Science Round-Up Seconds: Breast Cancer, GH Induced Insulin Resistance, Stretch + Contraction Increase Molecular Hypertrophy Signals and Probiotics & the Obesity Pandemic

When we are talking about the extinction of endangered species such as the Siberian tiger, we are adopting a perspective that will also help us to understand such things as the pitfalls of probiotic supplementations as a "solution" to the diabesity epidemic

It's Friday the day after the SuppVersity Science Round-Up (download the podcast) and you all know what that means: Right! Time to summarize the stuff that did not make it into the show and provide you with a couple of thoughts, as well as additional information on the topics, Carl Lanore and I did already cover (this does also imply that you have to listen to the show if you want the info on the genetic and non-genetic underpinnings of breast cancer).

If I had to come up with a motto, something that connects the topics in the show and thus obviously also the ones that will be discussed in this article, I guess it would be "ecosystems". I have repeatedly pointed out in the past that I am not a believer in the "back in the good old days everything was better" interpretation of "Paleo". What I do believe in, however, is the notion that exposition entails adaptation.

You can't control the adaptation, but you can control the exposition

Now, these adaptation processes whether they be negative such as the growth of cancerous tissue in the breast or ovaries of a woman like Angelina Jolie are beyond our reach: The environment that triggers them, on the other hand, can be manipulated - whether that's by getting your breasts and ovaries removed to rid yourself of the 50-80% (you heard me right! the "real" chance carriers of a defect BRCA1/2 gene to develop cancer ranges from 50% to 80%, by the age of 70) or - and this is obviously a pretty drastic change of subjects, by emphasizing peak contractions in a semi-stretched position to benefit from the upregulation of the proteins p-Akt, p70S6K, p38 MAPK and ERK 1/2, i.e. the driving forces of protein synthesis, it's always your manipulation of the environment that will bring about "adaptation" (used in the broadest sense).

Figure 1: Graphical summary of the main results, i.e. the stretch initiated activation (+, ++, +++) of the signaling molecules on different conditions with either short, long (at maximal peak contraction) or slightly longer (+25%, but still way from lockout) positions and the corresponding tension on the soleus muscle of the rodents (Van Dyke. 2013)

If I was successful, the above introduction should have set the scene and thus provided an environment for your perspective on things to change / align with mine. I've manipulated the "cognitive environment" that determines or at least influences the way you are about to understand what follows, i.e. the missing side-kick on the recently observed negative effects of growth hormone on insulin sensitivity and glucose uptake in healthy men and the comprehensive discussion of the (imho) misunderstood role of the gut microbiome as both, a trigger and solution to the obesity epidemic.

Can exogenous growth hormone trigger insulin resistance?

Within our new cognitive framework you will probably have transformed the above question as follows, by now: "How does the exogenous administration of growth hormone change the the endocrine environment and why does this entail an adaptive response of which most people would say that it's highly detrimental?" From this "mini-evolutionary perspective", as you may call it, it's surprisingly easy to understand what exactly has happened in a recent study from the University of Aarhus in Denmark (Vestergaard. 2013).

In their effort to probe the hypothesis that there was a connection between ghrelin, growth hormone and the increases in retinol-binding hormone (RBP4, to be specific) that are observed in patients with developing and/or full-blown metabolic syndrome, Vestergaard et al. conducted two studies of which only the second one, which involved nine totally healthy young men in their twenties (23y; BMI 23kg/m²), will - without major qualifications - transfer to you me or other healthy physical culturists.

The men received a course of daily 2mg GH injections while consuming a previously standardized diet containing 50–60 % carbohydrates, <30 % fat, and roughly 10–15 % of protein (in % of total energy intake). Before and after the intervention period, the participants had to report to the lab at fasted and thus optimally prepared for the hyperinsulinemic euglycemic clamp test.

Figure 2: Basal fasting glucose and insulin concentrations, as well as M-value (=marker of insulin resistance) in healthy young men after eight days of placebo and GH administration, respectively (left; p-values over bars); glucose infusion rates (GIR) indicated by during hyperinsulinemia after placebo / GH administration (right, Vestergaard. 2013)

The selected results I plotted in figure 2 are quite unambiguous. As expected there was a huge increase in the IGF-I concentrations in response to the 8-day course of 2mg GH per day.

The 8% increase in fasting plasma glucose and even more so, the doubling of the insulin levels that were required to keep these elevated glucose levels stable, certainly come as a surprise, if you're thinking about it from an broscientifically influenced mechanistic point of view. I mean, doesn't broscience tell us that GH is the good guy that's going to make you lean and ripped?

How come we are seeing a -34% reduction in glucose sensitivity (this is actually what's measured as the so-called "M value" in the euglycemic clamp studies).

Within our previously established cognitive framework, the answer to this question is actually quite straight forward. To get to the bottom of the counter-intuitive effects of GH we just have to think about the "natural" environment that will trigger the release of GH from the somatotropic cells within the lateral wings of the anterior pituitary gland.

Did you know that the normal GH response to hypoglycemia is blunted in the obese and the reduced obese (Ball. 1972)? Without GH to get their blood sugar back up, overweight individuals and formerly obese will thus have to resort exclusively to corticosteroids (cortisol) to regulate their blood sugar levels.

In this context, it's also worth mentioning that insulin induced hypoglycemia is still considered a valid - yet maybe not optimal - in children who are suffering from retarded growth. With the injection of exogenous insulin and the kids becoming hypoglycemic the body should compensate for that by secreting growth hormone. If that's not the case, this is a good indicator of a general malfunction of the pituitary gland.

Hah? Right! Hypoglycemia or borderline hypoglycemia is among the primary triggers of somatotropin aka GH release. Now, think about it - would it make sense that a hormone that's supposed to increase fatty acid oxidation to supply your body with glucose would at the same time increase insulin sensitivity and thus have your muscles suck up all the precious glucose your brain is longing for?

On the contrary, it is only logical that GH - just like it's falsely vilified potent cousin cortisol (yeah, you heard me right, you won't see both at the scene on the same time, because they serve a similar purpose at least wrt to glucose metabolism) - will decrease the insulin sensitivity of your muscles in order not to "waste" the precious glucose which should be scarce once GH goes up.

In the study at hand, the environment in which the high growth hormone levels occur are totally different: Once you plug people to a euglycemic clamp, there is a mismatch between the actual environment, which is normal / high glucose, and the natural (if you will "evolutionary) expected environment for elevated GH levels - and what you see in figure 2 is the inevitable consequence of this mismatch: a significantly lowered glucose sensitivity... quite cool, how a small change in the way we are looking at things allows us to understand phenomena that do initially appear totally inexplicable, right?

Lifestlye changes, not probiotic supplements are the solution to the diabesity epidemic

Now that we have first-hand evidence for the explanatory power of our new perspective let's stick to it and apply it to the false expectations studies such as the recently released investigation into the "anti-obesity" effects of the common gut bug Akkermansia muciniphila in a rodent model of diet-induced obesity (Everard. 2013).

Figure 3: The AM count is reduced in response to the dietary enviroment, the environment - not the lack of bacteria - is the root cause of the negative effects on fasting glucose, fat mass gain and thickness of the intestinal mucus lining all of which can be partly (the latter even fully) restored to normal with supplementation (Everard. 2013)

If we take a look at the data in figure 3 it is undebatable that the provision of exogenous live (this does not work at all with dead bacteria) Akkermansia muciniphila (AM) can significantly reduce the weight and fat gain in the rodents receiving a species inappropriate high fat diet. As the data on the AM content of the gut microbiome of the obese mice on the right hand side of figure 3 reveals this effect is yet a simple result of the restoration of the "original" microbial composition in the intestinal tract of the rodents.

Siberian tigers on corn fields!? Does this really make sense?

Since the term "original" refers only to the amount of the bacteria Dr Antoon Akkermans identified as one of the many bacteria the count of which is decreased / changed in obese rodents (and humans), it is yet not surprising that we are seeing nothing but ameliorative effects.

Glutamine may offer another way to accelerate gut healing and improve amino acid absorption or rather avoid the "abuse" of BCAAs, arginine etc. for other metabolic purposes (learn more)

Within our cognitive framework of "ecosystems" and "adaptations", the chronic administration of living bacteria to counter a specific aspect of the diet induced detrimental effects on the gut microbiome has may be compared to the laughable efforts of biologists to save certain animals from extinction by breeding them in a Zoo and releasing them into an environment, where deforestation, pollution and all the other nasty things, we, the crown of evolution, enjoy about as much as the average Westerner likes to wash down his super-sized fast food menu with a "refreshing" *rofl* 2L XXL pot of coke (drinking plenty is healthy for you, ain't it? ;-), will have them die before their time unable to reproduce in time to contribute to the species' natural survival.

Once you understand that, you will have to realize that you are wasting your time and money on false promises if you don't change the environment, i.e. the way you live and the foods you eat first before you even think of using probiotic supplements as an adjunct to accelerate the normalization process, which should - just like the detoriation - take place irrespective of the supplementation as a mere results of the dietary modulation of your gut microbiome, anyways.

With these insights, I am going to release you into the weekend... and who knows, maybe you'll notice the effects the environment you expose yourselves to in the coming days has all sorts of beneficial or detrimental influences on your physical and mental health. Listening to even more non-science-based Angelina Jolie news on the television and radio, for example, is probably not going to have beneficial effects on your psyche ;-)

References:

• Ball MF, el-Khodary AZ, Canary JJ. Growth hormone response in the thinned obese. J Clin Endocrinol Metab. 1972 Mar;34(3):498-511.
• Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013 May 13.
• Van Dyke JM, Bain JL, Riley DA. Stretch activated signaling is modulated by stretch magnitude and contraction. Muscle Nerve. 2013 Apr 26.
• Vestergaard ET, Krag MB, Poulsen MM, Pedersen SB, Moller N, Jørgensen JOL, Jessen N. Ghrelin and growth hormone induced insulin resistance: no association with retinol-binding protein-4 Endocr Connect EC-13-0019; published ahead of print May 7, 2013, doi:10.1530/EC-13-0019

Energy Drinks Before Workout Make You Thirsty. Single HIIT Session Every 14 Days Maintains Fitness in the Off-Season. Postprandial Walk Decreases HbA1c by 5%. Cardio Before Weights Increases pAKT +87% Over Weights Alone

You simply cannot start "working out" too early - even if it's just child's play.

"Three for one!" No, I am not trying to sell you three bottles of "uberpotent" test-boosters for the rat of one. Three for one that's the SuppVersity Figure of the Week and it is the ratio of the decrease in breast cancer risk in women and the hours of physical activity per week during their adolescence.

According to a 2004 review by Lagerros, Hsieh and Hsieh, each additional* hour of weekly physical activity is associated with a -3% risk of developing breast cancer later in life (Lagerros. 2004)

Needless to say that the "additional" hours are in addition to the low physical activity in the laziest of the study participants, who had a 20% higher risk of developing breast cancer than their most active peers.

So what else do we have today? With this primer on the importance of physical activity esp. in the critical periods of your / your children's and grand-children's lives, let's delve right into a "special edition" of the Saturdaily "Short News" with a focus on a selection of very recent results from exercise-related studies.

• Energy drink before a workout make you thirsty. don't enhance performance (Tanskanen. 2013) While the mantra of the "intra-workout" beverage producer that you need at least a small amount of carbohydrates to optimally absorb the added salts, a recent study from the University of Jyväskylä in Finland showed that the ingestion of both high- and low-carb (33g vs. 10g) caffeine-containing energy drinks before the workout resulted in a temporary increase in thirst compared to to both caffeinated (106mg, just as the two energy drinks) an non-caffeinated water.
  
  

  

  With +1kg Fat in 4 Weeks from less than 2 energy drinks/day, thirst may be the least problem you will have if you guzzle "energy drinks" (learn more).

  The fact that the increase in thirst was only transient, and decreased in the course of the 60min cycling exercise (60% VO2max) the healthy young adults had to perform, as well as the non-existent differences in hydration status between the groups do yet show that these effects were practically irrelevant. Incidentally, the latter has to be said for the promised / expected performance enhancing effects of energy drinks - with the relatively low amount of caffeine in the drinks, there were no significant differences between the the time the 10 participants cycled on an incremental test to exhaustion that followed the "steady-state-cardio" during each and every of the four testing days of this randomized, crossover study.

  ---

  Putting things into perspective: The fact that previous trials yielded different results, esp. wrt to the performance enhancing effects of caffeine, is probably attributable to a the low dosage of caffeine. Another very recent study by Ranchordas & Kenzie, for example has just confirmed that a compbination of 32g of carbs and 300mg of caffeine can "enhance some aspects of soccer-related fitness including acceleration, maximal velocity, 20-m sprint speed, speed-endurance, and lower RPE during repetitive sprints compared with CHO-only and PLA beverages." (Ranchordas. 2013)

 

• 

  Remember the "Iranian HIIT Solution" - 9% body fat in 12 weeks? Perfect evidence: HIIT is not for athletes, only.

  It does not take much to stay fit, a single every other week HIIT session is enough (Rønnestad. 2013) Right from the former Olympia "Metropolis" *rofl* Lillehammer comes a study which shows that trained athletes like semiprofessional soccer players can maintain their baseline fitness levels in the off-season by no more than a single HIIT session, which consisted of five bouts of 4 min running at 87–97% of age-predicted maximum heart rate, every other week.
  
  The overall loss in the distance the subjects covered during the 20-m shuttle run did obviously decline (-8% ± 6%), but the difference to the control group that performed the same HIIT sessions on a weekly basis was non-significantly different from the every-other-week group.Moreover, both groups maintain their VOmax over the whole six week study period.

  ---

  Bottom line: A little of HIIT can go a long way ... wait, this is almost the title of a previous SuppVersity post, i.e. "Some HIIT For Life & Less LISS For More! How to Burn 27,300 Kcal Extra W/out Losing a Single Extra Pound of Fat!", of which I would really suggest you read it now, in case you are still not convinced that a reasonably dosed amount of HIIT makes a valuable addition to almost every trainees regimen.

 

• Hit the weights! If you want to do more than just increase your daily activity levels to lower your HbA1c, don't waste your time on the treadmill. Increase your daily activity level and lift weights! Three supervised resistance training sessions per week for 10 weeks have been shown in a 2009 study by Bweir to be significantly more effective in lowering the Hb1Ac levels than in adults with type II diabetes than an isoenergetic (=spending the same energy during the workout) treadmill exercise (Bweir. 2009).
  The postprandial stroll in the bark is an effective means to lower your HbA1c (Nygaard. 2013) While the former post on the conservation of the conditioning of a trained athletes by HIIT does confirm the notion that "aerobic exercise" in the original sense of the meaning, which would imply that you increase your body's exercise capacity (as evidenced by VO2max), another recently published study shows that metabolic benefits of exercise can be achieved with much lower intensities.
  
  At least in the in the South Asian immigrants with high risk of type 2 diabetes who participated in a recently conducted 12-week intervention, it took nothing but the figurative "walk in the park" (30min+ of physical activity of any sort) after a meal, to reduce their HbA1c levels - a marker of long(er) term glucose levels - by allegely relatively unimpressive, but statistically highly significant ~3% (p = 0.012). That the intervention in the course of which the average subject increased his / her daily activity by 40min compared to the control group did not yield any significant changes in body composition should yet be as evident as the fact that it was 100% side-effect free.

  ---

  Bottom line: It really depends on where you are and if you are a sedentary slob, even 40min of extra (light) activity a day can make a difference. After all, previous studies have shown that each 1% increase in HbA1c is associated with a 1% increase in cancer risk (data fro 25,476 patients with type 2 diabetes registered in the Swedish National Diabetes Register; cf. Miao Jonasson. 2012). 

• Rodent study says: Cardio does not hamper anabolic signalling (Souza. 2013) While the comprehensive review by Wilson et al. you've read about here at the SuppVersity several times (e.g. April 2012, January 2013, etc.) found that there is a
  

  "significant negative relationships between frequency (-0.26 to -0.35) and duration (-0.29 to -0.75) of endurance training for hypertrophy, strength, and power." (Wilson. 2012)

  a very recent study from the Universidade de Sao Paulo would suggest that the negative influence of endurance training on the anabolic stimulus of restistance training is either
  
  1. species specific and occurs only in humans, but not in rodents,
  2. occurs only with chronic high volume trainging, or
  3. is at least not related to changes in the AMPK, TSC2, mTOR, or p70S6K1 ratios
  Now while each of the former is certainly possible, my best bet would be that the training volume, i.e. 5 sets of 10 reps on a "rodent leg trainer" and a 60min endurance workout on the treadmill, and the fact that the protocol was performed only once are the main reasons that the AMPK, TSC2, mTOR, or p70S6K1 ratios were identical.

  ---

  

  Doing cardio before strength workouts results in a higher testosterone:cortisol ratio after the workout (learn more)

  One thing is remarkable, however: The scientists observed a pretty remarkable +87% increase in Akt phosphorylated/total ratio that occurred 2h post only in those rodents who performed a 60min bouts of treadmill running before their leg workout. What? Yeah, that's actually what Carl and I have been talking about in the past - "pre-workout glycogen depleting cardio as intensity technique" (learn more)

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So what's left to do now? Ah, yes of course. The best wishes for the weekend and a brief link-list for those of you who can't be without SuppVersity news for another 24h.

• 

  "Going Nuts On Berries: Ellagic Acid in Rasp- and Blueberries, Pecans, Walnut & Co Protects Against Visceral Obesity" - I hope you are not one of the guys who spits the tiny seeds of the raspberries out. That is not just disgusting, you would also spit away ~90% of their ellagic acid content (learn more).

  Do you stand right? Scientists investigate the influence of dynamic vs. static posture on leg stiffness and future risk of fall (read more)
• Anabolic steroid use has distinct effects on tendons. Scientists speculate that the increased stiffness and higher modulus contribute to the frequent ruptures in chemical athletes (read more)
• Oldie but goldie: Do you cook the creatine out of your steaks? A mid 20th century paper shows that cooking degrades creatine to creatinine (read more)
• More walnut lovin' Despite the fact that you have to be careful with what you say about the health effects of walnuts, these days a group of reseachers does not fear the repressions from the FDA and says: "We found two novel mechanism that explain why walnuts are good for your heart!" (read more)

These and other news are already waiting for you on Facebook and you can bet that there will be at least half a dozen additional ones posted before the next official SuppVersity article will see the light of the day, tomorrow.

References:

• Bweir S, Al-Jarrah M, Almalty AM, Maayah M, Smirnova IV, Novikova L, Stehno-Bittel L. Resistance exercise training lowers HbA1c more than aerobic training in adults with type 2 diabetes. Diabetol Metab Syndr. 2009 Dec 10;1:27. doi: 10.1186/1758-5996-1-27.
• Miao Jonasson J, Cederholm J, Eliasson B, Zethelius B, Eeg-Olofsson K, Gudbjörnsdottir S. HbA1C and cancer risk in patients with type 2 diabetes--a nationwide population-based prospective cohort study in Sweden. PLoS One. 2012;7(6):e38784.
• Nygaard H, Grindaker E, Rønnestad B, Holmboe-Ottesen G, Høstmark AT. Long-term effects of daily postmeal physical activity - Preliminary results.International Journal of Sport Nutrition and Exercise Metabolism,2013, 23, S1 -S15.
• Ranchordas M, Kenzie J.Effect of carbohydrate only and carbohydrate plus caffeine co-ingestion on a battery of reliable soccer-specific tests. International Journal of Sport Nutrition and Exercise Metabolism,2013, 23, S1 -S15.
• Rønnestad BR, Slettaløkken G. High-intensity interval training every second week maintains VO2max in soccer players. International Journal of Sport Nutrition and Exercise Metabolism,2013, 23, S1-S15.
• Souza EO, Tricoli V, Bueno Junior C, Pereira MG, Brum PC, Oliveira EM, Roschel H, Aoki MS, Urginowitsch C. The acute effects of strength, endurance and concurrent exercises on the Akt/mTOR/p70S6K1 and AMPK signaling pathway responses in rat skeletal muscle. Braz J Med Biol Res. 2013 Apr 19:0.
• Tanskanen M, Heikkinen T, Linnamo V. Effects of caffeine drinks on endurance performance, fluid balance, and subjective feelings. International Journal of Sport Nutrition and Exercise Metabolism,2013, 23, S1 -S15.
• Wilson JM, Marin PJ, Rhea MR, Wilson SM, Loenneke JP, Anderson JC. Concurrent training: a meta-analysis examining interference of aerobic and resistance exercises. J Strength Cond Res. 2012 Aug;26(8):2293-307.

Get Lean & Stay Lean Quickie: Add Cinnamon to Cereals. NPY Detrimental? Melatonin Beneficial! 50,000IU Vitamin D3 Useless. Phtalate DHEP Dangerous! PPAR, AKT & GLUT-4 Agonist From False Black Pepper Surprisingly Potent!

In 1998 the Consumer Union wrote a letter to the FDA complaining about the occurrence of DEHP and other "endocrine disrupting chemicals" in cheese and dairy of which they suspected that they were partially emitted from the plastic wrappings (read more)

Those of you who are following the SuppVersity news on Facebook very closely, will be aware that I announced yesterday, already that there was going to be another installment of On Short Notice, today... another "Quickie", so to say with a couple of selected news on getting and staying lean. Something I know is pretty much a pain in the a** of most of us and if you take a closer look at the news about phtalates it is actually no wonder. I guess on their own those nasty plasticizers would probably not even be a problem, but together will all the other byproducts of our convenient lives, they form a perfect storm.

And you know what's worst, simply wrapping all those plastics that 'infect' even organic foods with the 'P-Virus' around your waist while you're working out will probably make things worse, not better.

Let's get down  to business ;-)

Enough of that! Are you ready for today's quickie -- Note: The next installment of the Athletes' Triad is scheduled for next week. I am honestly sorry for these delays, but I just have "real" work to do on the weekends at the moment and no time to do the respective research that would be necessary to provide you with not just any, but actually useful information. In the mean time I hope you like this post, as well.

• 6g of cinnamon stretch postprandial glucose response to cereals over more than 2h. That's the result of the latest study from the Ball State University in Muncie (Magistrelli. 2012). Interestingly the effects of 6g of ground Cassia Cinnamon were independent of the body weight and metabolic health of the thirty-seven 18 to 30 year-old normal-weight and obese study participants.
  
  

  

  Figure 1: Postprandial blood glucose with plain cereal containing 50g  carbs and the same cereal with cinnamon in all subjects, normal-weight and obese; by the way if you go by the AUC I doubt there is a benefit, after all the glucose does not drop base to baseline within 120min (Magistrelli. 2012).

  There is however one slight downside to this study: The scientists measured the blood glucose response for only 120min. If you take a look at the graph in figure 1 you will immediately notice that the co-ingestion of 75g of "Cream of Wheat", an instant farina cereal, with 6g of regular cinnamon did lead to a 24% reduction in the area under the glucose curve, but only if you discard what happened after the 120-min period the scientists used to measure. After all, the co-administration of Cassia cinnamon did not do anything that could not be ascribed to a mere reduction in glucose uptake - there is no evidence for an improvement of insulin sensitivity here. On the other hand, the absence of spikes in blood glucose will protective effects against the development of type II diabetes, esp. in the presence of a diet that's overall high in carbohydrates where one blood sugar spike chases the other.
  

  "To date, no study has documented cinnamon's influence on postprandial blood glucose after a mixed meal. Although preliminary in nature, the available research suggests cinnamon supplementation can significantly reduce short-term glycemic response in healthy adults." (Magistrelli. 2012)

  The last information is actually pretty surprising. Personally I expect the effects to be less pronounced with mixed meals, but since we still don't really know the underlying mechanism it's difficult to predict what exactly is going to happen, when you eat a spoon full of cinnamon right before your steak with rice. This as well as the previously discussed prolonged elevation of blood glucose (see figure 1)  actually raise some doubts about the real-world usefulness of eating tons of cinnamon if you don't actually like it, just as a way to manage blood glucose - specifically if you are not a type II diabetic (or on your way to become one) and avoid "food" like cereals and similar junk, anyways.
• Neurpeptide Y (NPY) does not protect against obesity -- Based on the results of a recent rodent study from the University of Turku in Finland, it seems that the exact opposite is the case. In that it does not seem as if it would fail to make you satiated and happy. Rather than that it appears to put your metabolism in "high efficacy" mode, so that you gain weight despite the fact that you are not eating more.
  
  The Finish researchers exposed two strains of mice to a typical Western type diet (high energy, high fat, high carbohydrate) for seven weeks. One strain, the OE-NPY(DBH) mice, had 'naturally' high amounts of NPY in the noradrenergic neurons of the brain, the other were normal wild type mouse. Actually, the scientists had expected that the high NPY expressing mice would gain less weight than their wild-type peers, but much to their surprise, the exact opposite was the case.
  
  

  

  In 1990 Kaye et al. conducted post-mortem analyses on the brains of patients with anorexia nervosa and found highly elevated levels of NPY. These results do actually stand in line with those of the study at hand, after all anorexic patients don't feel any exuberant hunger (in the later stages of the disease) and their bodies are running in a mode that is meant to conserve even the smallest amount of energy they consume.

  And as if that was not already strange enough, the scientists also found that female OE-NPY(DBH) were much more prone to gain significantly more weight and larger white and brown fat depots with no difference in UCP-1 levels, hyperphagia (=overeating) or decreased activity. And the weight gain was not without consequence, as these mice
  

  "...also displayed impaired glucose tolerance and decreased insulin sensitivity. OE-NPY (DBH) and WT males gained weight robustly, but no difference in the degree of adiposity was observed." (Ruohonen. 2012)

  Now what's interesting is that similar effects were only observed in 40% of their male counterparts and in exactly none of the wild type males on the Western type diets. These observations lead Ruhonen et al. to the conclusion that ...
  

  "[...] increased NPY release may predispose females to a greater risk of weight gain under high caloric conditions." (Ruhonen. 2012)

  And if you asked me this must be mediated by whatever gender-specific direct effect on feed efficacy and the changes in brown adipose tissue morphology the researchers observed in the NPY overexpressing mice. This would be good news, since brown fat figure much less in human beings than in rodents. Unfortunately, with identical body temperatures and UCP-1 expression in all animals that is at best one of the causative factors. It can hardly explain all the profound weight and fat gains in the non-hyperphagic (not overeating) OE-NPY mice.
  
  Now, at least for me this raises the question if this is not yet another instance, where the artificially increased NPY levels in the absence of the natural confounding factors, such as increased GLP-1 levels, for example (click here to learn more about GLP-1), couldn't be the actual reason and any conclusions with respect to pro- or anti-obesogenic effect of NPY based on the results at hand would be as unwarranted as the usage of drugs that target this and other neuropeptides in isolation.

• 

  Just in case you have missed the Circadian Rhythm Series, this would be the right time to read about how to boost / not hamper melatonin, live by your internal clock and get healthy and lean (and stay the same) - light and foods timing are key, here (learn more).

  Thiazolidinediones + melatonin, a dynamic duo vs. insulin resistance -- A group of researchers from the Indira College of Pharmacy in Tathawade, India, have just published a study on the combined effects of PPAR agonists and melatonin as a means to ameliorate dexmethasone (artificial cortisol) induced insulin resistance in rodents (Ghaisas. 2012).
  
  The data of the study casts a particularly good light on melatonin which does, contrary to the potentially fattening PPAR agonists pioglitazone and rosiglitazone, not entail a simple increase in glucose storage within the adipose tissue. The combination treatment did also normalize the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates, an effect the scientists partly ascribe to the antioxidant effects of melatonin , as well (the reduced blood glucose is obviously another factor) 
• 50,000 IU of vitamin D per week improve 25OHD in previously vitamin D deficient subjects but don't produce the expected improvements in insulin sensitivity. Contrary to one of the most underrated dietary supplement, namely melatonin (see previous news item), the most overrated, namely vitamin D3, does not do anything for insulin sensitivity -- even when the subjects are deficient to begin with and their 25OHD levels do actually respond to supplementation (Simha. 2012).
  
  Despite a weekly dose of 50,000 IU of vitamin D3 and a + 42% increase in 25-OHD levels (to be fair it must be said that the levels were still relatively low and nowhere near where some experts want to see it), the researchers from the Department of Internal Medicine at the Texas Tech University Health Sciences Center at Permian Basin did not observe any improvements in glucose uptake after 8 weeks of supplementation in their 12 healthy subjects with baseline plasma 25-hydroxy vitamin D (25OH-D) levels of less than 20 ng/mL.
• More about DEHP and its occurrence in your environment: Prepackaged foods are among your best sources to get your detrimental dose of DEHP every day. Belgian children have been shown to get up to 80% of their DEHP and other phtalates from school lunch. And bread was the worst offender (Sioen. 2012) - probably because it's packed 'sandwich style' in plastic containers of which Cirillo et al. were able to demonstrate that these and other plastic packagings leech the phtalates right into the food (Cirillo. 2011). It is therefore no wonder that the packaged hopsital foods are full of it (Teresa. 2012).
  

  Apropos, having a venyl flooring in either schools or hospitals will only increase the DEHP load due to the emission of the plasticizer into the air (Yu. 2012) and the DEHP content of the bags with blood transfusions are so high that the anti-doping agencies use it as a marker of illegal blood transfusions (Monfort. 2012). Moreover, phtalates leech into milk and dietary products fat-enriched food such as cheese and cream during processing and storage (Kappenstein. 2012); vegetable oils in plastic containers are likewise full of it (Wu. 2012).

  Cooking seems to remove some of the phatalates, but that does not work for vegetables for example (Fierens. 2012). No wonder foods are still the #1 source, followed by bottled water and indoor air of phatalate exposure in Westerners (Martine. 2012).
  

  Unfortunately, the negative effects of DEHP and its metabolites are not restricted to obesity or the prenatal period, they also induce insulin resistance and metabolic syndrome later in life (Rajesh. 2012) - effects which can be ameliorated by increased vitamin C + E intakes. DEHP has also been shown to reduce progesterone and lead to apoptosis of the ovarian granulosa cells and subsequent infertility (Li. 2012a). Similar detrimental effects have been seen in male rodents (Li. 2012b).
  Natural metabolite of ubiquitous plasticizer DEHP sets you and your unborn kids up for obesity DEHP is used in a wide range of soft PVC products ranging from lifesaving medical devices such as medical tubing and blood bags, to footwear, electrical cables, packaging, tarpaulins for lorries, flooring, stationery and roofing. According to a recent study that's been published in Bioscience Reports its natural metabolite MEHP [mono-(2-ethylhexyl) phthalate] has the potential of turning you into a fat, sick slob:
  

  "In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders." (Hao. 2012)

  In the latest risk assessment of the EU and the DEHP Information Center it is of course 100% save... which bags the question, whether the guys working there simply consider being obese normal, so that anything that makes you even fatter is "save" and does not pose any more of a health threat than life in general, or if they just deliberately ignore that molecules rarely go in and out of our bodies unmetabolized and thus settled for a set of totally meaningless petri dish experiments, before they concluded:
  

  "The use of DEHP has been carefully considered by EU scientists and it is already well regulated by European legislation relating to toys and childcare articles, cosmetics, food contact materials and medical devices." (DEHP Information Center. 2009)

  Hallelujah! Unfortunately it's metabolite MEHP [mono-(2-ethylhexyl) phthalate] obviously is not such a nice guy :-/  

• 

  Figure 2: Serum markers and adiposity, as well as mRNA expression in adipose tissue of male and female mice after 14 weeks on "high fat" diets (based on Estrany. 2012)

  High fat diets (Western style) for women only? I know, this is once again a rodent study, but it is still intriguing that scientists from the Universitat de les Illes Balears in Palma de Mallorca and the Instituto de Salud Carlos III in Madrid, Spain, found that male rodents become insulin resistant and obese, when they are fed a high fat diet (30% fat, in other words high fat + high carb), the female rodents, on the other hand, switch to a 'fat burning mode' or as the scientists state they ...

  "[...] counteract excessive fat intake by improving their ability to use lipid fuels, which limits adiposity and maintains insulin sensitivity." (Estrany. 2012)

  Just as in a previous study neither the male nor the female rats showed the usual symptoms of hyperphagia (overeating), and the body weight gains in all groups were normal.
  
  "Normal" body weight gain and insulin resistance? That should actually ring a bell. Correct! "Normal-weigh obesity" or being skinny fat! And in fact, the underlying reason for Estrany et al.'s observations seems to be that the diet increased the inflammation in the male rats, while it did not do so in the female rodents. What exactly it was that made the difference here, will yet still have to be elucidated, but my best bet is estrogen, which is by no means just the bad guy as which it is portrayed within the fitness community.
• Molecule in false black pepper aka Embelia ribes turns out to be natural GLUT-4 + PI3K/AKT activator, PPAR-gamma agonist and anti-diabetic. What's particularly exciting about the embelin the active ingredient in Embelia ribes Burm, a member of the species Myrsinaceae, which is widely distributed in India and and has a documented history of being used as a diabetes 'medication' in the Ayurvedian traditional medicine system, is that it increases insulin sensitivity without predisposing to further weight gain and adiposity, as the standard Thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone do.
  
  Using the same streptozotocin (STZ) induced rodent model of type II diabetes you have encountered in numerous other studies that have been covered here at the SuppVersity a group of researchers from the Loyola College in Chennai and the University of Madras (Gandhi. 2012), have found that 50mg/kg body weight of embelin that had been extracted from fresh E. ribes fruits by drying and eluting the raw material in benzene...
  

  • 

    Figure 3: Effects of embelin vs. rosiglitazone on insulin levels and rel. expression of antioxidant enzyme activity (Gandhi. 2012)

    reduced body weight gain, blood glucose and plasma insulin in treated diabetic rats,
  • modulated the altered lipid profiles and antioxidant enzymes,
  • exerted cytoprotective effects on the β-cells of the pancreas,
     
  • increased the PPARγ expression in epididymal adipose tissue,
  • inhibited adipogenic activity (=fat gain),
  • mildly activated PPARγ levels in the liver and skeletal muscle, and
     
  • regulated insulin mediated glucose uptake in epididymal adipose tissue through translocation and activation of GLUT4 in PI3K/p-Akt signaling cascade.
  And best of all, contrary to most natural anti-diabetes, these effects were no mere downstream effects of the antioxidant effects of Embelin, but can be ascribed to direct receptor binding: The active ingredient from false black pepper does not only show a high binding affinity for PPARγ, in the experiments Gandhi et al. condcted, it also had stable binding affinities for the active sites of PI3K, p-Akt and GLUT.
  
  
  Embelia ribes in Ayurveda The false black pepper is no newcomer to the scene of natural medicine / health supplements. Embelia ribes has been used in Ayruveda for centuries as an appetiser, laxative, carminative, anti tape-worm cure, to ameliorate / protect from snake bites, against skin deseases, bronchitis and urinary discharges, versus dyspepsia, liver ailments, jaundice, and glatulence.
  The results certainly are exciting, specifically in view of the fact that emeblin could be interesting not just for type II diabetics and individuals with insulin resistance, but also for lean mean women who are looking for a tool that would optimize their insulin sensitivity without the pro-obesogenic effects that render most other "insulin sensitizer" at best useless. And if we assume that similar effects on PI3K and p-AKT do occur in skeletal muscle, as well (this was unfortunately not measured in the study at hand), embelin could even help you build some muscle. Just as its general efficacy in human beings the last hypothesis does of course still require experimental verification... but don't worry, you know that I will keep you posted on any future studies!

That's it! What? You want more? But that's what a quickie is supposed to be it's the frequency that makes it worthwile not the length... ah, I guess I better wish everyone a happy Sunday before I am starting to go into further details here ;-)


References:

• Cirillo T, Fasano E, Castaldi E, Montuori P, Amodio Cocchieri R. Children's exposure to Di(2-ethylhexyl)phthalate and dibutylphthalate plasticizers from school meals. J Agric Food Chem. 2011 Oct 12;59(19):10532-8.
• DEHP Information Center. DEHP Fact Sheet (revised). June 14, 2012. <  www.dehp-facts.com/upload/documents/webpage/ECPI%20-%20factsheet%20DEHP%20revised%20-%20140609.pdf > retrieved on Nov. 03, 2012.
• Estrany ME, Proenza AM, Gianotti M, Lladó I. High-fat diet feeding induces sex-dependent changes in inflammatory and insulin sensitivity profiles of rat adipose tissue. Cell Biochem Funct. 2012 Oct 30.
• Fierens T, Vanermen G, Van Holderbeke M, De Henauw S, Sioen I. Effect of cooking at home on the levels of eight phthalates in foods. Food Chem Toxicol. 2012 Sep 14;50(12):4428-4435.
• Ghaisas MM, Ahire YS, Dandawate PR, Gandhi SP, Mule M. Effects of Combination of Thiazolidinediones with Melatonin in Dexamethasone-induced Insulin Resistance in Mice. Indian J Pharm Sci. 2011 Nov;73(6):601-7.
• Gandhi GR, Stalin A, Balakrishna K, Ignacimuthu S, Paulraj MG, Vishal R. Insulin sensitization via partial agonism of PPARγ and glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway by embelin in type 2 diabetic rats. Biochim Biophys Acta. 2012 Oct 24. doi:pii: S0304-4165(12)00302-9.
• Hao C, Cheng X, Xia H, Ma X. The endocrine disruptor mono-(2-ethylhexyl) phthalate promotes adipocyte differentiation and induces obesity in mice. Bioscience Reports. 2012; 32:619–629.
• Kaye WH, Berrettini W, Gwirtsman H, George DT. Altered cerebrospinal fluid neuropeptide Y and peptide YY immunoreactivity in anorexia and bulimia nervosa. Arch Gen Psychiatry. 1990 Jun;47(6):548-56.
• Li N, Liu T, Zhou L, He J, Ye L. Di-(2-ethylhcxyl) phthalate reduces progesterone levels and induces apoptosis of ovarian granulosa cell in adult female ICR mice. Environ Toxicol Pharmacol. 2012 Sep 1
• Li XW, Liang Y, Su Y, Deng H, Li XH, Guo J, Lian QQ, Ge RS. Adverse effects of di-(2-ethylhexyl) phthalate on Leydig cell regeneration in the adult rat testis. Toxicol Lett. 2012 Oct 11. 
• Martine B, Marie-Jeanne T, Cendrine D, Fabrice A, Marc C. Assessment of Adult Human Exposure to Phthalate Esters in the Urban Centre of Paris (France). Bull Environ Contam Toxicol. 2012 Oct 23.
• Magistrelli A, Chezem JC. Effect of ground cinnamon on postprandial blood glucose concentration in normal-weight and obese adults. J Acad Nutr Diet. 2012 Nov;112(11):1806-9. 
• Monfort N, Ventura R, Balcells G, Segura J. Determination of five di-(2-ethylhexyl)phthalate metabolites in urine by UPLC-MS/MS, markers of blood transfusion misuse in sports. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Sep 21. doi:pii: S1570-0232(12)00560-0.
• Rajesh P, Sathish S, Srinivasan C, Selvaraj J, Balasubramanian K. Exposure to diethyl hexyl phthalate (DEHP) to adult male rat is associated with insulin resistance in adipose tisssue: Protective role of antioxidant vitamins (C & E). J Cell Biochem. 2012 Sep 18.
• Ruohonen ST, Vähätalo LH, Savontaus E. Diet-induced obesity in mice overexpressing neuropeptide y in noradrenergic neurons. Int J Pept. 2012;2012:452524. doi: 10.1155/2012/452524. Epub 2012 Oct 18. 
• Simha V, Mahmood M, Ansari M, Spellman CW, Shah P. Effect of Vitamin D Replacement on Insulin Sensitivity in Subjects With Vitamin D Deficiency. J Investig Med. 2012 Oct 29.
• Wu P, Yang D, Zhang L, Shen X, Pan X, Wang L, Zhang J, Tan Y, Feng L, Ying Y. Simultaneous determination of 17 phthalate esters in edible vegetable oils by GC-MS with silica/PSA-mixed solid-phase extraction. J Sep Sci. 2012 Nov;35(21):2932-9.
• Xu Y, Liu Z, Park J, Clausen PA, Benning JL, Little JC. Measuring and Predicting the Emission Rate of Phthalate Plasticizer from Vinyl Flooring in a Specially-Designed Chamber. Environ Sci Technol. 2012 Oct 23.

Trimethylglycine aka Betaine Sets the Anabolic Stage for Increased Muscle Growth: Higher IGF-1 & Lower Cortisol - Statistically Significant, but Physiologically (Ir-)Relevant?

Figure 1: Betaine content (in mg/100g) in some common food items (data based on Craig. 2004). Makes me wonder if Popeye ate wheat germ as well or whether he was celiac and stuck to spinach to get his daily dose of pro-anabolic betaine?

Trimethylglycine (TMG) the sciency name for a molecule most of you probably know by the name "betaine" is actually no longer a new-comer to the supplement scene (please note that this is not betaine HCL(!), the stuff you will find in digestive aids). I have already written about its purported ergogenic effects several times and there are actually quite a handful of proprietary blends with mostly undisclosed, but judged based on the total serving size and amount of ingredients in them, hilariously underdosed amounts of the zwitterionic compound and a methyl derivative of glycine in it on the market.

Friends and followers of the SuppVersity will also be aware that betaine is also found naturally in a variety of food sources such as sugar beets, wheat bran, spinach, shrimp, and many others (see figure 1) and that it can be synthesized from choline in your body, when dietary intake exceeds your current metabolic demands (Ueland 2011).

What you probably don't know, however, is...

... that the latest study from the Human Performance Laboratory at the Department of Kinesiology,
of the University of Connecticut, shows that "betaine (vs. placebo) supplementation enhanced
both the anabolic endocrine profile and the corresponding anabolic signaling environment, suggesting increased protein synthesis" (Apicella. 2012).

Figure 2: Effects of a standardized full-body workout (see text for details) on growth hormone (µmol/L), IGF-1 (nmol/L) and cortisol (µmol/L) levels in 12 recreationally trained young men after 2 weeks supplementation with betaine (2x 1.5g/day) or placebo (data based on Apicella. 2012)

And if we temporarily lose sight of the fact that the devil is in the detail, the data in figure 2 certainly looks as if you should run to the next best store with fishing equipment and get yourself a huge pot of trimethylglycine, of which the shop assistant will probably tell you that "This is a good choice Sir! The carps love the sweet taste!" But I am digressing, so let's get back to what's really sweet, namely ...

• stable growth hormone levels (vs. -17% in the placebo group)
• an 18% increase in IGF-1 (vs. a -10% decrease in the placebo group), and
• a -5% reduction in cortisol (vs. a 6% increase in the placebo group)

- they all sound pretty sweet, as well. Especially in conjunction with the stable p-AKT levels the scientists observed, when they analyzed the tissue samples. Unfortunately (but earnestly), Apicella et al.'s conclusion, still contains one word, too many people who read the abstract, are probably going to ignore:

"Betaine (vs. placebo) supplementation enhanced both the anabolic endocrine profile and the corresponding anabolic signaling environment, suggesting increased protein synthesis." (Apicella. 2012; my emphases)

Which one is it? A tip: It is none of the words I emphasized in bold. After all, that would make it way too easy for you... ha? Yeah! I see you've done your homework. Suggest(-ing) is in fact the most important word in this and the conclusions of many objectively written scientific papers.

So, the study "suggests increased protein synthesis"...

... and this means it does not even prove that the protein synthetic response in the immediate vicinity of the workout was increased in response to the to the two weeks of BID (=twice daily) supplementation with 1.25 g of betaine. In other words, all we know is that the funky gene essays for p-AKT and serum tests for growth hormone, IGF-1 and cortisol "suggest" that it could be the case, if we assume that marginally higher IGF-1 levels, stable growth hormone levels and lower cortisol levels (rememeber we are not talking about increasing any of them into the supraphysiological range, here) would

1. result in increased protein synthesis and ultimately
2. greater lean mass accrual,

because, if we are honest, no one is interested in a number you can measure, when you infuse a marked amino acid into the circulation and check how much of it goes into the muscle, but doesn't come out of it, afterwards.

Something to remember: What I find remarkable - and this is by no means something you will see only in this study, neither is it "fraud" or whatever, is how by simply adding a break into the Y-axes of the graph and thus omitting the lower 80% of the bar Apicella et al. give the impression that the effects on IGF-1 were more than twice as large than they actually are... remember that, because you will encounter that in many studies, and reproductions of graphs from scientific papers, especially if they are used to market certain products.

What we want is to get bigger, stronger and all that faster, and whether the 12 recreationally trained men (age 19.7±1.2 years; lean body mass 65.2±8.8 kg; fat mass 15.6±8.5 kg; body fat percentage 18.7±7.0 %; BMI 28.2±4.0) would have gained even a single inch of muscle more on whatever body part, if they had performed a real workout instead of the funky "AES" (=acute exercise session) that consisted of

• 10x maximal vertical jumps without pause, 
• 1x 10-s isometric squat, 
• 1x 10-s isometric bench press on a smith machine, and
• 1x 10 min of repeated box lifting (RBL)

is more or less guesswork. In view of the previously discussed results from the researchers at the McMasters University in Ontario (see "Anabolic Workouts Revisited"; a brief reminder. the systemic hormonal response to an acute exercise bout is irrelevant, if anything higher cortisol levels correlate with greater increases in lean muscle mass) and the "statistically significant", but physiologically probably irrelevant increases and decreases in IGF-1 and cortisol at least highly questionably (please take a look at the additional information in the red box to the right, as well).

... but there are still way too many "ifs" in here!

The sheer number of "suggests", "is touted", "is likely", "also possible", "as we presume", etc. is honest and speaks in favor of the quality of the study, but against the reliability of the statement that followeed the initially cited "suggests" in the conclusion. Moreover, the researchers freely admit that...

"[...] the mechanisms by which betaine may have affected the hormones measured in this study are still unclear and require further research" (Apicella. 2012)

so that even the fact that betaine is an organic osmolyte and could thus help stabilize skeletal muscle protein, promote / maintain optimal hydration and protect against

• hypertonic stress (Alfier. 2006), 
• urea-induced inactivation of muscle myosin ATPases (Ortiz-Costa. 2002), and 
• structural changes in myosin due to urea accumulation (Ortiz-Costa. 2002)

does lend credibility to the hypothesis that betaine could help you build muscle, but it does not prove it. In conjunction with the results of previous trials, like...

Betaine does not increase nitric oxide While I have no idea why everyone is so keen about those nitrate supplements, one thing is for sure: Betaine has no effects on serum nitrate or nitrite levels. The vasolidation effect of beet roots / beet root juice is simply a result of the nitrate that's in there along with the betaine (+ the sugar and the insulin spike, which will also trigger an increased NO-response).

At least this is what a study by Bloomer et al. which consisted of three independent experiments using 1.25 and 5.00g B, acutely, 2.5g per day for 14 days, chronically, and a combination of chronic (6g for 7 days) + acute (6g acutely before the test) betaine supplementation (Bloomer. 2011).

• Hoffman. 2009 - 2.5/day for 14 days; jump squat, squat, bench press; "Two-weeks of betaine supplementation in active, college males appeared to improve muscle endurance of the squat exercise, and increase the quality of repetitions performed." 
• Lee. 2010 - 2x 1.25g/day for 14 days; bench squat and jump tests; "[Betaine] supplementation increased power, force and maintenance of these measures in selected performance measures, and these were more apparent in the smaller upper-body muscle groups."
• Hoffman. 2011 -  2.5g/day for 15 days; 5 training + testing sessions; "15 days of betaine supplementation did not increase peak CON or ECC force outputs during an isokinetic chest press but did appear to reduce subjective measures of fatigue to the exercise protocol"
• Trepanoswki. 2011 - 2.5g/day for 14 days; resistance training; "moderate increase in total repetitions and volume load in the bench press exercise, without favorably impacting other performance measures."
• del Favero. 2012 - 2g/day for 10 days; muscle strength and power, muscle PCr content, and body composition, three "familiarization sessions" preparing the participants only to perform the tests; "we showed that betaine supplementation combined or not with creatine supplementation does not affect strength and power performance in untrained subjects."
• Pryor. 2012 - 2.5g/day for 7 days; cycling performance; "betaine ingestion significantly increased average peak power (3.4%; p = 0.026), maximum peak power max (3.8%; p = 0.007), average mean power (3.3%; p = 0.034), and maximum mean power (3.5%; p = 0.011) in recreationally active males and females"

... there is still room for long-term improvements in muscle gains as a consequence of the general ergogenic effects of betaine (every rep more counts!), but it appears unlikely that the "anabolic" hormonal milieu observed in the study at hand are the fundamental cause of the latter.

Reminder: If you want to try it, you got to get yourself "trimethylglycine" (TMG) not "betaine HCL" and you better don't buy it in capped form if you don't have lots of money to burn. I just checked with the next best bulk supplier - they got 1kg for $33.50. Even if you double dose, i.e. take 2x 2.5g per day (most studies mixed it with Gatorade) this will last you for 200days(!), which is probably the time it will take until you can actually see and not just measure any potential, possible, suggested, etc. anabolic effects ;-)

References:

• Alfieri RR, Bonelli MA, Cavazzoni A et al (2006) Creatine as a compatible osmolyte in muscle cells exposed to hypertonic stress. J Physiol 576:391–401.
• Bloomer RJ, Farney TM, Trepanowski JF, McCarthy CG, Canale RE. Effect of betaine supplementation on plasma nitrate/nitrite in exercise-trained men. J Int Soc Sports Nutr. 2011 Mar 18;8:5.
• Craig SA. Betaine in human nutrition. Am J Clin Nutr. 2004; 80: 539–549.
• del Favero S, Roschel H, Artioli G, Ugrinowitsch C, Tricoli V, Costa A, Barroso R, Negrelli AL, Otaduy MC, da Costa Leite C, Lancha-Junior AH, Gualano B. Creatine but not betaine supplementation increases muscle phosphorylcreatine content and strength performance. Amino Acids. 2012 Jun;42(6):2299-305.
• Hoffman JR, Ratamess NA, Kang J, Rashti SL, Faigenbaum AD. Effect of betaine supplementation on power performance and fatigue. J Int Soc Sports Nutr. 2009 Feb 27;6:7.
• Hoffman JR, Ratamess NA, Kang J, Gonzalez AM, Beller NA, Craig SA. Effect of 15 days of betaine ingestion on concentric and eccentric force outputs during isokinetic exercise. J Strength Cond Res. 2011 Aug;25(8):2235-41.
• Lee EC, Maresh CM, Kraemer WJ, Yamamoto LM, Hatfield DL, Bailey BL, Armstrong LE, Volek JS, McDermott BP, Craig SA. Ergogenic effects of betaine supplementation on strength and power performance. J Int Soc Sports Nutr. 2010 Jul 19;7:27. 
• Ortiz-Costa S, Sorenson MM, Sola-Penna M (2002) Counteracting effects of urea and methylamines in function and structure of skeletal muscle myosin. Arch Biochem Biophys 408:272–278
• Pryor JL, Craig SA, Swensen T. Effect of betaine supplementation on cycling sprint performance. J Int Soc Sports Nutr. 2012 Apr 3;9(1):12.
• Trepanowski JF, Farney TM, McCarthy CG, Schilling BK, Craig SA, Bloomer RJ. The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men. J Strength Cond Res. 2011 Dec;25(12):3461-71.
• Ueland PM. Choline and betaine in health and disease. J Inherit Metab Dis. 2011;34:3–15.

Speed Up Your Regeneration and Propel Your Gains by Taking a HOT Bath Bath 2-Days Before Arduous Workouts

Image 1: Are women tougher than men, because bathe more often? If you define toughness by your muscles resistance to eccentric exercise damage, the answer could be "YES!"

If you listened to Brooks, Carl and me on Super Human Radio, yesterday (download the podcast), you may remember me stating that 48h appears to be a good rule of thumb, as far as the rest periods between workouts for individual body parts are concerned (this assumes that you are young, healthy, reasonably conditioned and lift heavy). A recently published paper by Chad D. Touchberry  does now suggest that there may be another 48h window before your workout (Touchberry. 2012). One you would use a priori to improve your recovery a posteriori - preconditioning in a hot bath for 20 min at 41°C, 48h before a hard workout or competition!

Eccentric treadmill running = maximum muscle damage

At least in a rodent model, those 20 min of heat exposure in 41°C warm water lead to statistically highly significant decreases in exercise induced muscle damage, improved and accelerated the recovery process and, contrary to what could be assumed based on previous research on the expression of heat proteins (Frier. 2007), did not hamper, but promote muscle gains in response to an exercise protocol consisting that consisted of running at 18m/min down a -16% grade for 5 min. This protocol has been used as a model for injurious exercise repeatedly in the past and constitutes one of the standard tests in rodent, but also in human studies (e.g. Pumpa. 2011).

Figure 1: Creatine kinase (CK) activity and immune cell infiltration after eccentric exercise with (EE+HS) and without (EE) preconditioning via hot bath 48h before (data calculated based on Touchberry. 2012)

As the data in figure 1 goes to show, the hot bath (EE+HS) had significant ameliorative effects on both the muscle damage (indicated by CK and the black sections in the H&E-stained soleus muscle cross-sections in figure 1, right), of which the researchers state that, despite the fact that "the mechanism by which heat shock protects skeletal muscle from damage is currently unknown", the protection of skeletal muscle against damage in mice overexpresssing HSP70 (McArdle. 2004a) as well as the differential HSP72 elevation in the HS group 2h and 48 h following exercise collectively

[...] suggest that HSP72 or another heat sensitive protein (i.e.,alphaB-crystallin) may play a role in mediating cytoprotection of skeletal muscle cells.

Moreover, Touchberry et al. explain the existing discrepancies between their own results and previous results by Mc.Ardle et al. (Mc. Ardle. 2004b), who did not find reduced muscle damage after pre-treatment with hsp-inducing concentric exercise 10h prior to the (in my humble opinion questionable) in-vitro application of eccentric strain to skeletal muscle tissue, with the "greater time for HSP accumulation prior to the exercise stressor" in their (48h) vs. the Mc.Ardle study (10h), which is obviously yet another indicator that rest is one of the most under-appreciated determiners of workout efficiency (cf. my words on SHR ;-)

Regeneration is one thing, but are muscle gains another?

Now, I am well aware that one of the main reasons regeneration isn't sexy, is that it does not trigger the phosphorylation of Akt, m-TOR and all the rest of the sciency terms with which laymen are bombarded by the supplement industry these days.

Figure 2: Total protein, new myosin heavy chain (MHCNEO) content and p-Akt expression in soleus muscle 2h and 48h after the eccentric exercise bout (data calculated based on Touchberry. 2012)

The study at hand does even show that heat pre-treatment will actually reduce, not promote the phosphorylation of AKT 48h after the exercise bout (cf. figure 2). If you do yet take into account that the total protein concentration and MHCneo (novel myosin-heavy-chain motor proteins) content in the soleus muscle of the rodents was increased profoundly, I guess you will have to agree that it is unlikely that less damage, a faster regeneration, and as a consequence less need for protein to be recruited via p-AKT only to repair the damage is going to propel, not diminish your gains!

Practical implications & open questions

Once again, the obvious message of this study is: Not he who trains the most, but he who regenerates and rebuilds the best, gains the most! And adequate rest aside, preconditioning in a hot (not a "cold thermogenic" bath ;-) can help dampen the exercise induced damage and accelerate your recovery.

Note: In February 2012, Bayley et al. published a paper that shows that the application of passive heat in form of a 42°C hot water bath for 40min immediately prior to a bout of HIT leg extensor exercises reduced the time to fatigue in seven healthy men by a whopping -36%  (Bayley. 2012). Impatience, or rather the unwillingness to grant your body the time it needs to recover is thus detrimental even if the stressor is "just" a hot bath!

Whether the same would be true if you train today and do the hot water immersion immediately, 2h, 10h or 12h post and thus 48h, 46h, 38h or 36h before your next workout is yet about as questionable, as whether or not similar effects could be elicited by switching back and forth between light and heavy days every 48h.  Both may appear likely, but aside form the fact that the optimal timing or workout intensity will still have to be elucidated, are still in the state of an interesting research hypothesis, not more, but also not less.

Update - Suggested reading: Since there have been questions pertaining to the usefulness of hydrotherapy post-workout, i.e. as a means of "classic" re- and not "precovery", I thought I rather refer you directly to my buddy Sean's E-book on the issue. Here is a snippet from the book

Image 2: Don't miss Sean's free e-book on classic hydrotherapy

Quick Hit Summary Water therapy is a common modality to enhance muscle recovery post workout. Sitting in chest high thermoneutral water for 20-30 minutes may accelerate waste removal while increasing blood flow to working muscles. Cold, hot and contrast water temps are also commonly used to assist recovery. The goal of cold water therapy is to reduce inflammation whereas hot water purportedly increases muscle blood flow. Contrast water therapy involves alternating between hot and cold water baths to induce a vaso-pumping effect. Current evidence does not support the theory behind these latter 2 therapies simply because the heat (from the water) is incapable of penetrating more than a couple centimeters into the skin. Thus, there is no stimulus to increase muscle blood flow

You can get this e-book alongside two other books for free if you register for Sean's newsletter, which is, take my word on it (!), not a weekly advertisement piece!
 
References:

1. Bailey SJ, Wilkerson DP, Fulford J, Jones AM. Influence of passive lower-body heating on muscle metabolic perturbation and high-intensity exercise tolerance in humans. Eur J Appl Physiol. 2012 Feb 10.
2. Briese E. Normal body temperature of rats: the setpoint controversy. Neurosci Biobehav Rev. 1998 May;22(3):427-36. Review. 
3. Frier BC, Locke M. Heat stress inhibits skeletal muscle hypertrophy. Cell Stress Chaperones. 2007 Summer;12(2):132-41. 
4. McArdle A, Dillmann WH, Mestril R, Faulkner JA, Jackson MJ. Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age-related muscle dysfunction. FASEB J. 2004a Feb;18(2):355-7.
5. McArdle F, Spiers S, Aldemir H, Vasilaki A, Beaver A, Iwanejko L, McArdle A, Jackson MJ. Preconditioning of skeletal muscle against contraction-induced damage: the role of adaptations to oxidants in mice. J Physiol. 2004b Nov 15;561(Pt 1):233-44. Epub 2004 Aug 26.
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45x More Testosterone Yet Identical Increase in Protein Synthesis: MPS Response to Exercise + 25g Whey in Men vs. Women Challenges Common Wisdom About Androgens

Image 1: Is it not testosterone that makes the difference?

It is an open secret that women are having a much harder time building muscle than men, and it is another instance of (bro-)scientific wisdom that the obvious lack of testosterone in female strength athletes would be the underlying reason. Right from Stuart M. Phillips lab at the Department of Kinesiology of the McMaster University in Hamilton, Ontario, Canada, comes a new study (West. 2012) which puts yet another questionmark behind the anabolic prowess of testosterone (if you still believe that a transient increase in testosterone will help you build muscle, I suggest you read up on "The Big T" in the Intermittent Thoughts on Building Muscle).

Women are different, but it's not about protein synthesis

In the recently conducted trial Daniel W.D. West, who has also been the lead author of the "Never Sip Your Whey" study, I covered back in November 2011, undertook another attempt to identify the intricate endo- and paracrine mechanisms of skeletal muscle hypertrophy and its sex-specific variability. To this ends, West et al. recruited 5 male and 5 female subjects, who "who were habitually engaging in two to five sessions of physical activity per week including", yet did not train legs more than twice a week.

Image 1: In this case, testosterone took a backseat, as well. With synthol, protein synthesis is yet unnecessary anyway.

Note: The selection of advanced trainees as study participants is the first huge plus of this study. After all, we all know that the exercise induced hypertrophy response diminishes with training and those of you who read the whole Intermittent Thoughts on Building Muscle series will also be aware that the protein synthetic response is limited by the maximal domain size. Further growth thusly requires restructuring / the recruitment of satellite cells and installment of new myonuclei (cf. "Growing Beyond Temporary Physiological Limits"), a time-consuming and complex process which is probably one of the underlying reason for the "growth difference" between beginners and advanced strength athletes.

On the day of the experiment, the study participants, who had consumed a standardized diet containing 15% fat, 30% protein and 55% carbohydrates (the macronutrient ratio was adapted to their habitual diets) on the previous day, reported to the lab at 6am. After the infusion of the tracer that is necessary to evaluate the protein flux and an initial biopsy, all subjects performed a bout of  intense, high-volume lower body exercise consisting of

• 5 sets of 10 repetitions of leg press at ~90% of their individual 10RM, and
• 3 super-sets of 12 repetitions of leg extension/leg curl at ~90% of 12 RM

The rest intervals between the sets were 60s, so that the whole workout should not have lasted longer than max. 20min. Directly thereafter, the subjects consumed the "obligatory" (for Phillips lab this has in fact become obligatory ;-) 25g of whey protein from the usual New Zelandian source, Phillips et al. used in all their previous study (as ridiculous as this may sound but this is a nice means of standardization ;-) and rested in a supine position for the rest of the trial. Biopsies were taken and the subjects who were sent home with a launch packet consisting of their standardized meals had to report back to the lab on the following morning for another three biopsies 24h, 26h and 28h after the test workout (the subjects remained fasted and received another 25g of whey 26h post, i.e. before the last four blood samples were drawn and the last biopsy at 28h post was performed).

Figure 1: Serum testosterone levels (in nM) and myofibrillar fractional protein synthesis rate (in %/h) before and after the resistance workout, as well as on the morning and at noon of the 2nd day (data adapted from West. 2012)

As the data in figure 1 shows, the (expected) huge difference in both basal as well as exercise induced increases in circulating androgen levels (45-fold in men vs. women) had no (not even a statistically non-significant) beneficial impact on the exercise induced increase in protein synthesis in the 28h window of opportunity (cf. "Opening the 'Anabolic Barn Door' with the Key of Science").

Akt Ser473 phosphorylation increased at 1h ( P < 0.001, main effect for time) and to a greater extent in men (sex × time interaction, P = 0.018). Phosphorylation of mTOR Ser2448 was increased at 1, 3 and 5 h (P < 0.001; Figure 4B); there was a main effect for sex (men > women, P = 0.003). Phosphorylation of mTOR Ser2448 was elevated similarly between sexes after next-day protein feeding, approximately 26 h after the exercise bout (sex  × time interaction,  P = 0.49; main effect for time, 28 > 26 h,  P = 0.006).  Phosphorylation of p70S6K1 Thr389 increased at 1, 3 and 5 h (all  P < 0.001; sex × tim e interaction,  P = 0.13) and there was a significant interaction with next-day feeding (28 > 26 h in women only, sex × time interaction,  P = 0.016; data not shown). Androgen receptor content was greater overall in men (P = 0.049) but there was no significant interaction ( P = 0.47).  

The greater increase in mTOR and Akt (both hitherto regarded as the "gas pedals" of the skeletal muscle protein synthetic machinery) are not only less pronounced, than one would expect if there was a direct interaction with testosterone levels, they also lack real world significance. After all, the area under the myofibrillar protein synthesis curve (a measure for the total protein synthetic response to exercise) was identical in the 1-5h period right after the exercise and - although West et al. did not include the respective data in their article - I would suspect that the data from the subsequent day (cf. figure 1, right) would even suggest that it must have been slightly greater in the female participants.

Testosterone useless and mTOR and Akt unreliable indicators at best?

Now, which conclusions shall be drawn from these results? Is testosterone useless? Does it not contribute to the overall greater muscle mass in men compared to women? It stands to reason that this conclusion would be about as flawed as the notion that testosterone alone would suffice to build muscle. Rather than its "inefficiency" in building muscle, this study only shows that its importance in relation to the exercise-induced increase in protein synthesis is probably way overrated.

A similar point could be made for mTOR and Akt, as well, though. Or as West et al. put it in their discussion of the results and the respective implications for future studies:

In light of this disconnect, it is worth recognizing that the phosphorylation of signalling proteins is a temporal snapshot of the propagated signal for translation initiation. It is also unclear if there is a minimum threshold signal required to initiate and completely activate or  ‘turn on’ translation. If  there is such a threshold then it seems plausible that greater phosphorylation above such a  threshold would be unlikely to further amplify the signal/lead to increased rates of translation.

For a physicist or anybody who knows a thing about "energy levels" the existence of "threshold" levels in processes taking place at a molecular level should not come as a surprise.

I suspect, we are still missing the boat with our focus on protein synthesis alone

Another question, I have been hinting at in many of my previous blogposts on the insightful studies from Stuart Phillips lab at the McMaster University, is yet whether or not the acute increase in protein synthesis (alone) is actually an acceptable predictor of skeletal muscle hypertrophy, a process which, as I have explained in detail in the Intermittent Thoughts on Building Muscle is only partly mediated by the simple accrual of amino acid chains (=proteins) within existing myofibrillar domains.

Figure 2: Graphical illustration of the processes and their respective triggers which contribute to the exercise induced increase in skeletal muscle mass (click here for detailed elaborations).

If you take another look at the complex network of endo- and paracrine signalling cascades and the number of factors which contribute to a process that is generally reffered to as "skeletal muscle hypertrophy" (cf. figure 2) and is, at least in my mind, falsely reduced to the influx of amino acids into the muscle, it should be clear that testosterone does play a central role in the actual exercise induced growth response. That the latter is less pronounced than bro-science would have it (esp. when we are talking about physiological levels, cf. "Quantifying the Big T") and that testosterone itself and its metabolites, DHT and estrogen are probably of greater importance in the "restructuring" process, which in turn facilitate the accrual of even more protein within the muscle, does after all not imply that the huge differences in androgen levels are not the reason for the differential hypertrophy response in men and women - and I guess, I don't have to tell you that you just have to take a glimpse at the female IFBB (International Federation of Bodybuilding and Fitness) competitors to know that androgens can make a difference ;-)