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.

The Dipeptide Advantage!? 43% More Muscle Glycogen With Whey Hydrolysate Compared to Matched Amino Acid Mixture

The bigger the choice, the harder it is to choose. If you had to pick just one, go for the concentrate, if you want to afford two, get an isolate or hydrolysate and a casein protein.

"Whey is still the way to go." I believe I wrote, or at least thought just that only a couple of days ago, when I wrote about the wheat gluten hydrolysate in the last installment of the SuppVersity Science Round Up Seconds (click here to read all previous installments). Unfortunately, there is not just one way... ah, pardon me, I do of course mean "whey", there are many! And in order to completely confuse their customers supplement companies will spike their concentrates, isolates and even hydrolysates with free form amino acids, or - which is even more confusing - advertise their BCAA and EAA products as being made from whey protein. I mean, who cares if the damn molecules are unbound and indistinguishable, anyway? But let's get to the point, a soon to be published study from Japan could yield at least some insights into demonstrable and purported benefits of one over the other.

Whey hydrolysate or simply its aminos, what gets pro-glycogen job done?

Based on results from previous experiments in the course of which the researchers had found that the acute provision carbohydrate + whey protein hydrolysate (WPH) had superior effects on muscle glycogen repletion compared to iso-nitrous amounts of BCAAs (Morifuji. 2010a) Kanda et al. speculated that chronic supplementation with whey protein hydrolysate (WPH) should elicit similarly beneficial effects and could help them clarify the underlying mechanism of this glycogen boosting effects of WPH. To this ends, the researchers put a group of mice on diets that differed only terms of the protein composition of the diet.

• 

  Table 1: Composition of the test diets

  The control group's exclusive protein source was the casein from the standard chow.
• The whey amino acid (WAA) group received a chow, where 50g of the casein protein was replaced by an iso-nitrogenous amount free amino acids that was matched to the amino acid composition of the whey hydrosolate.
• The whey hydrolysate group received 20% of the original casein from the standard chow in form of a whey hydrolysate from Meiji Co., Ltd.

In the course of the 4-week study period, body weight and food intake of the animals were measured on a weekly basis. The mRNA expression, protein levels, and phosphorylation of glycoregulatory enzymes were measured in the gastrocnemius muscle. All rodents performed a regular 30-min swimming exercise protocol  in a fancy adjustable-current water pool five times per week and had to 'survive' a weekly (endurance-)performance test in the course of which they had to swim to absolute failure (defined as being drowning for 7s, already).

Figure 1: Food intake, liver weight, and visceral fat (left), as well as time to total fatigue during swimming exercise (right) of the rodents on control, WAA and WPH diets  (data adapted from Kanda. 2013)

Contrary to the data from this test, the body composition markers in figure 1 do not show any significant inter-group differences (positive or negative) the same goes for the food intake and the liver weight, as well as for the total body weight of the mice, which was totally identical (not shown in figure 1). The said swimming performance of the WAA and WPH group, on the other hand, were 32% and 48% higher than in the control group.

More glycogen synthetase = more glycogen content = more endurance

Now, despite the fact that this increase did - for whatever reason - not reach statistical significance, Kanda et al. are convinced that this increase in endurance must be a direct consequence of the increase in glycogen storage, which has been observed by Evans and Hughes in 1985 (Evans. 1985), already, and has been confirmed numerous times thereafter.

Figure 2: Glycogen content and glycogen synthetase levels (GS), as well as mRNA expression of glycogen synthase I and the ratio of phosphorylated to unphosphorylated GS (data based on Kanda. 2013)

And, as you can see, the actual data in figure 2 clearly confirms this hypothesis. The mice who had received whey protein hydrolysate (WPH) in their diets for the whole 4-week study period had significantly (p < 0.05) higher muscle glycogen levels than their peers in the control group (73%) and still more than 40% more total glycogen than the mice who had been fed the amino acid enriched chow (WAA). Quite impressive, right? And all that is just a consequence of a peptide induced elevation in glycogen synthetase and it's activity, which is indicated by the lower ratio of phosphorylated (=incative) to un-phosphorylated (=active) levels of this tightly regulated enzyme.

There is more to whey than BCAAs

The total amount or activity of the glucose transporter (GLUT-4) as well as the hexokinase activity (which figures in the phosphorylation of sugars) were not different between treatments and though the dreaded gluconeogenesis in the liver was not measured it is, given the high amount of carbohydrates in the diets of the rodents, very unlikely that the higher susceptibility of "fast" protein sources to be oxidized, when no other nutrients are available, played a significant role in the 'pro-glycogenic' of whey hydrolysate (after all the rodents consumed the protein as part of their chow), so that the most likely explanation for the superiority of the whey protein hydrolysate over the iso-nitrous amino acid mixtures remains their peptide content. In this regards, the authors of the study remark:

"The amino acid compositions of the two diets used in this study contained equal amounts of BCAA and leucine; however, muscle glycogen accumulation varied between diets. This result strongly suggests that not only the BCAA content but also the molecular form of BCAA found in the protein source might be important for muscle glycogen storage." (Kanda. 2013)

Kanda et al. do then refer to a previous study, in which his group had been able to demonstrate that BCAA-containing peptides in WPH, which have been shown to be markedly elevated (meaning they are not digested) after the consumption of whey protein hydrolysates (Morifuji. 2010) in a follow up study on human beings, do actually have the ability to stimulate the rate of glucose uptake in vitro (Morifuji. 2009).

Figure 3: Insulin response after the ingestion of 12.5g of either soy or whey protein or their respective hydrolysates (Morifuji. 2010)

"And what about insulin?"

I know that this question is now on your minds and in way you are right the only slight caveat you have to keep in mind before you blindly follow the scientists' outspoken advice to consume "carbohydrates mixed with WPH[to] enhance sport performance by increasing glycogen storage" (Kanda. 2013) would in fact be be the increased insulin response. Of the latter, the scientists found in the aforementioned 2010 human trial (Morifuji. 2010) that it is ~70% more pronounced in the first hour after the the ingestion of 12.5mg of whey protein hydrolysate and, once more compared to regular whey protein, still ~17% higher over the whole 2h period (the different proteins you see in figure 3 were all ingested on an empty stomach after an overnight fast by the 10 normal-weight subjets; the data I mentioned refers to the AUC values on the bottom of figure 3).

The insulin 'spike' is not necessarily a problem. At the right time in the right person it can even be highly beneficial.

Nevertheless, the results of the study at hand to actually confirm that before you invest in all sorts of useless pills, it may make more sense to make sure that you a) have more than just a single protein powder in your supplement arsenal and that you b) have been reading enough SuppVersity articles to be able to use them properly ;-) ... What? You still don't know how? Well assuming you have no problems with high insulin levels and are mainly interested in building muscle, you could start out with 20-30g whey + 15-25g casein (depending on your body size and needs) after a workout (see "Whey & Casein Work Hand in Hand for Muscle Protein Anabolism") and a 40g casein shake pre-bed (see "3.2kg of Lean Mass Overnight").

By the whey *lol*, I suppose you will see similar benefits from a whey isolate, although this would have to be tested. What does not need any tests, on the other hand is that you better make sure you don't forget the carbs! I mean, what is your body supposed to use as a substrate for the increased glycogen synthetase activity, if you are depriving yourself of carbohydrates? The protein your liver converts to blood glucose? Yeah, what a glorious idea... whatare your brain and your other organs going to use then? Ketones? No way, if you are pounding tons of fast acting glucogenic amino acids in form of protein shakes.


References

• Evans, W. J.; Hughes, V. A. Dietary carbohydrates and endurance exercise. Am. J. Clin. Nutr.1985, 41 (5, Supplement), 1146−1154.
• Kanda A, Morifuji M, Fukasawa T, Koga J, Kanegae M, Kawanaka K, Higuchi M. Dietary Whey Protein Hydrolysates Increase Skeletal Muscle Glycogen Levels via Activation of Glycogen Synthase in Mice. J Agric Food Chem. 2013 Oct 31.
• Morifuji, M.; Koga, J.; Kawanaka, K.; Higuchi, M. Branched-chain amino acid-containing dipeptides, identified from whey protein hydrolysates, stimulate glucose uptake rate in L6 myotubes and isolated skeletal muscles. J. Nutr. Sci. Vitaminol. 2009, 55(1), 81−86.
• Morifuji, M.; Kanda, A.; Koga, J.; Kawanaka, K.; Higuchi, M. Post-exercise carbohydrate plus whey protein hydrolysates supple-mentation increases skeletal muscle glycogen level in rats.Amino Acids 2010a, 38(4), 1109−1115.
• Morifuji, M.; Ishizaka, M.; Baba, S.; Fukuda, K.; Matsumoto, H.; Koga, J.; Kanegae, M.; Higuchi, M. Comparison of different sources and degrees of hydrolysis of dietary protein: Effect on plasma amino acids, dipeptides, and insulin responses in human subjects. J. Agric. Food Chem. 2010b, 58(15), 8788−8797.

On Short Notice: Red Onions For Glutathion & Jiagulan For Muscle Glycogen, Low Iron & Obesity, Sodium Caprate, Useless Probiotics & Leaky Gut, Perivascular Fat & Heat Shock Proteins for Your Heart & Magnesium vs. Migraine

Image 1: You may already have read it on the SuppVersity Facebook Wall; "Sacrificing sleep in order to study won't improve your college grades..." it could however easily whack your circadian rhythm and give you headaches. If those turn into a migraine, you may be happy to have read about beneficial effects of magnesium on the incidence of these crippling and painful attacks (see last item in this installment of "On Short Notice" ).

In order to avoid having another weekend of "On Short Notice" posts, I decided to post the first collection today, already. The topics are, as usually, only loosely related and I hope that each and everyone of you will find something he or she considers interesting. We'll start out by having a brief look at the amazing antioxidant effects of red onions, and then delve deeper into the connection between obesity and low ferritin levels and a brief reminder that sometimes good things can become bad, if they are not handled properly, next on the list are the tight gut junction opening effects of sodium caprate which may be a good thing if your goal is to increase the bioavailability of berberine, but a very bad thing, if other molecules take the opportunity and pass through the open doors, as we are then going to see Dr. Shirota's probiotics are probably not going to help you avoid this problem and they are certainly not helping patients with metabolic syndrome: The latter is probably also true for PPAR-gamma antagonists, which may help prevent visceral fat accumulation, but could at the same time precipitate to heart disease by decreasing the surprisingly heart-healthy perivascular fat.

Although more of an ergogenic, Gynostemma penthaphylum (aka Jiagulan) is probably a more promising strategy to get in better shape. If it allows you to train harder, it will also allow you to make better use of potential systemic health effects of exercised induced heat shock protein expression... and just in case all that was so much information that you are having a headache once you have arrived at the end of this blogpost, a 500mg dose of magnesium could help you reduce the incidence of migraine attacks by more than 60% whether additional 500mg of carnitine make this treatment even more effective does yet remain to be elucidated!

• Do your liver and body antioxidant system a favor and add a couple of red onions to your diet! That's the straight forward take home message from a recently conducted study by a group of Korean scientists (Lee. 2013). The researchers had investigated  the effect of red onion on the total activity of antioxidant enzymes in 18-week-old Sprague-Dawley rats. To this ends the rodent had been kept on a diet enriched with red onion peel, flesh or both (all pulverized and mixed into the standard chow for a total content of 5g per 100g) for for weeks.

  

  Figure 1: The red onions outperformed easily outperformed their uncolored white brethren and cousin, white onions and garlic, in the in vitro dish and had profound antioxidant boosting effects in the in vivo study (Lee. 2013).

  The results, (a) a significant increase in plasma SOD activity in the red onion peel and red onion (peel + flesh) groups, (b) a significantly higher GPX (enzyme that recycles glutathione) activity in the in the red onion flesh group and (c) a general tendency towards higher catalase and ORAC activity in the livers and profoundly reduced liver malondialdehyde (=marker of lipid peroxidation) levels in the red onion groups provide an in vivo (allegedly only "in rodent vivo" ;-) confirmation of the in vitro data in figure 1 which is - as usual - to be treated with caution before respective experiments in complex, real organisms confirm that they are more than artifacts of the respective essay.
• Low iron (ferritin) associated with obesity in adolescents, but simple eating more iron probably won't solve either the iron deficiency, nor the (central) obesity. That's at least what the results of a recent investigation in normal and fat Greek kids would suggest, after all the fat kids did already consume more iron in their diets than their lean age-mates (Moschonis. 2013).
  What makes this study worth mentioning is the (as usual hasty) conclusion that iron must be a bad guy, when just its mismanagement (probably as a result of adiposity induced liver problems, or, as a handful of older and recent studies would suggest vitamin A deficiency; e.g. Arruda. 2009; Citelli. 2013; Yohsikawa. 2013) is a problem - so don't get fooled, donating blood every other week won't lean healthy people out, it will just drain them out.

• 

  Figure 2: Sodium caprate won't "open" the tight gut junctions for berberine, only, but also for all sorts of other, mostly unwanted junk - self-induced temporary leaky gut so to say!

  Sodium caprate opens tight junctions of the gut and let's berberine in. The consequence is an amplification of the hypoglycemic effects of berberine (Lv. 2013), but at the same time it is likely to amplify the effects of whatever you else put into your mouth or the critters that live in your stomach are pooping out - I guess it should be obvious that I am referring to the LPS assault from your gut microbiome, here and that the potential increase in lipopolysaccharide could well outweigh (in a negative sense) the benefits you would see from an increased bioavailability (~1.5-2.3 fold; cf. Lv. 2010) of berberine.
  
  Against that background I am really not sure how sensible the use of sodium caprate or other "tight junction openers" of natural or pharamacological origin really is. But hey, that's just me - maybe you are less cautious...  if there are not yet any products like that on the market, it probably won't be long until the first "enhanced" berberine appear in the line-ups of the large "health supplement" vendors on the Internet.

• 

  Image 2: Patented lactobacillus strains are all the rave, and probably big business... that does yet not mean that they work - regardless of whether they carry the name of famous Drs or not ;-)

  Probiotic supplements don't cure everything - although many ads may give just this impression. In a recently published study, Swiss researchers were not able to show any beneficial effects of the patented L. casei Shirota strain on the increased gut permeability of 28 patients with metabolic syndrome (Leber. 2013). In the course of the three months study period, it rather exasperated the already elevated C-reactive protein levels, due to liposaccharide leakage through the leaky gut into the system and I bet the only reason that the conclusion states that the dosage may have been too low instead of "this is initial evidence that the use of L. casei Shirota is not useful if  not counter-indicated in to treat gut permeability in patients with MetS", was the financial support by Yakult Europe the patent holder of L. casei Shirota ;-)
• PPAR-gamma ablation leads to loss of perivascular adipose tissue (PVAT). What may at first sound great could in fact be deadly. The recently published results of Chang et al. show quite clearly that non-tissue-specific blockade of the "fat builder" PPAR-gamma (cf. "Tangeritin, Natural Metformin from the Rind of Mandarin Oranges Hits the OFF-Switch on Diet Induced Obesity") is a dangerous undertaking. While keeping the differentiation and growth of body fat at bay, especially in the abdominal region, would be a good thing, the high rate of atherosclerosis among the mice from the laboratories of the University of Michigan confirms that "not all body fat is created evil" (Chang. 2013).

  

  Figure 3: Fitzgibbons et al. were already able to show that the UCP-1 expression, which is a marker of metabolic activity, in PVAT is equally high as in the meanwhile infamous brown adipose tissue. In short - PVAT just like BAT will not just store superfluous lipids, it will also burn them and prevent them from accumulating in the vasculature (Fitzgibbons. 2011)

  As it turned out, PVAT, rather than being proinflammatory and hazardous, actually has a protective function on the vasculature it is sourrounding. In fact, the results Chang et al. are presenting in the latest issue of Circulation suggest the assumption that PVAT is anti-inflammatory and functionally similar to the metabolically active brown adipose tissue that has gotten quite some attention by experts ad laymen as of lat. When it's suddenly missing, the lipids inside the vascular can no longer be cleared into the perivascular adipose tissue where they would be oxidized and disposed of. In addition, the ensuing pro-atherogenic coupled with the absence of PVAT-derived prostacyclin, a prostanoid that's metabolized from endogenous arachidonic acid through the cyclooxygenase (COX) pathway and acts as a potent vasodilator (cf. Ruan. 2010) could thus easily set you up to die before your time - regardless of how lean you may have become...
  And though it is very unlikely that this is going to happen from the use of one of the freely available herbs with anti-PPAR-gamma effects (e.g. tashinones from Salvia miltiorrhiza, or the previously cited tangeritin), it certainly is a good reminder of how fatal our constant black-and-white thinking can be, when it is injudiciously applied to such complex matters as our own body.

• 

  Image 4 (dracoherbs.com): Gynostemma penthaphylum is also known as Jiaogulan, is often mentioned in the same breath with ginseng in TCM

  Gynostemma penthaphylum boosts endurance by ROS scavenging and multiplying skeletal muscle glycogen stores. Not yet another potent anti-oxidant was what I first thought,when I hit upon the soon-to-be published study from Shaanxi Normal University in Xi'an, China, but after taking a closer look it turned out that the way this century old adaptogen that goes by the name jiaogulanin TCM and is an herbaceous vine of the family Cucurbitaceae (cucumber or gourd family) indigenous to the southern reaches of China, northern Vietnam, southern Korea, and Japan, could actually make quite an exciting supplement (Chi. 2013). After all its high ROS(radical oxygen specimen) scavenging abilities are only part of what allowed the rodents in the study by Chi, Tang, Zhang & Zhang that had been treaded with isolated polysaccharides from this plant to go significantly longer during a standardized exercise performance test.
  The more intruiging part of the performance boost, however came from the direct pro-gluconeogenic and glyocogen storage promoting effects of the alpha variety of the three Gynostemma penhaphylum polyssacharides the scientists had extracted. If similar effects would be seen in humans, GP would certainly make a valuable addition to the regimen of anyone who does not just perform 1-rep maxes day in and day out - and let's face it: In view of the fact that the glycogen can't be synthesized from nothing, it could also help to burn body fat, by it's repartitioning effects.

• 

  Figure 4: It would certainly be an unwarranted overgeneralization to ascribe all beneficial effects of exercise to the systemic expression of heat shock proteins. But still, there is increasing evidence that their controlled expression does at least contribute to the numerous beneficial effects exercise has on our brains, hearts and other organs; interestingly these effects are likewise mediated by the breakdown and the protection and "recycling" of organ tissue.

  Will training your biceps, heal your heart and protect your brain!? You probably know that the scientists at the McMaster University have put the myth of the pro-anabolic effects of systemically circulating hormones that are released response to isolated muscle training (eg. "train your legs to increase your testosterone and see your arms grow") at rest, years ago. Now, a study that's soon going to be published in theh Journal of Experimental Biology suggests that testosterone, growth hormone and co. may not be the only molecules we should be looking for, when we talk about possible non-localized effects of exercise (Jammes. 2013). Another class of proteins that has gotten quite some attention esp. in the context of the profound effects of occlusion training, the so-called heat-shock proteins, which are released in response not just to heat, but to exhaustive contractions / trauma / hypoxia / etc., could in fact play a likewise, probably more important role not so much in skeletal muscle growth, maybe, but in the overall systemic response to exhaustive skeletal muscle contractions. 
  After all, Jammes et al. observed a delayed, but significant elevation of non phosphorylated HSP25 and HSP70 in skeletal and respiratory muscles, kidney, and brain. Now, of HSP70, for example, it has long been known that it exerts cardio-protective effects (Martin. 1997). In addition to its anti-apoptotic effects, it does yet also contribute to the proteolysis (=protein breaking) that's a necessary part of the continuous clean-up processes that remove the "junk" and "clutter" (defect protein structures) from your body in order to keep everything functional (Lüders. 2000). Similarly, HSP25 (aka HSPB1) exerts both cytoprotective effects due to its ability to modulate reactive oxygen species and raise glutathione levels, as well as proteolytic effects and is working hand in hand with HSP70 by inhibiting protein aggregation and stabilizing partially denatured proteins, so that they can be refolded by the former. That the latter could be of particular importants in view of the neuroprotective effects of exercise is also supported by a couple of trials in which HSPB1, to be precise, its exogenous administration or endogenous overexpression, have been evaluated as treatment or preventive strategies in ALS (Lou Gehrig's Disease), Huntington's, Parkinson's, Stroke and acute nerve injury (for an overview see table 3 in Brownell. 2013).

• 

  Figure 5: The benefit of l-carnitine is questionable, despite the fact that the serum l-carnitine in the Mg group dropped to a similar extent as in the control group; over time the carnitine depletion could however become important (Tarighat Esfanjani. 2013)

  Headaches? Magnesium and l-carnitin help! At a dosage of 500mg/day magnesium oxide, alone did already have significant beneficial effects on the occurrence of migraine in  106 females and 27 males volunteers who were diagnosed with headache according to the International Headache Society criteria, were between the age of 18 and 55 years old and "had severe and continual headache lasting from 4 to 72 h, unilateral and pulsating headaches with moderate or severe intensity, migraine with or without aura, at least two attacks per month, headaches which were aggravated by routine physical activity and associated with nausea and/or photophobia, and phonophobia" (Tarighat Esfanjani. 2013).
  So, if that sounds like you (I don't hope it does) magnesium should be the least you should take, the additional 500 mg/day L-carnitine is questionable - just as whether ALCAR may have provided greater benefits. Apropos, you do realize that this is neither transdermal nor any fancy chelated magnesium or at least magnesium citrate that did the trick? Yeah, right: The same "worthless" (put name of random nutrition guru, here) mg-oxide you find in the cheapest fizzy tablet from the supermarket did the trick!

If you are now thirsty for more, I suggest you check out the SuppVersity Facebook Wall (which is by the way updated several times a day), like the career-boosting information that sacrificing sleep in order to study is a bad idea, that Caucasians, compared to Asians, lose weight relatively easily, but have a hard time getting rid of their bellies, or, if all that ain't for you, how the wise producers of "functional foods" are planning to add a little wood aka methylcellulose into your yogurts and smoothies to curb the cravings you probably would not have, if they had not removed all the fat from it, before ;-)

 References:

• Brownell SE, Becker RA, Steinman L. The protective and therapeutic function of small heat shock proteins in neurological diseases. Front Immunol. 2013;3:74. Epub 2013 May 1.
• Chang L, Villacorta L, Li R, Hamblin M, Xu W, Dou C, Zhang J, Wu J, Zeng R, Chen YE. Loss of Perivascular Adipose Tissue upon PPARγ Deletion in Smooth Muscle Cells Impairs Intravascular Thermoregulation and Enhances Atherosclerosis. Circulation. 2013 Aug 1. 
• Chi A, Tang L, Zhang J, Zhang K. Chemical Composition of three Ingredients of Polysaccharides from Gynostemma pentaphyllum and Comparison of their Antioxidant Activity in Skeletal Muscle of Exhaustive Exercise Mice. Int J Sport Nutr Exerc Metab. 2013 Aug 14.
• Citelli M, Bittencourt LL, da Silva SV, Pierucci AP, Pedrosa C. Vitamin A Modulates the Expression of Genes Involved in Iron Bioavailability. Biol Trace Elem Res. 2013 Apr 14. 
• Fitzgibbons TP, Kogan S, Aouadi M, Hendricks GM, Straubhaar J, Czech MP. Similarity of mouse perivascular and brown adipose tissues and their resistance to diet-induced inflammation. Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1425-37.
• Jammes Y, Steinberg JG, By Y, Brerro-Saby C, Condo J, Olivier M, Guieu R, Delliaux S. Fatiguing stimulation of one skeletal muscle triggers heat shock proteins activation in several rat organs: the role of muscle innervation. J Exp Biol. 2013 Aug 16.  
• Leber B, Tripolt NJ, Blattl D, Eder M, Wascher TC, Pieber TR, Stauber R, Sourij H, Oettl K, Stadlbauer V. The influence of probiotic supplementation on gut permeability in patients with metabolic syndrome: an open label, randomized pilot study. Eur J Clin Nutr. 2013 Aug 8.
• Lee B, Jung JH, Kim HS. Assessment of red onion on antioxidant activity in rat. Food and Chemical Toxicology. August 10, 2013.
• Lüders J, Demand J, Höhfeld J. The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. J Biol Chem. 2000 Feb 18;275(7):4613-7. 
• Lv, X.Y., Li, J., Zhang, M., Wang, C.M., Fan, Z., Wang, C.Y., Chen, L., 2010. Enhancement of sodium caprate on intestine absorption and antidiabetic action of berberine. AAPS.PharmSciTech. 11, 372–382. 
• Martin JL, Mestril R, Hilal-Dandan R, Brunton LL, Dillmann WH. Small heat shock proteins and protection against ischemic injury in cardiac myocytes. Circulation. 1997 Dec 16;96(12):4343-8. 
• Moschonis G, Chrousos GP, Lionis C, Mougios V, Manios Y. Association of total body and visceral fat mass with iron deficiency in preadolescents: the Healthy Growth Study. Br J Nutr. 2011 Nov 16:1-10.
• Ruan CH, Dixon RA, Willerson JT, Ruan KH. Prostacyclin therapy for pulmonary arterial hypertension. Tex Heart Inst J. 2010;37(4):391-9. 
• Tarighat Esfanjani A, Mahdavi R, Ebrahimi Mameghani M, Talebi M, Nikniaz Z, Safaiyan A. The Effects of Magnesium, L-: Carnitine, and Concurrent Magnesium-L-: Carnitine Supplementation in Migraine Prophylaxis. Biol Trace Elem Res. 2013 Aug 17. 
• Yoshikava O, Ebata Y, Tsuchiya H, et al. A retinoic acid receptor agonist tamibarotene suppresses iron accumulation in the liver. Obesity. 2013 Aug.
• Zhanga M, Lvc X, Lia J, Menga Z, Wangd Q, Changa W, Lia W, Chena L. Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis. Molecular and Cellular Endocrinology. 16 August 2013

Resveratrol from 100l of 1994 Pinot Noir Could Increase Fat Oxidation by 71%, Strength by 18-58% and Endurance by 20% - At Least, If You Could Afford and Drink It Every Day!

Image 1: Itadori (Japanese Knotweed) and selected varieties of red wine are the best yet vastly 'underdosed' sources of resveratrol (see red box, below)

At least in rodents, resveratrol, the red-wine polyphenol, has been shown to act as an exercise mimetic, exerting profound effects on PGC-alpha expression which protect muscle from wasting due to mechanical unloading (also know as extreme couch-potato-ing ;-) and rodents from the negative side-effects of obesogenic diets by directly modulation gene expression, lipid transport and fatty acid oxidation in skeletal muscle (Chen. 2011; Momken. 2011). Still, most of the oftentimes publicly puffed up data on resveratrol comes from in-vitro studies with dosages of which even the researchers often believe that they are not attainable via oral supplementation.

Rodents or petri dishes? Humans would be too expensive...

Compared with the aformentioned in vitro data, the numbers and gene essays in a recently published study by scientists from the University of Alberta are actually of great practical relevance (Dolinsky. 2013), because Dolinsky et al. administered their resveratrol orally* (4g in 1kg chow) to healthy rats and - what's even more important for the average trainee - 50% of those rats were exercised for 60min, 5x per week on a treadmill (10m/min to 20m/min; cf. Fenning. 2003) for 12 weeks.

Figure 1: Resveratrol content of selected red-wines and Itadori (Japanese knotweed) tea (based on Burns. 2005; equivalent consumption based on dose used in Dolinsky. 2013)

*Can I get my resveratrol from wine or food: I cannot emphasize enough that with ~75% of orally administered resveratrol being excreted via feces and urine and an oral bioavailability of resveratrol of almost ZERO (Vitaglione. 2005; Wenzel. 2005), there is no reason whatsoever to cope with any of the ~100 in-vitro studies that are published on a monthly basis hailing resveratrol for this and that and praising it as the god-sent natural remedy for every ailment, except the consistent ignorance towards the profound difference between a cell in a petri dish and a complex organism that is so prevalent among the human lab rats in their white coats, these days. And the data in figure 1 should make it pretty clear that similar benefits as they were observed in the study at hand are not just unlikely, they are simply impossible to be achieved without highly concentrated supplements - or do you want to drink 105+ liters of wine a day to get your daily dose of ~2g of resveratrol?

Let's assume you got the ~350$ for your 2g/day of resveratrol powder** to mix with your food (**calculated based on the current price of >90% pure bulk powder in Europe), what would be the results? Would you lose weight? Unlikely. Would you lose body fat? Possible! Would you gain muscle? Very unlikely. So what's all the fuss about then?

Figure 2: Body weight (in g), time to exhaustion (in min) and distance covered (in m) during a treadmill exercise test at the end of the 12-week study period (based on Dolinsky. 2013)

Much ado about nothing? Not really, no. After all, the ~20% increase in endurance (time to exhaustion and distance covered; cf. figure 2)  did not come out of nowhere and do - and this is actually the main reason this study did actually make it to SuppVersity - add to the benefits of regular training. The "resveratrol rats" had ...

Image 2 (ADAM): Resveratrol has already been shown to prevent pathological hypertrophy of the heart muscle by AMPK / AKT modulation (Chan. 2008)

• greater strength gains +18% tibialis anterior twitch force and +58% and +22% tetanic and twitch force, respectively, in soleus vs. training alone
• improved cardiac function as assessed by statistical significant improvements in left ventricular ejection fraction and decreased isovolumic relaxation time, as well as increased ratio of the peak mitral flow velocity (E-wave) to the peak velocity of the late filling wave of atrial contraction
• decreased cardiac stress due to a -30% reduction in left ventricular wall stress vs. training alone
• higher VO2 ~10% during the active period 
• increased PPAR signalling and fatty acid metabolism in the heart (+8.8% and +10.3% respectively; p < 0.00001)

Sexier than the strength gains and the utterly unsexy (but vitally important) improvements in cardiac performance are yet the statistically significant reduction in triglycerides which should help insulin sensitivity (not measured in the study) and are probably a beneficial downstream effect of the  resveratrol induced shift towards higher fatty acid and lower glucose oxidation (-6% respiratory exchange ratio, RER; cf. figure 3) that went hand in hand with a highly significant +71% increase in fatty acid oxidation:

Figure 1: Triglyceride levels, free fatty acids, respiratory exchange ratio (higher values = lower fat oxidation, higher glucose oxidation) and total fat oxidation at the end of the 12-week study period (all data expressed relative exercised control; based on Dolinsky. 2013)

Along with the +50% increase in AMPK (vs. exercise alone) and the 20% increase in the "mitochondrial builder" PGC1-alpha (cf. "Two days on High Fat Diet Increase the Activity of Irisin Releasing Transcription Factor PGC1-α") it is obvious that, taken at the right dosage, resveratrol is not the supplemental non-starter everyone is let to believe who spent $30 for 60 100mg caps of resveratrol and took a 3-day dose (3x 2g!) spread across a whole month - obviously without the desired outcomes result.

At the moment resveratrol is still an expensive toy for scientists

Table 1: Significant changes in heart muscle gene expression (based on Dolinsky. 2013)

As a tool to study (epi-)genetics and the downstream effects and interactions of reduction of cytokines, such as the inteferon-induced proteins, which regulate immune functions, cell growth and apoptosis (Sen. 2000), increases in mitochondrial uncoupling protein 3 (UCP3) and UCP1, higher expressions of adiponectin and thyroid responsive protein and the steroyl-coenzyme A desaturase-1 enzyme, which converts saturated to mono unsaturated fatty acids and plays an important role in controlling inflammation, preventing atherosclerosis, steatohepatitis (fatty liver) and pancreatic beta cell dysfunction (Brown. 2010) resveratrol is a must have. As one of the most expensive currently available supplement with little to no actual human data from studies on healthy subjects, its usefulness for physical culturists is questionable and its cost-benefit ratio is abysmal, to say the least.

References:

1. Brown JM, Rudel LL. Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery. Curr Opin Lipidol. 2010 Jun;21(3):192-7. 
2. Burns J, Yokota T, Ashihara H, Lean ME, Crozier A. Plant foods and herbal sources of resveratrol. J Agric Food Chem. 2002 May 22;50(11):3337-40. 
3. Chan AY, Dolinsky VW, Soltys CL, Viollet B, Baksh S, Light PE, Dyck JR. Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt. J Biol Chem. 2008 Aug 29;283(35):24194-201. Epub 2008 Jun 18.
4. Chen LL, Zhang HH, Zheng J, Hu X, Kong W, Hu D, Wang SX, Zhang P. Resveratrol  attenuates high-fat diet-induced insulin resistance by influencing skeletal muscle lipid transport and subsarcolemmal mitochondrial β-oxidation. Metabolism.  2011 Nov;60(11):1598-609. 
5. Dolinsky VW, Jones KE, Sidhu RS, Haykowsky M, Czubryt MP, Gordon T, Dyck JR. Improvements in Skeletal Muscle Strength and Cardiac Function Induced by Resveratrol Contribute to Enhanced Exercise Performance in Rats. J Physiol. 2013 Apr 2. [Epub ahead of print]  Epub 2011 May 31.
6. Fenning A, Harrison G, Dwyer D, Rose'Meyer R, Brown L. Cardiac adaptation to endurance exercise in rats. Mol Cell Biochem. 2003 Sep;251(1-2):51-9.
7. Momken I, Stevens L, Bergouignan A, Desplanches D, Rudwill F, Chery I, Zahariev A, Zahn S, Stein TP, Sebedio JL, Pujos-Guillot E, Falempin M, Simon C, Coxam V, Andrianjafiniony T, Gauquelin-Koch G, Picquet F, Blanc S. Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat. FASEB J. 2011 Oct;25(10):3646-60.
8. Sen GC. Novel functions of interferon-induced proteins. Semin Cancer Biol. 2000 Apr;10(2):93-101.
9. Vitaglione P, Sforza S, Galaverna G, Ghidini C, Caporaso N, Vescovi PP, Fogliano V, Marchelli R. Bioavailability of trans-resveratrol from red wine in humans. Mol Nutr Food Res. 2005 May;49(5):495-504.
10. Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005 May;49(5):472-81.

Saturated Fat & Postprandial Endotoxemia. Caffeine & Max. vs. Submaximal Exercise. Lactoferrin & the Battle Against Visceral Obesity. High Intensity Strength Training, Free Testosterone & the Use of Perceived Recovery Scales

Gram negative bacteria, as these E. coli bacteria which have been photographed with a low-temperature electron micrograph (magn. x10,000) tend to produce endotoxins in your gut, while gram positive bacteria tend to produce exotoxins on your food - nasty, ha?

It has been estimated that a single cell of Escherichia coli contains approximately 106 Lipid A or endotoxin molecules with a mass of about 100,000 Da (the exact mass varies according to the LPS type). The typical human intestinal tract can harbor approximately one gram of endotoxin, which is ~2-4x more than what scientists used in previous rodent studies as a "lethal dose" (Kawai. 1991). Aside from the information about the lethal dose of endotoxins in rodents, these figures, which are at the same time the SuppVersity figures of the week are part of the study by Mani et al. with which we are going to kick off this week's installment of On Short Notice. I guess these figures give you an idea of the toxic potential within your gut and why all the hoopla about leaky guts, the human microbiome, pro- and prebiotics, endotoxemia and co. is probably not all hype, but a hitherto largely neglected aspect of human health (and disease)

Saturated fat < > gut interaction sheds a dark shadow on the "benign fat of our ancestors"

(Mani. 2013) -- According to a study from the University of Iowa, the endotoxemia response to a meal, i.e. the amount of inflammatory innately produced toxins from your gut that enter circulation in the postprandial phase, is increased in response to a meal that's high in saturated fat.

Figure 1: Endotoxin permeablity and changes in serum endotoxin levels in the hours subsequent to the ingestion of a test meal containing either 50ml  coconut (CO), vegetable (VO) and fish oil (FO) in otherwise healthy pigs (Mani. 2013).

The scientists also found that omega-3 fatty acids from fish and cod liver oil reduced the amount of endotoxins hitting the blood stream and that olive, as well as vegetable oils exhibited a neutral effect. As the data in figure 1 (left) goes to show you, the underlying mechanism behind the saturated fat induced influx of toxins was a whopping +60% increase in the endotoxin permeability (Papp) of the guts of the 24 pigs on which the experiments have been conducted.

Click here to read more about a previous study that shed some light on the effects of certain nutrients on the gut microbiome.

Now you can certainly argue that the ground corn-soybean meal dough that was at the base of the test-meal was "the devil" here, but let's be honest, for the average Jane and Joe, there are similar "devils" in any standard meal, they consume, so that the finding that the addition of 50 ml fish oil (FO), vegetable oil (VO) or coconut oil (CO) made such a difference in terms of the influx of pro-inflammatory endotoxins is nothing you can simply ignore. The same goes for the fact these effects occurred in response to the ingestion of organic coconut oil (according to the researchers purchased from Spectrum Naturals Inc.), is actually somewhat unsettling and certainly not in line with some of the previously established benefits of coconut oil consumption, such as it's waist reducing effects in overweight subjects (click here to learn more).

What's also interesting is that previous rodent studies yielded different results. Laugerette et al., for example, found a similar increase as Mani et al. in mice, but in response to canola and sunflower oil (Laugerette. 2013). This raises the question in how far the effects may be mediated by the baseline diet and the corresponding bacterial composition of the small and large intestine (or species specific effects?). After all, the gram negative bacteria of which scientists believe that they increase in response to high fat diets have the highest endotoxin content. They populate the distal ileum and the colon and are supposedly the main sources for circulating endotoxin (Berg. 1999) - if you had less of them to begin with, you are not as likely to suffer from an acute influx of endotoxins in response to the ingestion of SFAs. Moreover, what it the endotoxins were released in response to the antimicrobial effects of coconut oil?

Update: Wyatt Brown left an interesting comment on this issue on the SuppVersity facebook wall, I do not want to deny anyone, so I thought I'd just update the post with it:

I'm glad people are talking about the endotoxemia thing, that's what we do at SuppVersity, have the discussions nobody else does! I think it's important to recognize that, especially for the paleo/ancestral types who accuse grains of inducing intestinal permeability and then go and eat diets that cause intestinal permeability...and because endotoxemia is bad...

But I don't think that all is lost, the evolutionary argument may just need to be modified a little. The current paradigm involves looking at individual foods, or worse yet (though that was supposed to be an improvement) broad classes of macronutrients, and our adaptation to them. Well, it looks like those might have been wrong in some ways, maybe we aren't fully adapted to some foods, but then again maybe we are adapted to a particular kind of diet that makes those foods all right.

Some of the antioxidants in orange juice prevent intestinal permeability from dietary fats it seems the bile acids secreted during digestion are to blame, and it's an oxidative mechanism, so the orange juice prevents this (Ghanim. 2010). It also works with grape polyphenols (Ghanim. 2011).

Moreover, it seems that feeding mice a diet rich in fermentable fibers prevents endotoxemia - maybe due to butyrate production and its protective effects on intestinal cells (Cani. 2007). And acutely, fiber with a high fat meal also prevents the effect (Ghanim. 2013). It's probably due its ability to sequester excess bile acids (Vahouny. 1980)

So it would appear that we are adapted to a diet containing those fats but also containing fruit and fiber.

As you see, Wyatt makes a pretty valid point, when he hints at other contributing factors of which I know that they got forgotten way too often in the paradigmatic and downright stupid and unproductive high fat vs. low fat and the SFA vs. PUFA skirmishes on the Internet.

I guess, there is still much to learn here and I hope you are aware that the SuppVersity is the place you can do just that: Learn something new everyday!

Caffeine's effect on muscular fatigability during maximal vs. supramaximal stimulation

There is no question that caffeine can have beneficial effects on exercise performance - whether every athlete benefits to a similar degree is yet as questionable as the "ideal" dosage to elicit optimal fat loss effects without the negative side effects that are associated with the chronic overconsumption of any type of stimulant (click here to learn more about the narrow margin between "just enough" and "already too much")

(Tallis. 2013) -- In a very straight forward in vitro experiment, researchers from the Coventry University in the UK found that the ergogenic effects of caffeine depend on the intensity of the muscular contractions. When the scientists exposed isolated soleus muscles to up to 70µM of caffeine (that's still within what you would consider a "physiological dosis"), Tallis et al. observed that the muscular endurance increased only, when the muscles were challenged at submaximal intensities (+19.2%), while it decreased by 17.6% upon maximal challenge.

Whether or not this is important for the average strength trainee remains questionable. After all the "endurance" part of your regimen is usually conducted at submaximal intensities and weheter you can do one interval more or less probably doesn't matter as well. For a professional cyclist participating in a time trial, those 17.6% may well make the difference between victory and defeat. On the other hand, there is more to "endurance" than local muscular fatique, so that caffeines effects on the central nervous system will at least ameliorate, if not totally counter these potential downsides.

Lactoferrin, an overlooked visceral fat annihilator?

I don't even know if all of you are familiar with the globular glycoprotein lactoferrin that is widely represented in various secretory fluids, saliva, tears, nasal secretions and - above all - colostrum. It has a very important role in the immune defenses of your body and according to a recent review by Japanese scientists, it does also exert direct lipolytic (breakdown and release of fat from) and anti-adipogenic effects in vitro and in vivo.

All of you who read the "Ask Dr. Andro" installment on Milk & Colostrum should at least have heard of lactoferrin before. It's one of the anti-microbial, anti-fungal and immune modulating molecules in the white elixir of mammalian life that's also suppose to exert antagonist effects on the opioid receptors (read more).

A hitherto still unsolved problem is the delivery of the lactoferrin to the target tissue, but with the advent of specifically enteric coated lactoferrin which circumvents the breakdown of the 80kDa protein in the acidic milieu of the stomach and allows its passage via the lymphatic system into the mesenteric (visceral) fat pad, where it accumulates, interacts with the lactoferrin receptor LRP1 which is directly located on the adipocytes of the visceral adipocytes and suppresses the expression of PPARγ reduces the expression of perilipin and thus shuts down lipogenesis and increases lipolysis in existing adipocytes. Accordingly, respective supplements could in fact become "a highly safe and a promising dietary supplement" that has in addition to its already well-known beneficial effects on the immune system the ability the potential to "be used to promote human health globally" (Ono. 2013). But let's be honest, haven't we heard claims like that before?

Perceived recovery 48h after a workout correlates with free testosterone levels

(Sikorski. 2013) -- Yeah, I know the whole free testosterone after a workout discussion is pathetic, but what about free testosterone levels 48h hours after the workout, i.e. amidst the hot recovery phase? According to a soon to be published study in the Journal of Strength and Conditioning Research a standardized test to elicit the perceived recovery (PRS) appears to be surprisingly accurate to predict the drop in free testosterone after a session of high volume resistance training designed to elicit a large amount of fatigue and muscle damage. 

"All subjects participated in a high volume resistance training session consisting of 3 sets of 10-12 repetition maximum loads for each of the following exercises: full squats, bench press, deadlifts, pullups, bent over rows, dips, shoulder press, barbell curls and triceps extensions. Rest periods were 1 minute between sets, and 2 minutes between exercises." (Sikorski. 2013)

The scientists from the University of Tampa recruited 35 highly resistance-trained subjects (aged 21.3 ± 1.9 years) with an average squat, bench press, and deadlift of 1.7± 0.2, 1.38 ± 1.9 and 2.07 ± 2.7 times their bodyweight for their study. The subjects had a minimum experience of 3 years of resistance training and were thus probably way more capable to access their own recovery status than the average Jane or Joe after with a dozen of irregular workouts under her / his belt. Blood analyses, soreness and PRS tests were conducted at before, immediately after and 48h after the workout (total weight lifted in the training session was 16,353 ± 3,691.8 kg) and revealed ...

Read more about the hormonal effects of different workout styles in this previous SuppVersity post

• a significant increases in leg, chest and arm soreness from pre to post exercise,
• a significant increases in creatine kinase (CK; measure of muscle damage) from 189.4 ± 100.2 to 512 ± 222.7 U/L (p < 0.05),
• no changes in cortisol, testosterone, and free testosterone from pre to immediately post workout,
• a significant moderate, and inverse relationship between leg soreness and PRS scores and  low, inverse relationships between chest and arm soreness and PRS scores, 
• a significant, moderate inverse relationship between CK and PRS 

yet only when the CK values peaked 48h after the workout, however, the aforementioned "low, direct relationship with PRS" (Sikorski. 2013) was observed. As the researchers point out this result could be

"[...] important for those individuals that have neither the resources (time, monetary or otherwise) nor the expertise to draw blood and perform chemical assays to determine recovery status and or muscle damage. [...] This, in the bigger picture, may help appropriately design periodization plans designed aimed at functional overreaching and ensure proper overload. Moreover, and perhaps more importantly, the ability to indicate level of recovery following heavy resistance training expeditiously and accurately may be a critically important step in prevention of overtraining." (Sikorski. 2013)

The scientists do yet also emphasize that "future work is needed addressing other variable influencing recovery and long-term studies investigating the usefulness of the PRS in training" before a more general recommendation can be issued.

---

That's it for today folks. As usual there are a couple of interesting facebook posts for you to check out and discuss

• Upping your vitamin D levels does nothing to reduce knee pain or cartilage loss in patients with symptomatic knee ostearthritis (read more)
• "The one-two punch", retinoic acid suppresses obesity by both promoting energy expenditure and by inhibiting adipogenesis (read more)
• More evidence of intrauterine dietary priming: Low protein in the womb + high caloric diet afterwards => insulin resistance (read more)

and obviously, you are invited to post your thoughts or questions on any of today's items in the comment area of this post.Aside from that, I wish all of you an exciting weekend ;-)

References:

• Berg RD. Bacterial translocation from the gastrointestinal tract. Adv Exp Med Biol 1999, 473:11–30. 
• Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, Gibson GR, Delzenne NM. Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007 Nov;50(11):2374-83.
• Ghanim H, Sia CL, Upadhyay M, Korzeniewski K, Viswanathan P, Abuaysheh S, Mohanty P, Dandona P. Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression. Am J Clin Nutr. 2010 Apr;91(4):940-9.
• Ghanim H, Sia CL, Korzeniewski K, Lohano T, Abuaysheh S, Marumganti A, Chaudhuri A, Dandona P. A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal. J Clin Endocrinol Metab. 2011 May;96(5):1409-14.
• Ghanim et al. The Intake of Fiber Suppresses the High-Fat High-Carbohydrate Meal-Induced Endotoxemia, Oxidative Stress and Inflammation. Endocr Rev, Vol. 33 (03_MeetingAbstracts): OR03-1
• Kawai Y, Kaneda K, Morisawa Y, Akagawa K. Protection of mice from lethal endotoxemia by use of an ornithine-containing lipid or a serine-containing lipid. Infect Immun. 1991 Aug;59(8):2560-6. Erratum in: Infect Immun 1992 Jan;60(1):320.
• Laugerette F, Furet JP, Debard C, Daira P, Loizon E, Geloen A, Soulage CO, Simonet C, Lefils-Lacourtablaise J, Bernoud-Hubac N. Oil composition of high-fat diet affects metabolic inflammation differently in connection with endotoxin receptors in mice. Am J Physiol Endocrinol Metab. 2013;302:E374–386.
• Mani V, Hollis JH, Gabler NK. Dietary oil composition differentially modulates intestinal endotoxin transport and postprandial endotoxemia. Nutrition & Metabolism. 2013;10(6).
• Ono T, Morishita S, Murakoshi M. Novel  function of bovine lactoferin in lipid metabolism: Visceral fat reduction by enteric-coated lactoferrin. Pharma Nutrition. 2013 [accepted manuscript] 
• Sikorski EM, Wilson JM, Lowery RP, Joy JM, Laurant CM, M-C Wilson S, Hesson D,
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