation of a diet only intervention yielded a slightly larger total weight loss yet with only 65% of the weight coming from the fat stores).

The one thing I am a bit skeptical about is whether Hall's prediction that the weight loss will be sustainable with no more than 20min/day of, once again, "vigorous" exercise per day. I mean that probably would be true in the sheltered environment of the weight loss camp. In a real life scenario, on the other hand, the super size menus, family pizzas and cosy TV couches are probably too much of a temptation for the many of the Big Losers.

---

Wine was yesterday! Chocolate liqueur is the future of healthy alcohol consumption (learn more)

That's all for today, at least as far as On Short Notice is concerned. By now the majority of you should yet be aware that there's always more... correct, the Facebook News - not sure if you notices, but you can actually see the latest items in the side-bar of the SuppVersity. To make sure you don't miss any of them it would yet be wise to simply "like" the SuppVersity on Facebook and/or register as a follower to my Twitter Account. It's hard-wired to the Facebook page, so if you are into tweeting.. maybe you prefer being notified this way.

Whatever your social media service provide of choice may be, I am pretty sure that you don't want to miss news such as the one on the total phenols, flavonoids, flavan-3-ols and proanthocyanidins of chocolate liqueur and how this may make it a better choice for your daily dose of "healthy" alcohol than wine ;-)

References:

• Carpiles VD, Aréas JADG. Effects of prebiotic inulin-type fructans on structure, quality, sensory acceptance and glycemic response of gluten-free breads. Food & Function. 03 Oct 2013 [Epub] 
• Garcia-Garcia E., Narbona E, Carbonell-Barrachina AA, Sanchez-Soriano J, Roche E. The effect of consumption of inulin-enriched Turrón upon blood serum lipids over a 5-week period. International Journal of Food Science & Technology. 2013; 48(2):405–411.
• Gelinas P. Preventing constipation: a review of the laxative potential of food ingredients. International Journal of Food Science & Technology. 2013; 48(3):445–467. 
• Hall KD. Diet versus exercise in "The Biggest Loser" weight loss competition. Obesity (Silver Spring). 2013 Oct 3. doi: 10.1002/oby.20065. [Epub ahead of print]
• Lai MN, Ng LT. Inhibitory effects of medicinal mushrooms on α-amylase and α-glucosidase – enzymes related to hyperglycemia. Food & Function. 2013 [Epub ahead of print].
  
• Millan MJ. Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie. 2005 Sep-Oct;60(5):441-60.
• Munro IA, Garg ML. Prior supplementation with long chain omega-3 polyunsaturated fatty acids promotes weight loss in obese adults: a double-blinded randomised controlled trial. Food & Function. February 2013 [Epub ahead of print].
• Nongonierma A,  Schellekens H, Dinan T,  Cryan JF, Fitzgerald D. Milk protein hydrolysates activate 5-HT2c serotonin receptors: influence of the starting substrate and isolation of bioactive fractions. Food & Function. 2013 [Epub ahead of print]
• Piaggi P, Thearle MS, Bogardus C, Krakoff J. Lower Energy Expenditure Predicts Long-Term Increases in Weight and Fat Mass. JCEM. 2013; jc.2013-3529;

Fat From Serotonin. MS Despite Vitamin D. DHA & DPA Feel at Home in Your Cellwalls. Weightloss Obstacle Late Lunch? Wrist Predicts Diabetes Risk. Viagra Detoxes the Brain. Acetyl Cysteine Battles Acne. Propolis Increases GLUT-4

Yet another reason why calorie counting is not good for your sanity: The "average" sexual intercourse burns only 14 kcal more than watching TV.  and significantly less than a fast paced walk on the inclined treadmill. Luckily weight loss & maintenance is more complex than calories in vs. out, anyway ;-)

"14" that's the SuppVersity figure of the number of extra calories you will expend when you and your significant other decide to have sex instead of sitting on the couch watching TV tonight. I got that figure from a paper my buddy Sean Casey from CasePerformance has brought to my attention. Published in the latest issue of the prestigious New England Journal of Medicine (Casazza. 2013), it discusses the 7 most commonly held "false and scientifically unsupported beliefs about obesity" the scientists identified in a thorough analysis of popular media and scientific literature.

"The scientific community needs some more honesty"

While the sex-myth, which originally states that you would burn at least 100kcal, with a little more action"" even 300kcal per intercourse, is obviously my favorite, there are also a couple of  less sexy "presumptions about obesity" (e.g. simply eat more veggies and fruit and you lose weight) and "facts about obesity" (e.g.  the scientists dug up and debunked in a paper that ends with the wise words:

"While we work to generate additional useful knowledge, we may in some cases justifiably move forward with hypothesized, but not proved, strategies. However, as a scientific community we must always be open and honest with the public about the state of our knowledge and should rigorously evaluate unproved strategies." (Casazza. 2013)

Actually the term "the state of our knowledge" is an ideal segue to what follows - the "short" news! Originally the On Short Notice column was actually intended as a very brief overview over what has been going on in the "community" as of late. And since we are talking about honesty, I must admit that I have failed miserably in the past installments as far as the tiny word "short" in the column's title is concerned. 

The new short news are short again ;-)

So, as of now, I will be doing my very best to bring the On Short Notice column back on the short track, so to say. I guess, we will see in a couple of paragraphs, how successful my efforts will be ;-)

• Does serotonin make you fat? It's pro-fat storage effects would suggest so
  
  

  

  If 5-HT can make you fat and creatine blunts its increase PWO (learn more), what does that tell us about creatine? Nothing, but it leaves room for speculations.

  (Gres. 2013) -- If you trust in TV wisdom the reason women eat chocolate, whenever they feel sad or alone is it's ability to boost serotonin (5-HT). The latter is yet not the reason Sandra Grès et al. say that serotonin could make you fat. Rather than that, it's the ability of 5-HT to stimulate the obesogenic peroxisome proliferator-activated receptor γ (PPAR-γ, learn more), on adipose cells, which will increase fat storage and the recruitment of new fat cells from the stem cell reservoir.
  
  These effects happen in the periphery (vs. the brain) and are totally unrelated to the centrally mediated effects of serotonin.

• MS patients benefit from the sun, not vitamin D
  
  (Zivadinov. 2013) -- Where is your vitamin D supposed to come from? From your skin, right. And where does your skin get it from? From tablets? No. It manufactures it from the "bad" cholesterol, when it's  exposed to the "bad" sunlight.
  
  

  

  In the upper left of this image you see, where the magic is - the rest is just a nice bonus.

  With all those supposedly bad, but in fact vital things being important for much more than vitamin D synthesis it is therefore not surprising that a recently published paper on the asociations of sun-exposure and/or vitamin D with MRI measures in multiple-sclerosis patterns revealed that
  

  "[...] sun exposure was associated with increased grey matter volume (GMV, r_p=0.16, p=0.019) and whole brain volume (WBV, r_p=0.20, p=0.004)" (Zivadinov. 2013).

  ...and that totally irrespective of whether the subjects had high or low vitamin D levels. If you wanted to say it fancily, you'd say the beneficial effects of sun exposure on the brain volume in MS patients was found to be disassociated from the effect the sun has on vitamin D levels (suggested read: Vitamin D, Epstein Bar & MS)

• If you want to up the omega-3 levels in your tissue, pick DHA and / or its precursor DPA over EPA
  
  

  

  Figure 1: Incorporation various lipid fractions in different tissues (Kaur. 2013)

  (Kaur. 2013) -- According to a very recent rodent study docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) are much more readily incorporated into two of your most vital organs, namely your brain and liver and likewise the preferred phospholipid in the cell walls of your kidneys and muscle tissue. Only your fat cells don't really like these long(est) chain omega-3s the incorporation of which was ~50% lower than that of oleic acid (OA; that's the mono-unsuaturated fatty acid in olive oil), which was used as a "neutral" control.
  
  The one question I would still like to have an answer to is how beneficial it actually is, if the phospholipids (PL, figure 1) in your cell membranes are full of easily oxidizable fatty acids.
  
  Also, what do we make of the other lipid fractions? Cholesterol (CHOL), diacylglycerol (DGL) and NEFAs + triglycerides (NE+TG)? Where do we actually want those good omega-3 fatty acids to accumulate? ... just some food for thought  for your DPA and DHA lovin' brains ;-)

• 
  On a side note: If you like GMO, you won't have to eat fish any longer to get your omega-3 PUFAs
  
  (Petrie. 2013) -- Researchers from the CSIRO Food Futures National Research Flagship have already engineered the first GMO brassica species with a higher DHA yield >11% than fish. The invention is hailed as "a breakthrough in the development of sustainable alternative sources of DHA as this technology should be applicable in oilseed crops" (Petrie. 2013)

• When late eating (spec. lunch) and certain genes come together weight loss can become pretty difficult - reasons still not fully understood, though
  
  (Garaulet. 2013) -- Late lunch and certain genotypes appear to make weight loss difficult for some. And the relation holds even after possible confounding factors like energy intake and even appetite hormones, were measured.
  

  

  Skipping breakfast. Yay or Nay? (read more)

  "Late lunch eaters lost less weight and displayed a slower weight-loss rate during the 20 weeks of treatment than early eaters (P=0.002). Surprisingly, energy intake, dietary composition, estimated energy expenditure, appetite hormones and sleep duration was similar between both groups." (Garaulet. 2013)

  While this is not a general argument against intermittent fasting, skipping breakfast and thelike, it does still go to show you that we are not all created exactly equal and any cookie cutter approach to weight loss therefore counter-indicated. 

• Show me your wrist and I'll tell you something about your glucose metabolism.
  
  (Nudeh. 2013) -- A study that was published in the latest issue of the The Journal of Clinical Endocrinology & Metabolism reveals: Wrist circumference is a significant predictor of diabetes in both genders of adult population.

  

  Figure 2: Incidence of diabetes during 8.8 years of follow-up in different tertiles of baseline
  wrist circumference among male and female populations (significant trend in both genders; Noudeh. 2013)

  What's particularly interesting is that this association which was observed in cohort of 6393 subjects (2716 males and 3677 females), who had been subjected to a standard 2-hour postchallenge plasma glucose, test holds independent of BMI and waist circumference - allegedly in women, only. 

• Sildenafil Citrate Attenuates the Deleterious Effects of Elevated Ammonia
  
  (Arafa. 2013) -- You will probably remember the problems with ammonia accumulation due to huge BCAA and protein intakes (learn more). If you trust the latest results of two Egyptian researchers from the Zagazi University it would look as if a solution to that problem (which shouldn't be one, if your liver is healthy and you don't go overboard on pro-ammonia foods, anyway) would already exist: Sildenafil citrate aka Viagra can help.
  
  In their study the researcher administered 10mg/kg sildenafil to rats that were treated with daily intraperitoneal (i.p.) injection of ammonium chloride (100 mg/kg body weight) for eight weeks. This treatment resulted in a significant reduction in serum liver enzymes, lipid profile and - maybe most importantly - brain lipid peroxidation and caspase-3 mRNA. It also increased the nitric oxide (NO) levels in the blood and lead to a significant increase in cGMP, antioxidants and endothelial nitric oxide synthase (eNOS) gene expression in the brains of hyperammonemic rats.
  

  

  List of various foods and their ammonia content (Rudnan. 1973)

  "Our results showed that sildenafil exerts a protective effect on the brain by reversing oxidative stress during hyperammonemia and this could be due to (i) cytoprotective, antioxidant and anti-apoptotic effects ii) increasing cGMP and enhancing the proper metabolism of fats which could suppress oxygen radical generation and thus preventing oxidative damage in the brain."

  Until now, the scientists cannot tell how exactly the human equivalent of 1.62mg/kg sildenafil citrate work, but its modulatory effect on the NO/cGMP pathway is the most likely candidate. That these effects are of real world significance has incidentally been shown, already. In 2003, for example, the learning abilities of rats with hyperammonia was restored by a similar regimen (Erceg. 2003) 

• Acetyl cysteine - don't swallow, but rub it... onto your skin, if you have acne
  
  (

  

  The comedo count is a measure of the number of comedones, i.e. the open black "pores" like those on the forehead of the person shown on this photo

  Montes. 2013) -- According to a study published in the latest issue of Skinmed, the application of a 5% acetylcysteine topical gel proved to be "significantly superior to placebo (P = .04)" in reducing the comedo counts. The results were comparable in  male and female participants and would suggest that "acetylcysteine is an effective therapeutic option for the treatment of mild to moderate acne". Whether it is an alternative to the retinoid based standard drugs, is yet still questionable.
  
  By the way, the latter, or rather the most prescribed of these retinol-like drugs, namely tretinoin has only recently been found to synergize with Aloe vera for even better results (Saeedi. 2013).

• Brazilian propolis ethanol extract promotes glucose uptake and translocation of insulin-sensitive glucose transporter (GLUT) 4 in skeletal muscle
   
  

  

  In the unfortunate case you missed the news: The commonly ignored BCAA Isoleucine also boosts GLUT4 (read more)

  (Ueda. 2013) I guess you will have heard about the miracles "royal jelly" is supposed to work on your health, right? Well, the cheap "packaging" material bees use to seal the smaller gaps in their hives (the larger ones are usually filled with beeswax) seems to have similarly outstanding - and in this case scientifically backed effects.
  
  When propolis was administered at a human equivalent dose of 20mg/kg to mice, those rodents saw increases in both PI3 and AMPK modulated increase in the glucose transporter 4 activity and skeletal glucose uptake.
  
  The main active polyphenols were artepillin C, coumaric acid, and kaempferide. All of them promoted GLUT4 translocation in a subsequent ex-vivo analysis using L6 myotubes, but kaempferide, which can also be found in acovado seeds (Pahua-Ramos. 2013) and cordia sinensis aka  grey-leaved saucer berry extracts (Martinetti. 2010), was the most potent one.

Now you are surprised, right? Me too. Nine individual items and all of them still qualify as "short news". I guess in view of the sheer abundance of news you won't need anything else till tomorrow, but in case you do, I have a couple of suggestions to check out on the SuppVersity Facebook Wall:

• Lycopene works as an anti-cancer agent, because some of it's metabolites "look" like retinol (vitamin A) and dock to the retinol receptor (read more)
  
• Curcumin is a hormetic agent (learn more about hormesis), but not all curcuminoids are created equally effective (read more)
• White poison!? Low sugar diet does not improve insulin sensitivity but decreases glucose levels in obese subjects (read more)
• Myostatin knockout mice have increased brown fat - Does this mean that myostatin suppression will increase browning of fat in man, as well? The recent SuppVersity article on PGC-1A4 already confirmed that (read more) 
• Fish oil for alcohol withdrawal - Only three weeks on low dose EPA (60 mg/day) and high dose DHA (252 mg/day) supplement yielded significant decreases in distress symptoms and basal cortisol secretion in abstinent alcoholics (read more)
• SuppVersity Suggested Read: The Hunter-Gatherer Within: Health and the Natural Human Diet - "Don't get your food from the same place your car does" (read more)

There are going to be a couple of more news before the official next SuppVersity post will be posted in ~24h - so "like" the SuppVersity on Facebook and make sure you don't miss any of them. Have a nice weekend!

References:

• Arafa MH, Atteia HH. Sildenafil Citrate Attenuates the Deleterious Effects of Elevated Ammonia. Toxicol Mech Methods. 2013 Jan 23. 
• Casazza K, Fontaine KR, Astrup A, Birch LL, Brown AW, Bohan Brown MM, Durant N, Dutton G, Foster EM, Heymsfield SB, McIver K, Mehta T, Menachemi N, Newby PK, Pate R, Rolls BJ, Sen B, Smith DL Jr, Thomas DM, Allison DB. Myths, presumptions, and facts about obesity. N Engl J Med. 2013 Jan 31;368(5):446-54.
• Erceg S, Monfort P, Hernández-Viadel M, Rodrigo R, Montoliu C, Felipo V. Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts. Hepatology. 2005 Feb;41(2):299-306.
• Garaulet M, Gómez-Abellán P, Alburquerque-Béjar JJ, Lee YC, Ordovás JM, Scheer FA. Timing of food intake predicts weight loss effectiveness. Int J Obes (Lond). 2013 Jan 29.
• Grès S, Canteiro S, Mercader J, Carpéné C. Oxidation of high doses of serotonin favors lipid accumulation in mouse and human fat cells. Mol Nutr Food Res. 2013 Feb 6.
• Jahangiri Noudeh Y, Hadaegh F, Vatankhah N, Momenan AA, Saadat N, Khalili D, Azizi F. Wrist Circumference as a Novel Predictor of Diabetes and Prediabetes: Results of Cross-Sectional and 8.8-Year Follow-up Studies. J Clin Endocrinol Metab. 2013 Feb;98(2):777-84.
• Kaur G, Molero JC, Weisinger HS, Sinclair AJ. Orally administered [14C]DPA and [14C]DHA are metabolised differently to [14C]EPA in rats. British Journal of Nutrition. 2013; 109, pp 441-448. 
• Martineti V, Tognarini I, Azzari C, Carbonell Sala S, Clematis F, Dolci M, Lanzotti V, Tonelli F, Brandi ML, Curir P. Inhibition of in vitro growth and arrest in the G0/G1 phase of HCT8 line human colon cancer cells by kaempferide triglycoside from Dianthus caryophyllus. Phytother Res. 2010 Sep;24(9):1302-8.
• Montes LF, Wilborn WH, Montes CM. Topical acne treatment with acetylcysteine: clinical and experimental effects. Skinmed. 2013 Nov-Dec;10(6):348-51.
• Pahua-Ramos ME, Ortiz-Moreno A, Chamorro-Cevallos G, Hernández-Navarro MD, Garduño-Siciliano L, Necoechea-Mondragón H, Hernández-Ortega M. Hypolipidemic effect of avocado (Persea americana Mill) seed in a hypercholesterolemic mouse model. Plant Foods Hum Nutr. 2013 Mar;67(1):10-6.
• Petrie JR, Shrestha P, Zhou XR, Mansour MP, Liu Q, Belide S, Nichols PD, Singh SP. Metabolic engineering plant seeds with fish oil-like levels of DHA. PLoS One. 2013;7(11):e49165. 
• Rudnan D, Smith RB 3rd, Salam AA, Warren WD, Galambos JT, Wenger J. Ammonia content of food. Am J Clin Nutr. 1973 May;26(5):487-90.
• Ueda M, Hayashibara K, Ashida H. Propolis extract promotes translocation of glucose transporter 4 and glucose uptake through both PI3K- and AMPK-dependent pathways in skeletal muscle. Biofactors. 2013 Jan 28.
• Zivadinov R, Treu CN, Weinstock-Guttman B, Turner C, Bergsland N, O'Connor K, Dwyer MG, Carl E, Ramasamy DP, Qu J, Ramanathan M. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 Feb 5.

Dopamine, Serotonine, Creatine: Creatine Supplementation Modulates Post-Exercise Neurotransmitter Levels in Man

Can creatine beneficially influence your neurotransmitter so that you can run longer?

I guess, some of you will remember, while others will still ignore the discussion revolving around the serotonin (5-HT) depleting effects of high doses of BCAA (see news item "BCAAs inhibit serotonin metabolism"). To those who remember and may even have followed the ensuing discussion it is probably no news that the acute ingestion of ~60g of BCAAs suppresses 5-HT, raises prolactin and lowers dopamine to such a degree that it has a direct negative impact on emotional decision making in human beings (Sevy. 2006). Against that background you may probably be assuming the worst, when I am now telling you that every gymrat's darling, creatine monohydrate, does also exhibit non-negligible effects on the levels of the two important neurotransmitters.

All clear: Creatine probably won't make you depressed

Contrary to BCAAs which exert their effect irrespective of whether you do or don't exercise. The current evidence suggests that creatine does the same only in the context exhaustive aerobic exercise (I would bet it does the same with high volume training, though). In their recently published paper, Moghadasi et al. describe the dopamine, serotonin and prolactin response of 20 healthy, but sedentary male volunteers (BMI 23.5; body fat %: 20.5%) who received 4x5g creatine (standard loading protocol) for 7 days before they underwent an exhaustive aerobic exercise test, the so-called Bruce protocol, in the course of which participants are made to run on a treadmill to exhaustion, while incline and speed are increased every three minutes.

Figure 1: Dopamine and serotonin levels of the healthy, but sedentary volunteers before, immediately, 10 min and 20 min after the Bruce protocol (Moghadasi. 2013)

As you can see in figure 1 the preloading protocol  resulted in significantly different 5-HT responses to the exercise protocol and a trend towards higher, more stable dopamine levels. But this is not the only interesting observation the scientists made. Contrary to the common believe that creatine supplementation will make you look bloated in response to an increase in extra-cellular water, the participants in the creatine group of the Moghadasi study who gained a whopping 1.6kg of total mass in the course of the study period exhibited lower extracellular water levels than their peers in the control group.

Figure 2: Effect of creatine supplementation on BMI and intra- and extracellular water (Moghadasi. 2013)

The relative figures in figure 2 do obviously not exclude that the subjects in the creatine group still had a slight increase in total extra-cellular water. What's yet more important though is the more pronounced increase in the intra-cellular compartment, which has, as Moghadasi et al. rightly point out, "been identified as a universal anabolic signal, stimulating protein synthesis and net protein deposition." (Moghadasi. 2013)

Figure 3: Especially immediately after the workout the dopamine to serotonin ratio seems to suggest that there should be a significant effect. As far as the time on the treadmill was concerned there were yet no statistically significant intergroup differences in the study at hand (Moghadasi. 2013).

But all that is not new to you, I guess, so let's get back to the modified neurotransmitter response. Is that something we won't or something we don't won't? Well, from a performance perspective it turned out to be useless (just as the 5-HT blockade by BCAAs, by the way). Participants from both groups flagged after roughly 15.5-16.0 minutes on the treadmill - how accurate the Bruce Test is, specifically as a measure of central fatigue, is yet still a matter of ongoing scientific debate. Machado et al. for example have pointed out that peripheral fatigue in the legs may set in well before the purportedly 5-HT mediated central fatigues forces the study participants to jump off the treadmill (Machado. 2008), so that we cannot really tell whether the supplementation had an effect on central fatigue. After all, the leg musculature of sedentary subjects is obviously tiring faster than the fortified quads, glutes and hams of trained athletes.

The same is unfortunately true for the actual effects of the modified neurotransmitter response, while the authors are right to point out that 5-HT has been imlicated as a factor that induces mental and subsequently central fatigue, whereas dopamine is known as the "motivational neurotransmitter", previous studies by Wantanabe et al. suggested that respective cognitive benefits from creatine supplementation were facilitated by an increased oxygen utilization in the brain - not via changes in the neurotransmitter levels. And though these changes may not have reached statistical significance in the study at hand, there is actually better evidence for potential pro-dopaminergic effects of creatine, which has been shown to increase DA synthesis in the substantia nigra of mice by protecting against striata DA depletion (Klivenyi. 2003) and / or by enhancing the tyrosine hydroxylase activity and thus increasing the production of dopamine from its precursoe tyrosine (Matthews. 1999).

Much ado about nothing?

Is there a connection between creatine and prolactin: While the prolactin levels were not measured in the study at hand. The results of a 1996 study, in which Prysor-Jones et al. were able to show that the "creatine analogue" beta-guanidinopropionic acid (GPA) which is in fact a competitive inhibitor of creatine, increased the TRH induced release of prolactin. By implication this could mean that creatine will do the exact opposite. This hypothesis would also be supported by the increased dopamine levels after the workout - after all, dopamine is a natural prolactin antagonist (and vice versa).

There is however one study, by Hadjicharalambous et al. that appears to support the hypothesis that the modified 5HT-to-DA ratio may in fact figure large. The authors found that 7 days of creatine supplementation effectively reduced the central fatigue index of subjects who had to exercise in the heat. In that, they observed that the additional creatine blunted the increase in the free tryptophan-to-tyrosine ratio, which suggests that the brain 5-HT and DA levels were modulated by the supplementation protocol, as well. According to Hadjicharalambous et al. this effect was yet single-sided and related to an overall reduction in serotonin levels, while there were no significant difference between two groups as far as their dopamine levels were concerned.

Bottom  line: As it is the case in so many of the complex processes underlying human performance and the effects of proven and purported ergogenics, these insights into the effects of creatine as a potential mediator of the exercise induced neurotransmitter-response are still very preliminary. That may be surprising if you take into accaunt that millions of consumers are currently using creatine monohydrate or supplements that contain it, but in the end it's not much different from the way the same people use to train: Things that work will prevail - irrespective of whether or not the mechanisms have already been fully understood. 


References:

• Machado M, Sampaio-Jorge F, Dias, N, Knifis FW. Effect of oral creatine supplementation in soccer players metabolism. Revista Internacional de Ciencias del Deporte. 2008; 4:44-58. 
• Moghadasi M, Rahimi E, Mahani MS, Molaee, AA. Effect Of Creatine Supplementation On Brain Neurotransmitters After An Exhaustive Aerobic Exercise. Brazilian Journal of Biomotricity. 2013; 6(3):213-221. 
• Sevy S, Hassoun Y, Bechara A, Yechiam E, Napolitano B, Burdick K, Delman H, Malhotra A. Emotion-based decision-making in healthy subjects: short-term effects of reducing dopamine levels. Psychopharmacology (Berl). 2006 Oct;188(2):228-35.