Coffee - 3 Cups Per Day Keep Insulin at Bay: You Better Start Today if You Want to Retain Your Insulin Sensitivity, and Stay Cancer & CVD Free Beyond Your Own Centennial!

I am not entirely sure how often I have used the sentence "consistency is key", here at the SuppVersity, but there is no way I don't reiterate it in the context of the never-ending debate over the pros and cons of habitual coffee drinking, once again. While much of the experimental evidence would suggest that coffee, or to be precise, caffeine the major methylxanthine in the brown brew is a bad sympathetic nervous system activator that stresses your body and will deteriorate your glucose and fat metabolism, the majority of the epidemiological evidence points into the exact opposite direction.

A paper that's going to be published in the next issue of AGE the Journal of the American Aging Association could however help not just to bridge the widening gap between the ever-increasing number of epidemiological studies showing between moderate caffeine consumption and metabolic, cardiovascular, neurological, and cellular health (see list at the end of this post) and the conflicting evidence from experiments that investigate the acute response to caffeine ingestion in both caffeine-naive individuals and habitual caffeine consumers.

Consistent caffeine consumption is the key to "chronic health" ;-)

I am pretty sure this study won't close the lit on the never-ending debate about the pros and cons of caffeine consumption - mostly because it's a rodent study, but also in view of the fact that there is no definite border between "habitual consumption" and "chronic abuse", when it comes to a substance the stimulating side-effects of which can keep you functioning (and training!), when your body would otherwise long have called a halt.

Against that background it is important to realize that the rodents in the study at hand were leading a happy, more or less stress-free life. They consumed what you would consider a "healthy" diet for a rodent and had free access to a wheel, the average male and female Wistar who has neither television, nor Internet or a PlayStation in his or her cage, will actually make good use of.

Figure 1: Body weight (in g), visceral fat weight (in g/kg body weight) and skeletal muscle glucose transporter 4 expression (GLUT4 activity relative to glucose breakdown) over the course of 24 months with or without the provision of the human equivalent of caffeine of roughly 3 cups of coffee in the drinking water (data based on Guarino. 2013)

Accordingly, you should not wonder, let alone be disappointed that there is no magical "fat destruction" such as the one we've seen about a months ago in the CLA-study (see "CLA Destroys Body Fat: Effect Borders Pathological Lipodystrophy!"). Remember: Consistency is key! And some of the benefits of today's coffee may not show before you are in your late 70s... but let's get back to the results data from figure 1 and their implications for your current and future health:

Additional observations:

• the decrease in visceral fat mass was not due exclusively to increased lipolysis
• the increase in insulin sensitivity induced by caffeine was not attributable to weight loss, increased NO production, caffeine-mediated antioxidant effects, decreased cortisol levels, or decreased SNS activity
• caffeine intake did not modify blood pressure, endogenous NO production, or antioxidant capacity in aged animals 
• caffeine administration restored Glut4 expression in the elderly group, but it was not able to increase Glut4 expression above amaximal level in the 12Mgroup

• the rodents were kept on a normal diet, a healthy body weight is thus only a sign of overall metabolic health (remember: skinnier does not equal healthier!),
• the 42% lower visceral fat levels in what would be middle aged rodents (12 months) is one of the most significant predictors of healthy aging (optimal brain and metabolic health + no cancer), and
• the maintenance of skeletal muscle GLUT4 expression is of fundamental importance to ward of those increasingly common "age-related" diseases of which we already know that they are at least precipitated by insulin resistance and high glucose levels, such as Alzheimer's and "regular" dementia (e.g. Rönnemaa. 2008; Accardi. 2013; Williamson. 2013)

Against the background of the previously mentioned conflict between experimental (caffeine induces stress and thwarts glucose and fatty acid metabolism) and epidemiological (caffeine correlates with metabolic health) evidence it is also important to mention that these beneficial effects were not negated by the dreaded stress-induced increases in non-esterified fatty acids (NEFA), which is the most commonly heard argument of the opponents of caffeine / coffee consumption. On the contrary, the ...

"[...] increase in insulin sensitivity induced by caffeine was not attributable to weight loss, increased NO production, caffeine-mediated antioxidant effects, decreased cortisol levels, or decreased SNS activity [so that caffeine effectively] restored [otherwise elevated] circulating NEFA in aged animals to values observed in young 3 M control rats." (Guarino. 2013)

In the absence of increased NEFA levels, an increased sympathetic tone (=higher catecholamine and cortisol levels) and in the presence of optimal GLUT-4 expression and low visceral fat levels in the young and middle aged rodents, there is actually no reason why we would see any of the putative negative effects on glucose metabolism of about which you will probably have read and heard numerous times in the laypress.

Figure 2: Glucose clearance during ITT (in % glucose/min), basal plasma and insulin levels (in mM) over the course of 24 months (basically one rodent lifespan) with or without the provision of the human equivalent of caffeine of roughly 3 cups of coffee in the drinking water (data based on Guarino. 2013)

And, as a matter of fact, the data in figure 2 does confirm just that: The chronic administration of caffeine at a dosage of which the researchers state, that it will generate plasma caffeine levels "comparable to those in moderate to low consumers of caffeinated beverages" (Guarino. 2013), i.e. people who drink about 3 cups of the delicious brew per day (300-500mg caffeine; Gasio. 2002), is probably one of the most delicious and convenient ways to ward off age-related declines in glucose tolerance... this does yet not mean that drinking coffee (let alone Coke or energy drinks) could make up for a sedentary lifestyle and (ab-)using caffeine pills and stims to keep functioning will probably even have the opposite effects.

Glucose management figures everywhere and so does coffee!

Did you know that the data from a recently published trial suggests that "14-day caffeine supplementation [at 5mg/kg body weight] can probably decrease exercise-induced inflammatory response (CRP elevation and Leukocytosis) following 30 min downhill running in male non-athletes" (Jafari. 2013)? That's actually pretty intruiging, as it shows that the already mentioned differences between the chronic and acute effects of trimethylxanthie aka caffeine are not restricted to its effect on overall and metabolic health, especially as, caffeine has hitherto not exactly been known as a an ergogenic the effects of which build up over time... in fact, rather the opposite is usually assumed, although the evidence for the decline of the ergogenic (not the stimulant!) effects of caffeine are still inconclusive.

In view of the major role of glucose management in all sorts of the metabolic, endocrine and neurcrine diseases, it is thus no wonder that study after study finds beneficial effects of moderate caffeine consumption on...

• risk of heart failure (Mostofsky. 2013)
• perceptibility to arrhythmia (Klatsky. 2011)
• venous thromboembolism (Enga. 2011)
• general cardiovascular disease (Bøhn. 2013)
• dementia & Parkison's (Cao. 2013; Campdelacreu. 2013)
• diabesity (Hjellvik. 2011; Matsuura. 2013)
• pancreatic cancer (Dong. 2011), as well as 
• bladder, breast, buccal and pharyngeal cancer (Yu. 2011) 
• colorectal, endometrial, esophageal cancer (Yu. 2011) 
• hepatocellular, leukemic, and prostate cancers (Yu. 2011)

And though, I could certainly extend this list by a dozen or so references for each item and half a dozen additional items, I guess I'd rather end today's blogpost on the note that coffee (and tea) contain way more than just caffeine. I would therefore suggest you don't rely on caffeine alone, but rather grab yourself an old-fashioned black cup of coffee (ad some creme if you can't stand it black, or coconut oil, if you like that better) and the time it takes to savor the aroma and taste of it... I can guarantee: That will exponentiation its health effects and will allow you to catch up on the 5 minutes you may have lost in no time.

References:

• Accardi G, Caruso C, Colonna-Romano G, Camarda C, Monastero R, Candore G. Can Alzheimer disease be a form of type 3 diabetes? Rejuvenation Res. 2013 Apr;15(2):217-21.
• Bøhn SK, Ward NC, Hodgson JM, Croft KD. Effects of tea and coffee on cardiovascular disease risk. Food Funct. 2013 Jun;3(6):575-91.
• Campdelacreu J. Parkinson disease and Alzheimer disease: environmental risk factors. Neurologia. 2013 Jun 13.
• Cao C, Loewenstein DA, Lin X, Zhang C, Wang L, Duara R, Wu Y, Giannini A, Bai G, Cai J, Greig M, Schofield E, Ashok R, Small B, Potter H, Arendash GW. High Blood caffeine levels in MCI linked to lack of progression to dementia. J Alzheimers Dis. 2013;30(3):559-72.
• Dong J, Zou J, Yu XF. Coffee drinking and pancreatic cancer risk: a meta-analysis of cohort studies. World J Gastroenterol. 2011 Mar 7;17(9):1204-10.
• Enga KF, Braekkan SK, Hansen-Krone IJ, Wilsgaard T, Hansen JB. Coffee consumption and the risk of venous thromboembolism: the Tromsø study. J Thromb Haemost. 2011 Jul;9(7):1334-9.
• Gasior M, Jaszyna M,Munzar P,Witkin JM, Goldberg SR. Caffeine potentiates the discriminative-stimulus effects of nicotine in rats. Psychopharmacology (Berl). 2002; 162:385–395 
• Guarino MP, Ribeiro MJ, Sacramento JF, Conde SV. Chronic caffeine intake reverses age-induced insulin resistance in the rat: effect on skeletal muscle Glut4 transporters and AMPK activity. Age (Dordr). 2013 Sep 14.
• Hjellvik V, Tverdal A, Strøm H. Boiled coffee intake and subsequent risk for type 2 diabetes. Epidemiology. 2011 May;22(3):418-21.
• Jafari A, Kherad N, Melekirad AA. Effect of short-term caffeine supplementation on downhill running induced inflammatory response in non-athletes. Journal of Cell. Winter 2013; 2(4):377-385
• Klatsky AL, Hasan AS, Armstrong MA, Udaltsova N, Morton C. Coffee, caffeine, and risk of hospitalization for arrhythmias. Perm J. 2011 Summer;15(3):19-25.
• Matsuura H, Mure K, Nishio N, Kitano N, Nagai N, Takeshita T. Relationship between coffee consumption and prevalence of metabolic syndrome among Japanese civil servants. J Epidemiol. 2013;22(2):160-6.
• Mostofsky E, Rice MS, Levitan EB, Mittleman MA. Habitual coffee consumption and risk of heart failure: a dose-response meta-analysis. Circ Heart Fail. 2013 Jul 1;5(4):401-5. Epub 2013 Jun 26.
• Nature.com Reviews. Heart failure: Moderate coffee consumption linked with reduced risk of HF. Nat Rev Cardiol. 2013 Jul 17;9(9):492.
• Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, Degerman-Gunnarsson M, Berne C, Lannfelt L, Kilander L. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology. 2008 Sep 30;71(14):1065-71.
• Williamson R, McNeilly A, Sutherland C. Insulin resistance in the brain: An old-age or new-age problem? Biochem Pharmacol. 2013 Sep 15;84(6):737-45.
• Yu X, Bao Z, Zou J, Dong J. Coffee consumption and risk of cancers: a meta-analysis of cohort studies. BMC Cancer. 2011 Mar 15;11:96.

Tangeritin, Natural Metformin from the Rind of Mandarin Oranges Hits the OFF-Switch on Diet Induced Obesity

Image 1: Tell me the truth! How much "natural metformin" did you throw away with those mandarine rinds in your life? Update (08/11/2013) Scroll down to the red box on dosing, I added, to check out why you better start saving your mandarine rinds now to be able to do a "tangeritine cycle" in a couple of years ;-)

I guess it is about time for another longer post on the "Supp" part of SuppVersity and what would be better suited than providing my readers from inside the business to spice up their #1 selling product which has as of late lost yet two other "all natural" ingredients in the never-ending arsenal of funky herbs, spices, -amines and -ephrines. Luckily the supplies nature has in stock are endless and with 5, 6, 7, 8, 40-pentamethoxyflavone (I am not kidding, now that 1,3 DMAA is gone, you will have to remember a couple more numbers ;-) the "next big" thing that's ready to get out of the starting blocks could actually prove to be more than just a stim and an actual weight loss adjuvant! After all, the AMPK boosting effects of tangeretin, which is abundant in the rinds of citrus fruits, such as mandarin orange, rutaceae and yuhu in Korea, appear to be everything but "ordinary" and they are not even the most interesting effect this compound may have on your metabolism.

Tangeritin, is not be be confused with citrus aurantium, is no stim and could thus actually work!

In a paper that has recently been published in the Journal of Molecular and Cellular Endocrinology Kim et al. report that the administration of of 200mg/kg (human equivalent 1.3g) of tangeritin per day to mice on a high fat diet did not only slow down weight gain and the development of glucose intolerance and hypercholesterolemia, but also had beneficial modulatory effects on the secretion of the adipokines adiponectin, leptin and resistin, as well as the release of IL-6 and MCP-1.

Figure 1: Adipocytokine expression and body weight gain of mice after 27 and 55 days on control, high fat (HFD) or high fat diet with 200mg/kg tangeritin (HFD + 200Tan; left) and in vitro glucose uptake of isolated myocytes upon incubation with tangeritin at doses of 25, 50 and 100mMol (right; data adapted from Kim. 2013)

For Kim et al. the profound effects wich lower leptin, aidponectin, resistin and IL-6 expression in the HFD + Tangeritin group than in the control (I wish we had the body fat levels, I am curious if those were not lower with HFD + tangeritin than in the control group, as well) did yet not come as a surprise.

Additional figure: How much rind (in g) do you need to produce 1g of tangeritin by water extraction at different temperatures and extraction times (data calculated based on Xu. 2013)

Update (08/11/2013): In response to questions both on Facebook as well as in the comment section I have compiled the graph on the right, which shows you how much rind (in grams) you need if you wanted to water-extract your 1g daily dose of tangeritin from Satsuma mandarin, which is probably the type of mandarin that is most widely sold here in the West and the more exotic, but tangeritin-rich Ponkan. If you take a closer look at the data from Xu et al. you will yet have to acknowledge that it is probably not feasible to produce your own extract at home - even if you you managed to extract ALL the tangeritin from the Ponkan, which obviously won't work by simply cooking it up, you would still need 232g of rind per day!

In previous in vitro experiments on isolated muscle cells (C2C12 myotubes), the researchers had already established that tangeritin, when it is appropriately dosed (!), exerts extraordinary powerful effects on the expression of the energy sensor and metabolic switch AMPK, which has as of late gotten quite some attention in  the laypress as the target for "the exercise pill", the "ultimate antiobesity + antidiabetes pill", the "anticancer and longevity pill",... well basically everything that could make a respective drug a pharmacological "bockboster" (read more about AMPK in the SuppVersity Intermittent Thougths Series: "The AMPK/mTOR Seesaw".

Figure 2: Hand in hand with the beneficial effects on adipocytokine production, the addition of tangerine to the high fat diet also ameliorated the growth and necrosis of adipocytes (Kim. 2013)

They also knew from previous studies that aside from its role as an inducer of AMPK and GLUT-4 expression in the muscle tissue, tangeretin posses anti-cancer, anti-oxidant and anti-inflammatory properties, as well (Yoon. 2011; Xu. 2008). Kim et al. also point out that

In addition to its anti-oxidant effects, tangeretin has been reported to inhibit the growth of hepatocytes both in vitro and in vivo via inhibition of mTOR/p70S6 kinase (Cheng. 2011). Regarding tangeretin-mediated effects on neuronal disease, a number of studies have shown that tangeretin reduces dopaminergic neurotoxin-induced neuronal injury and prevents tunicamycin-induced cell death in mice through an increase in glucose-regulated protein (GRP)78 and heme oxygenase (HO)-1 expression in renal tubular epithelium (Takano. 2007).

Moreover, another recent study by Choi et al. reports that tangeritin also has protective effects against the lipopolysaccharide (LPS) induced nitric oxide (NO) expression in the digestive tract and could thus offer acute and chronic protection from LPS induced cell damage (Choi. 2007).

Awesome? Well, in a way it may be, but in the end most of what we see is a result of pushing the right switches and in this regards tangeritin appears to be outstandingly good - for a supplement to say the least; that you don't need exercise in a pill if you hit the gym three to five times a week and lead an active life is something I don't have to tell you anyway, right?

Figure 3: Unlike thiazolidinedione like Rosiglitazone and "harmless" health supplements as fish oil (Neschen. 2006) tangeritin does not work its antihyperlipidemic (=triglyceride lowering) and anti-hyperglycemic (=blood sugar lowering) effects effects by inducing PPAR-gamma and thus allowing your body to stash away even more energy as body fat. On the contrary, reduces ppar-gamma expression and consequently stops the expansion of adipose tissue even in the presence of a hypercaloric high fat diet (cf. figure 1, tissue samples) - the beneficial effects of PPAR-gamma blockade have only recently been investigated by Lohdi et al. who call it an "off switch" for diet induced obesity (Lohdi. 2013).

Implications: Now, we are certainly not dealing with the "supplemental reinvention of the wheel here", and still: The effect size in the Tan200 group was so pronounced that I felt that the news on tangeritin, which had originally been part of last weeks "On Short Notice" deserved it's own post - not the least, because  it will not have you pay dearly for the improved glucose tolerance and lower blood lipid levels as thiazolidinediones like Rosiglitazone and even fish oil, both of which have been shown to reduce serum glucose and triglyceride levels via PAR-gamma dependent mechanisms (figure 3; specifically for fish oil Neschen. 2006) and thusly promote not block fat loss. Tangeritin, on the other hand decreases the PPAR-gamma activity and therefore acts as an "off-switch" for dietary induced obesity (Lohdi. 2013) .

Moreover, the reduced obesity was not a mere side effect of a loss of appetite and subsequent anorexia. The animals in the HFD and the HFD + Tan200 group consumed the exact same amount of chow - with the one small but absolutely critical difference that the rodents in the Tan200 group did not store the superfluous energy as body fat. It is this "anti-fat" effect which is not borne by negative health effect as it is the case for conjugated linoleic acid (CLA), for example (cf. "CLA Destroys Body Fat") which makes tangeretin a very interesting candidate for a weight loss supplement for both obese and lean dieters and, when I come to think about it, probably even for people who want to bulk.

There are however a few potential downsides and questions that remain to be answered before we celebrate the advent of yet another "next big thing" that will then line up with the rest of the supplemental non-starters:

• First of all, the mechanism of action does remind me of alpha lipoic acid (ALA), which is still a very good supplement for obese or at least insulin resistant dieters, but turned out to be useless, even potentially counterproductive in exactly those lean selectively (muscle) insulin sensitive athletes it is currently heavily marketed to as "repartitioning agent" (see "Lean and Muscular With Alpha Lipoic Acid?"). So the question is: "Is tangeritin only another ALA?" Is it better or worse and will it work fr lean people as well as it did for the mice on the obesogenic diet in the study at hand?
• Secondly, despite the fact that tangeritin acts in an almost metformin-esque fashion via AMPK and PGC-1alpha, which is much more likely to work in humans as well than your usual beta-3 agonist (e.g. synephrine) or other thermogenic with promising rodent data and absolute no effects in human beings, we still need controlled human trials to see whether or not this nquestionably promising flavenoid does work in humans at all.
• And thirdly, in view of the fact that only the high dose tangeritin (100mMol) elicited a pronounced increase in glucose uptake in the in-vitro study (cf. figure 1), it will be of utmost importance that future supplements or pharmacological agents are appropriately dosed - and we all know that this is in 90% of the cases where the raw material is more expensive than caffeine anhydrous simply not the case. 

That said, I would venture the guess that (assuming one of the smaller supplement companies finds a bulk supplier in China) we are going to see "Tange(R)iburn" or a tangerine based substrate repartitioning agent (after all those sell pretty well, too) in the near future - before anyone has a clue what dosages will be necessary to see beneficial effects and probably with way less than the 1g+ of tangeritin in it than Kim et al.'s results would suggest as a minimal daily dose for an adult to see similarly outstanding results as our hairy friends in the study at hand.

References

• Cheng Z, Surichan S, Ruparelia K, Arroo R, Boarder MR. Tangeretin and its metabolite 4'-hydroxytetramethoxyflavone attenuate EGF-stimulated cell cycle progression in hepatocytes; role of inhibition at the level of mTOR/p70S6K. Br J Pharmacol. 2011 Apr;162(8):1781-91.
• Choi SY, Ko HC, Ko SY, Hwang JH. Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol. Pharm. Bull. Choi, S.Y., Ko, H.C., Ko, S.Y., Hwang, J.H., 2007. Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol. Pharm. Bull. 30, 772–778.; 30, 772–778. 
• Lodhi IJ, Yin L, Jensen-Urstad AP, Funai K, Coleman T, Baird JH, El Ramahi MK, Razani B, Song H, Fu-Hsu F, Turk J, Semenkovich CF. Inhibiting Adipose Tissue Lipogenesis Reprograms Thermogenesis and PPARγ Activation to Decrease Diet-Induced Obesity. Cell Metab. 2013 Aug 1.
• Neschen S, Morino K, Rossbacher JC, Pongratz RL, Cline GW, Sono S, Gillum M, Shulman GI. Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice. Diabetes. 2006 Apr;55(4):924-8. 
• Kim MS, Hur HJ, Kwon DY, Hwang JT. Tangeretin stimulates glucose uptake via regulation of AMPK signaling pathways in C2C12 myotubes and improves glucose tolerance in high-fat diet-induced obese mice. Mol Cell Endocrinol. 2013 Jul 6;358(1):127-34. 
• Takano K, Tabata Y, Kitao Y, Murakami R, Suzuki H, Yamada M, Iinuma M, Yoneda Y, Ogawa S, Hori O. Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin. Am J Physiol Cell Physiol. 2007 Jan;292(1):C353-61.
• Xu HG, Chen CJ, Liu DH, Minerals, phenolic compounds, and antioxidant capacity of citrus peel extract by hot water. J. Food Sci. 2008; 73, C11–C18. 
• Yoon JH, Lim TG, Lee KM. Tangeretin reduces ultraviolet B (UVB)-induced cyclooxygenase-2 expression in mouse epidermal cells by blocking mitogen-activated protein kinase (MAPK) activation and reactive oxygen species (ROS) generation. J. Agric. Food Chem. 2011; 59, 222–228

To Fail or Not to Fail - 5x10 or 10x5? The Energetic Demand of Your Workouts Doesn't Depend on Workloads, Alone

Image 1: PCr, ATP, whatever as long as there was energy left, Arnold kept pumping iron (pun intended ;-)

"To fail or not to fail", this question is probably about as ancient as the hilarious idea to engage in physical activity that is not in one way or another directly related to one of our two most fundamental needs, survival and procreation. Researchers from the Physical Education Department at the Sport Sciences University of the Basque Country and the Department of Health Sciences at the University of Navarra in Spain have recently examined this question from a slightly different angle than most of the articles you have probably seen in and on the various muscle mags and bodybuilding related websites on the Internet. What Esteban M. Gorostiaga and his colleagues wanted to know was:

Are There Significant Differences in Energy Metabolism When you Train to Failure?

Or, put another way: Does it make a difference if you fail from a molecular energetic point of view or is the mere number of reps the most fundamental determinant of the changes in muscle adenine nucleotides, inosine 59-monophosphate (IMP), phosphocreatine (PCr), creatine (Cr), lactate and energy charge during a workout. To answer this question the researchers recruited 6 healthy male volunteers (age 28-40y; BMI 23.3kg/m²; 1-RM_max on unilateral leg press 199+/-43kg) and had them perform a total of 50 repetitions with the same initial load (83% of 1-RM) on two separate occasions, either

• performed to failure, as a quintette of 5 x 10 (sets x reps), or
• stopped before failure, in a 10 x 5 fashion.

On both occasions the subjects rested 2 minutes between the sets. Furthermore, Gorostiaga et al. tried to eliminate "confounding factors", by equating the values of several variables such as initial load and total number of repetitions between both exercise sessions and making sure that whenever a "subjects could not lift the initial load during the following sets due to fatigue" the load was decreased by 15kg until the respective subject was able to complete all 50 repetitions (Gorostiaga. 2013).

Figure 1: Peak power output profiles (average for n=6 subjects) for each exercise during the two experimental conditions: when exercise was 5 sets of 10 repetitions to failure (10REP; open circles), and when exercise was 10 sets of 5 repetitions not to failure (5REP; filled circles; adapted from Gorostiaga. 2013)

It is plain to see from the data in figure 1 that performing all sets to failure (open circles) lead to a significant reduction in total workload (the area under the peak powder curve):

During 5REP all the subjects were able to complete all the repetitions with the initially load assigned (154+/-31 Kg; 83+/-8% of 1RM). During 10REP, however, most of the participants were unable to complete all the repetitions with this starting load, due to failure. The load had to be reduced by 7.2+/-3.8% after 27+/-16 repetitions and was progressively reduced, reaching 85+/-12%(P,0.05) of the initial load at the last repetition. Average load during the 50 repetitions of 10REP was 6.1+/-6.3% lower (P<0.05) than during 5REP. (Gorostiaga. 2013)

If we examine the graph further there are a couple of other interesting things to observe, though:

• the 2nd-3d rep was the one with the maximal power - so much about the value / validity of 1-RM maximum strength tests, then ;-)
• the power progressively declined from the 3rd rep on (35-45%) and that with an astonishing dip after the 5th rep - maybe because subjects are used to do 5 reps, so that this could also be a psychological factor
• while not training to failure with 10 sets of five reps allows to maintain almost identical average peak power on all sets, training to failure with 5 sets of 10 reps resulted in a net reduction of 33% from 812Watts on the first to 569 Watts on the last set
• the average peak power per set was accordingly 28% lower, when the participants trained to failure

What's the "energy charge"? The energy charge was calculated as the quotient of (ATP + 1/2 ADP)/(ATP + ADP + AMP) and does thus quantify the ratio of usable to used energy in the muscle samples.

Yet while the average mean power output changes paralleled those of peak power output in both experimental conditions, the opposite was the case for the aforementioned muscle metabolites - muscle adenine nucleotides, inosine 59-monophosphate (IMP), phosphocreatine (PCr), creatine (Cr), lactate and energy charge - the scientists measured by high-performance liquid chromatography from the muscle biopsies they had taken from the right legs of the subjects on each occasion.

Is light training an option, at all?

Very much in accordance with the subjective experience of many trainees, the data in figure 2 appears to confirm that working out to failure does induce muscular exhaustion, which manifests in the form of physically quantifiable changes in muscle metabolites in the training to failure group

• almost depleted PCr stores in the failure group (85% fall, P<0.05), and 
• reduced ATP (-21%), energy charge (-4%), and  
• reduced adenine nucleotides pool (-20%; ATP + ADP + AMP), in the presence of
• increased IMP (+8600%) and lactate (+1400%) levels

Which stand in stark contrast to the mediocre decrease in of phosphocreatine, the almost unchanged muscle ATP, IMP, energy charge and adenine nucleotide pool and comparatively marginal elevations in blood lactate in the 10 x 5 non-failure group.

Figure 2: Changes in ATP, ADP, AMP, phosphocreatine (PCr) inosine monophosphate (IMP) and lactate from pre to post workout in the 5 x 10 (failure) and the 10 x 5 (no failure) session (data calculated based on Gorostiaga. 2013)

As far as the correlation between these markers and the actual power output during the workout are concerned, the scientist say that they observed a ...

Figure 3: Relationship between muscle lactate concentrations and average peak power (from Gorostiaga. 2013).

• significant linear negative correlation (R²=0.59) was observed between the average changes in peak power output observed during the last two repetitions (expressed in percent of the initial two repetition values) and the decreases in ATP levels (expressed in percent of initial value).
• significant curvilinear negative correlation between the average peak power output changes observed during the last two repetitions of the first and last sets (expressed in percent of the initial two repetition values) and the corresponding levels of muscle lactate. 

From the curvilinear nature of this relationship (see figure 3) Gorostiaga et al. conclude that "when muscle lactate levels do not exceed the upper limit of 10–15 mmol/kg wet muscle, power output changes little from maximum values". The exact opposite is yet the case, when the lactate values exceed this critical upper value and the power output begins to decrease sharply.

Image 2: While training like a sissy will at best produce suboptimal results, maxing out on every set of every workout will work for max. 2-3 weeks until you will not just lose the gains you may have made but end up weaker and with less muscle in the hospital, when an injury or total burn-out forced you to finally see reason. Going to failure on one the last set of a selected exercise for each body group may be a way smarter, safer and more productive way. Combine that with planned 3-RM tests to gauge your strength progress and you should see some nice gains and can keep track of your strength gains without risking burn-out or injury and trust me this has little to do with being a sissy!

Implications: At first sight you may certainly argue that the study does not provide much novel information. If you do however compare the main results to common wisdom about various strength training regimen, the total depletion of the phosphocreatine stores in the "higher" rep group and the increase in IMP levels, of which Gorostiaga et al. rightly argue that they reflect the failure of ATP resynthesis to match ATP hydrolysis rates and eventually feed into the uric acid cycle (as reflected by the 19% increase in the failure group) put an emphasis on the often underestimated energetic and metabolic demand of training to failure. In this context, the pronounced loss of purines from the muscle, as it has also been observed by Hellsten et al. subsequent to profoundly lowered ATP levels in the course of a one-legged HIIT protocol on a cycle ergometer (Hellsten 1999), and the subsequent extraction of urate from the blood by the muscle to restore intramuscular urate levels (remember: urate acts as a free-radical scavenger during intense exercise; cf. Hellsten. 1997) may well be an overlooked factor, when it comes to assessing exercise recovery.

Still, while the former would suggest that you better avoid training to failure altogether and simply hit the gym for a "light" 10 x 5 workout everyday, the minor reduction in PCr (-15% vs. -80%) and the non-existent rise in plasma lactate and urate (no stress = no adaptation?) do indicate that frequent light training session will probably not result in the desired, or at least suboptimal muscular adaptations, which are the physiological bases for the strength and size gains, you are looking for (read all about "The Physiology of Building Muscle"). Moreover, the almost unchanged ATP/ADP ratio (see figure 3), which is the gauge by which AMPK works (cf. "Zoning in on AMPK"), could be the reason why many of the "sissy workout" studies report that strength training would not have the same / any beneficial effect on glucose tolerance, lipid levels and all the other standard parameters of metabolic health scientists usually measure in those trials.

Bottom line: While it is almost certain that you will out-train your own recovery potential by going to failure on every set of every workout, the results of this study put an emphasis on the fundamental difference between physical workloads and their immediate physiological effects (just a reminder, the workload, i.e. weight lifted x reps was identical for both groups). What we are still lacking to derive concrete reliable workout tips from data like this, though, are clear-cut mechanistic or at least probabilistic relationships between the short term effects of and the long-term adaptation to different workout regimen and their respective energetic demands... ah, and by the way, this goes for the incredible popular measurements of post-workout protein synthesis, as well. Until now, no-one can say how much predictive value temporary increases in fractional muscle protein synthesis actually have in terms of long(er) term muscle gains.

References:

• Gorostiaga EM, Navarro-Ame´zqueta I, Calbet JAL, Hellsten Y, Cusso R, et al. (2013) Energy Metabolism during Repeated Sets of Leg Press Exercise Leading to Failure or Not. PLoS ONE 7(7): e40621. 
• Hellsten Y, Tullson PC, Richter EA, Bangsbo J. Oxidation of urate in human skeletal muscle during exercise. Free Radic Biol Med. 1997;22(1-2):169-74.
• Hellsten Y, Sjodin B, Richter EA, Bangsbo J (1998) Urate uptake and lowered ATP levels in human muscle after high-intensity intermittent exercise.Am J Physiol 274: E600–E606.

Build a Bigger Mitochondrial Engine and Double Your Endurance With Chitooligosaccharides! Glucosamine Mix from Chitosan Acts on Sirt1 & AMPK, Similar to Resveratrol

Figure 1: Glucosamine composition of the chitooligosaccharide used in the study (data adapted from Jeong. 2013).

Usually I try to avoid this term, as it seems to imply that there is, or at least soon will be a pill that would allow you to stay the lazy bastard you are now and still make it into your old age, healthy lean, attractive and vigorous, but in this case the word "exercise mimetic" is unquestionably what describes the effects of 6 weeks of oral supplementation with chitooligosaccharide described in a recently published paper by scientists from the Amorepacific Corporation Research & Development Center and the Kyung Hee University in South Korea best. I have to give props to my friend Carl Lanore the voice (and brain) of Super Human Radio who shot me an email on this issue, yesterday.

A brief glance at the full-text was enough to realize that Carl who likes to pretend he was the idiomatic "blind man" with no scientific degree (I could hardly care less, by the way ;-) who hits upon things like this only perchance was up to something - those who now the show, will be aware that he is smarter than many of the experts he interviews, anyways... but I am getting derailed, here. Where was I? Ah yeah, the study...

COS - What we already know

• Ameliorates weight gain (-15%) and high blood lipids on HFD in mice in the absence of reduced energy intake (Choi. 2013)
• Promotes cytokine release in intestinal epithelial cells (Bahar. 2013)
• Inhibits pancreatic lipase and thus breakdown and subsequent uptake of dietary fat (Kang. 2013)
• Suppresses TNF-alpha induced collagen breakdown in-vitro (Ryu. 2013)
• Has neuroprotective effects (Joodi. 2011)

Promising in vivo rodent + in vitro cell line data: Very promising, but not yet field-tested

Hyun Woo Jeong and his colleagues fed 39 female Sprague-Dawley rats either normal or 0.05% chitooligosaccharide (COS produced by Bioland Korea Co. Briefly from chitosan by enzyme digestion, followed by deacetylation of chitin; cf. Hirano. 1989) enriched rodent chow for 6 weeks.

At the end of the study period, 50% of the rodents had performed an exercise test on the treadmill, in the course of which they had to run at a pace of 20m/min until exhaustion, while the rest of the animals were sacrificed before this final workout to assess their pre-exercise plasma profiles including ALT, AST, triglyceride, total cholesterol, lactate, and free fatty acid levels (none of which showed significant changes over the course of the 6-week study period).

Despite the fact that the scientists did not measure the total lean and fat mass of the rodents, the collective data in figure 2 clearly suggests that the -72% reduction in weight gain was not at the expense metabollically active muscle tissue.

Figure 2: Body weight and energy intake (left) and muscle weight vs. body weight (right) data at the end of the 6-week trial (data adapted from Jeong. 2013).

Despite a statistically non-signficant reduction in food intake (-6%) the chitooligosaccharide treated rodents had heavier soleus (slow twitch, type II fiber dominant muscle) muscles and a more favoreable plantaris (fast twitch, type II-X fiber dominant muscle) to total body weight ratio (indicative of a lower body fat percentage), than their non-supplemented peers. Moreover, a cursory glance at figure 3 does also reveal why this is the case.

Figure 3: Electron microscopic image of muscle tissue (top; small arrows and green areas indicate the presence of mytochondria), mitochondrial density in in-vitro control experiment after exposre to different doses of  resveratrol vs. chitooligosaccharide (bottom, left) and time to exhaustion during treadmill test (adapted from Jeong. 2013)

Even as a non-expert it is easy to see that the chitooligosaccharides had profound "anabolic" effects on the mitochondria of the lab animals.

COS activated AMPK and increased the cellular NAD+ / NADH ratio to induce Sirt1 activation. The activation of AMPK and Sirt1 increased the expression and activity of PGC1 and augmented the expression of mitochondrial genes. As a result of activation of AMPK, Sirt1, and PGC1, COS facilitated mitochondrial biogenesis. In rodents, the administration of COS significantly increased intramuscular mitochondrial content, resulting in enhanced exercise endurance and reduced plasma lipid profiles. (Jeong. 2013)

In the Petri-dish, it may be less potent than resveratrol on a per mg base (figure 3, bottom-left), but the real world effects in terms of both, increased mitochondrial biogenesis (see green mitochondria in the electron microscopic image of skeletal muscle; figure 3, top) and subsequent increases in average running time to exhaustion (+96%; figure 3, bottom right) speak for themselves.

Implications: Other than resveratrol, which has an oral biovailability that is hardly high enough to be quantified (Walle. 2004), chitooligosaccharide could actually be suitable for oral supplementation - at least if we assume similar pharmacokinetics in humans as in rats (which is likely, but not necessarily the case).

• especially sedentary individuals or people who rarely train could benefit from the exercise-mimicking effects 
• in a previous study by Cho et al. chitooligosaccharide lactate has been found to be superior to chitooligosaccharide HCL (Cho. 2010)
• the optimal dosage and, more importantly, whether trained and well-conditioned individuals would benefit to a similar extend / at all, would yet require further studies. 
• the human equivalent dosages for the study at hand would be 600-900mg/day depending on the individuals body weight

Image 1: COS is rather something for the "old" Mr C. than for Adelfo

Aside from the fact that there are (at least to my knowledge) no over-the-counter chitooligosaccharide supplements on the market, so that you would probably have to order a metric ton right from China at Alibaba.com, I would not expect too much from it, anyways. Firstly, the chances that it turns out to be another supplemental non-starter like resveratrol are high. And second- and more importantly, the beneficial effects will be less pronounced for well-conditioned individuals and could even be close to zero (and certainly not practically relevant) for people who go to the gym to train and not to pose, to chat or to flirt. People like you and me and Adelfo Cerame, whose new client Mr. C. is soon going to join the ever-growing community of physical culturists, who don't need a "mimetic" for something they love: Exercise!

References:

• Bahar B, O'Doherty JV, Maher S, McMorrow J, Sweeney T. Chitooligosaccharide elicits acute inflammatory cytokine response through AP-1 pathway in human intestinal epithelial-like (Caco-2) cells. Mol Immunol. 2013 Jul;51(3-4):283-91. Epub 2013 Apr 16.
• Cho SY, Lee JH, Song MJ, Park PJ, Shin ES, Sohn JH, Seo DB, Lim KM, Kim WG, Lee SJ. Effects of chitooligosaccharide lactate salt on sleep deprivation-induced fatigue in mice. Biol Pharm Bull. 2010;33(7):1128-32.
• Choi EH, Yang HP, Chun HS. Chitooligosaccharide ameliorates diet-induced obesity in mice and affects adipose gene expression involved in adipogenesis and inflammation. Nutr Res. 2013 Mar;32(3):218-28.
• Hirano S, Tsuchida H, Nagao N. N-acetylation in chitosan and the rate of its enzymic hydrolysis. Biomaterials. 1989;10: 574–576.
• Jeong HW, Cho SY, Kim S, Shin ES, Kim JM, Song MJ, Park PJ, Sohn JH, Park H, Seo DB, Kim WG, Lee SJ. Chitooligosaccharide Induces Mitochondrial Biogenesis and Increases Exercise Endurance through the Activation of Sirt1 and AMPK in Rats. PLoS One. 2013;7(7):e40073.
• Joodi G, Ansari N, Khodagholi F. Chitooligosaccharide-mediated neuroprotection is associated with modulation of Hsps expression and reduction of MAPK phosphorylation. Int J Biol Macromol. 2011 Jun 1;48(5):726-35.
• Kang NH, Lee WK, Yi BR, Park MA, Lee HR, Park SK, Hwang KA, Park HK, Choi KC. Modulation of lipid metabolism by mixtures of protamine and chitooligosaccharide through pancreatic lipase inhibitory activity in a rat model. Lab Anim Res. 2013 Mar;28(1):31-8. Epub 2013 Mar 21.
• Ryu B, Himaya SW, Napitupulu RJ, Eom TK, Kim SK. Sulfated chitooligosaccharide II (SCOS II) suppress collagen degradation in TNF-induced chondrosarcoma cells via NF-κB pathway. Carbohydr Res. 2013 Mar 1;350:55-61.
• Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004 Dec;32(12):1377-82. Epub 2004 Aug 27.

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.

Lean & Muscular With Alpha Lipoic Acid? You Could Be Just as Lean, But More Muscular W/out "Nutrient Repartitioner"!

Image 1: Lean enough? Ever thought it may be better to stop taking your ALA, now?

I know what you are probably thinking right now: "Not yet another rodent study on the insulin sensitizing effects of alpha lipoic acid!" And in fact, you would be totally right if the results of this very study, which is going to be published in the next issue of the European Journal of Nutrition could not just save you a lot of money but also propel, or rather restore your lean mass gains. After all, the real-world implications of the differential effects of alpha lipoic acid supplementation Prieto-Hontoria et al. observed in lean vs. obese rodents would suggest that your expensive "nutrient repartitioner" may repartitions the energy away from your muscles and thus impair your gains. Put simply: Alpha lipoic acid keeps you lean, yeah... lean, but probably undermuscled!


Now you are listening, right? 

Well, let's see what the Spanish researchers did, then. Basically Prieto-Hontoria and his colleagues repeated an experiment many other researchers have conducted before. They took a bunch of young male Wistar rats and fed them a...

• regular diet with a macronutrient ratio of 20/67/13 (protein, carbs, fats)
• regular diet + 0.25g racemic alpha lipoic acid per 100g chow
• high fat diet with a macronutrient ration of 20/20/60 (protein, carbs, fats)
• high fat diet + 0.25g racemic alpha lipoic acid per 100g chow

And while the existence of a ALA control group on a normal diet alone would be a very welcome twist on your average "lipoic acid helps vs. diet induced insulin resistance / obesity"-study, the existence of two pair-fed groups

• regular diet, pair-fed receiving the same amount of chow as the regular diet + ALA group consumed voluntarily, but without the ALA content
• high fat diet, pair-fed receiving the same amount of chow as the high fat + ALA group consumed voluntarily, but without the ALA content

Allows for unique conclusions in terms of which effects are actually ALA-mediated and which ones are nothing but a side-effect of the anorexic (=appetite / food intake reducing) effects of alpha lipoic acid.

What's good for obese pre-diabetics on the standard American diet ...

Body weight and food intake were recorded every 2–3 days. And blood glucose, insulin, HOMA-IR, white adipose tissue mass, body total body weight gain, serum adiponectin levels and AMPK levels in white and brown adipose tissue, as well as skeletal muscle were determine at the end of the 8-week experimental period.

Figure 1: Effects of 8 weeks of supplemental alpha lipoic acid on body composition of rodents on different diets; active treatment vs. control (left) and active treatment, pair-fed (with active treatment) and control (right; data based on Prieto-Hontoria. 2013)

If you take a look at the left graph in figure 1 you see, what you probably would have expected. The rodents in the ALA groups (ad-libitum fed) gained significantly less body weight and had significantly less body fat than their peers, regardless of which diet they were on. Ok, the "lean mass" (here simply the difference between total and fat mass and thus not necessarily 100% identical to muscle mass - the rodents in the ALA groups could for example also have lower bone or organ weights) is lower, but alas, at least they are lean! And you are right, lean they are, but their pair-fed peers in the regular diet group, who received the exact same amount of food, but without any supplemental alpha lipoic acid, were exactly as lean, but made significantly greater gains (cf. figure 1, right)!

... can be detrimental for healthy, lean individuals whose ideal body image is not just skinny!

Figure 2: AMPK expression in white & brown fat and muscle (top, based on Prieto-Honta. 2013), and implications (bottom)

Now that we know about beneficial effects for SAD dieters and the detrimental effects for physical culturists, it's about time to take a look why on earth this happens and the answer - as counter-intuitive as that may sound, is via downregulation of AMPK (click here to read my dissertation on the "mTOR <> AMPK Seesaw ") - yes, you heard me right. As it turns out the "beneficial" effects of ALA on 5' adenosine monophosphate-activated protein kinase activity are tissue- and downstream effects diet-specific. Therefore, the detrimental effects of the decreased skeletal muscle and brown adipose tissue AMPK activity are outweighed by the increase in white adipose tissue AMPK activity, the researchers observed in ALA supplemented rodents from both groups, was outweighed by the increase in white adipose tissue AMPK activity (and increases in adiponectin, see figure 2) only in the high fat diet group. The rodents who received the normal chow, on the other hand, achieved a much more favorable body composition by simply mimicking (obviously through pair-feeding and not voluntarily) the ALA induced (small) reduction in food intake.

"Hold on, what's all that AMPK b*s* about? Where's the connection to being lean & muscular?"

The downregulation of BAT AMPK activity, on the other hand, is as the analysis of the role of AMPK in cold thermogenesis by Mulligan et al. suggests, is a clear downside of ALA (Mulligan. 2007) and could in fact be related to its previously reported negative effects on thyroid metabolism, respectively the conversion of the "inactive prohormone" T4 to the metabolically active T3 (Segermann. 1991). Likewise, the reduction of skeletal muscle AMPK is not a benefit as the data in figure 1 clearly shows that the bro-scientific claims about muscle loss due to increased skeletal muscle AMPK activity don't hold. Something that should actually be obvious, in view of the role AMPK plays skeletal muscle glucose uptake, glycogen and ATP regulation (Kurth-Kraczek. 1999; Musi. 2002), and mitochondrial biogenesis (Hardie. 2010).

Figure 3: Insulin, HOMA-IR, adiponectin and adiponectin relative to white adipose tissue weight in control, pair-fed (same food intake as ALA, but no supplement) and ALA supplemented rodents after 8 weeks (based on Prieto-Hontoria. 2013)

Still, due to the profound increases (total and relative to fat weight) in adiponectin (cf. figure 3), a fat-derived hormonal with well-established insulin-sensitizing and anti-obesity effects (Yamauchi. 2001; Shehzad. 2013), which showed a statistically significant correlation (after correction for adiposity) with the HOMA index, a recognized marker of insulin resistance, and its preventive effects against diet induced obesity, alpha lipoic acid should remain among the recommended supplements for obese, insulin resistant or diabetic subjects.

Is alpha lipoic acid for you? If you are lean, this study says "NO"!

Image 2: If you are the fat endo at the bottom, ALA could be for you. If you are the guy on the left, mild cutting and bulking w/out ALA is for your. And if you are on the right, you better spend your money on protein, creatine, BC/EAAs.

Its merit for lean physically active people, who consume a energetically appropriate whole-foods diet and strive to build a lean and muscular, not just a skinny physique, its usefulness is yet somewhat questionable. After all, the pair-fed animals had an equally low amount of body fat as their peers on ALA, but statistically significant more lean body mass; and I personally don't believe that it is a realistic assumption that these effects could be countered by simply eating more without having negative effects on the total amount of body fat you would accumulate on this heavy-duty bulk.

Your best bet would to try and "exercise away" the negative effects on  skeletal muscle AMPK expression, but let's be honest: Would you rather wear a helmet instead of simply stopping to hammer your head against the wall? You would, ha? In that case you are beyond help, I guess... go ahead then and do what works for your obese neighbor.

Note (I know someone is going to ask this): If anyone can show me peer-reviewed in-vivo data that confirms the constantly made claim that the physiological effects (not the petri-dish or XYZ-essay effects) of R-ALA are superior, not just on a gram-per-gram base, but qualitatively, tho those of the cheap and obviously less profitable racemic ALA (= natural mix of R- and S-ALA), I would be inclined to answer the question "wouldn't taking R-ALA maybe make a difference".

References:

• Hardie DG. Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism. Proc Nutr Soc. 2011 Feb;70(1):92-9. Epub 2010 Nov 11.
• Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999 Aug;48(8):1667-71.
• Mulligan JD, Gonzalez AA, Stewart AM, Carey HV, Saupe KW. Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse. J Physiol. 2007 Apr 15;580(Pt. 2):677-84.
• Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, Zhou G, Williamson JM, Ljunqvist O, Efendic S, Moller DE, Thorell A, Goodyear LJ. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002 Jul;51(7):2074-81. 
• Prieto-Hontoria PL, Pérez-Matute P, Fernández-Galilea M, Martínez JA, Moreno-Aliaga MJ. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr. 2013 Jun 5. [Epub ahead of print]
• Segermann J, Hotze A, Ulrich H, Rao GS. Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels. Arzneimittelforschung. 1991 Dec;41(12):1294-8.
• Shehzad A, Iqbal W, Shehzad O, Lee YS. Adiponectin: regulation of its production and its role in human diseases. Hormones (Athens). 2013 Jan-Mar;11(1):8-20. 
• Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001 Aug;7(8):941-6.

Greater Strength Without Compromised Size Gains With Rest-Pause. Can Dietary Variety Contribute Cause Obesity? Catabolism & Anabolism Just 2 Sides of the Same Coin. GABA as a GH Promoting Brain Anabolic?

Can't squeeze out another rep? Not a problem have some intra-set rest and continue pumping thereafter.

I guess, I did this before, but I say it again: "Congratulations, Adelfo Cerame Jr.! You are the man." Obviously, we all knew he is, but as of now, even the judges have finally acknowledged that. Reason enough to do a Science Round-Up Special today, in the course of which Carl Lenore and me are going to pick Adelfo's brain and have him surrender all the secrets that made him finally achieve what he has been chasing for years, now: The status of a wheelchair pro bodybuilder.

Just like the regular show the live show will be kicking off at 1PM EST. If you miss it it's not a problem, there is also going to be a special edition of the "Seconds", tomorrow with Adelfo looking back at how the contest went and how he made sure to peak right on time (edit: you can download the podcast now).

And just to make sure that no one complains: I compiled a couple of news as a surrogate for the regular Science Round-Up, today (this was "last minute", so please ignore any typos and grammatical mistakes).  

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Rest-pause technique leads to greater strength w/ identical size gains (Oliver. 2013) -- The bad news first, I can't tell you exactly how long the 22 male subjects (25 +/- 5yrs, 179.71 +/- 5.0cm, 82.1 +/- 10.6kg, 13.6 +/- 4.3% fat, 6.5 +/- 4.5yrs training)  Jonathan Oliver recruited for the experiment he wrote his dissertation on actually rested withing (=intra) their sets. Usually you would expect something along the 10 deep breaths - just enough to get your game on, so to say.

Figure 1: 1-RM max and power on bench presses and squats before and after 12 weeks of classic (regular sets) and alternative intra-set rest interval (rest-pause) training in 22 young resistance trainees with >2y of training experience (Oliver. 2013)

You got to remember, though, that I cannot guarantee that the 10 deep breath version of the rest-pause technique will yield the same remarkable results you see in figure 1 until the embargo on the dissertation falls or a student of the Texas A&M who I believe should be able to peak into the actual full text gives me a hint on the details of the study protocol. In the mean time, take the increased strength gains (check the percentages above the bars in the post columns), as an incentive to (re-)incorporate rest-pause sets where you perform 2-5 reps, rack the weight, pause, pick it up again and perform another 2-5 reps with the same weight and so on until you hit your target rep range, e.g. 12 reps on the bench with 200lbs, where you usually cannot do more than 5, into your routine.

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Dietary variety does not protect us from from becoming fat (Vadiveloo. 2013) -- In a soon-to-be-published systematic review of epidemiological studies researchers from the Steinhardt School at the New York University report that dietary variety does not protect against obesity. In fact, the exact opposite can be the case if "your variety" is a variety of sugar + fat-laden junk foods. In that case you are even more likely to fall victim to the metabolic syndrome than someone who eats just Twinkies and does not switch to Dingdongs once in a while:

If you are interested in buying quality, you may want to revisit the post on pesticide residues in organic and regular produce (go back)

"The present review is an important first step in clarifying the associations between dietary variety and excess adiposity, which is currently limited by the methods used to assess variety.

In the present review, we found that (1) dietary variety within recommended and low-energy foods alone do not increase the odds of overweight and obesity, (2) greater variety within less healthful, energy-dense foods increases the odds of overweight and obesity and (3) the association between total dietary variety and adiposity is mixed and accurate evaluation of this association requires a consistent and theoretically valid measurement tool."

This is, allegedly not a really surprising finding, what may yet surprise you is that the scientists didn't find a positive association for a variety of healthy foods in the diet, either. Sounds like quality and quantity, but not diversity remain what determines our likelihood of becoming obese... but let's be honest, isn't eating - at least from time to time - so much more than just providing your body with the nutrients it needs?

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There is no protein synthesis without catabolism (Bentzinger. 2013) -- A very intriguing study that's about to be published in the next issue of Skeletal Muscle found that the constant and isolated expression of MTOR-1C in a rodent model leads to profound muscle catabolism and not as you may have expected exuberant muscle growth. The underlying reasons for this counter-intuitive effects are the m-TOR induced blockade of the p-AKT pathway which is also responsible of keeping the catabolic MuRF1 pathway in check:

The AMPK-mTOR seesaw

"Our study shows that the mTORC1- and the PKB/Akt-FoxO pathways are tightly interconnected and differentially regulated depending on the muscle type. These results indicate that long-term activation of the mTORC1 signaling axis is not a therapeutic option to promote muscle growth because of its strong feedback induction of the E3 ubiquitin ligases involved in protein degradation."

In view of the fact that few of you will be mutants with a constant (over-)expression of mTOR-1C the scientists most recent observation does actually have implications for you as a trainee. It does not only re-emphasize the importance of the cyclic nature and tight inter-regulation of protein synthesis and degradation, but should also remind you no to rely too heavily on studies measuring only increases in protein synthesis without accounting for the net protein retention.

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GABA exerts indirect "anabolic" effects on the brain (Thanapreedawat. 2013) -- In yet another advanced publication that happens to overlap with the sudden re-appearance of GABA supplementation within the health and fitness community, Thanapreedawat and colleagues report that the administration of gamma-amino-butyric in the drinking water (0.5% and 1.0%) of young rats lead to highly significant activation of the intra-cerebral mTOR pathway, a subsequent dose-dependent increase in S6K1 phosphorylation and corresponding increases in brain protein synthesis.

Figure 2: Relative changes (compared to control) in insulin, insulin-like growth factor (IGF-1) and growth hormone (GH) in response to 0.5% or 1.0% GABA in the drinking water of 3-week old Wistar rats (Thanapreedawat. 2013)

Now what's really interesting about the study is that these effects were not mediated centrally. In other words, the orally ingested GABA did not pass the blood brain barrier. That this was possible is sometimes touted by producers of respective supplements. Previous studies have yet conclusively shown that orally ingested GABA does not make it across an intact blood brain barrier in vivo, so that any effects GABA may have must originate in the periphery  and that's actually what the scientists believe happened here, as well.

The peripheral effects of the orally administered GABA, namely the pronounced increase in growth hormone (GH) (cf. figure 2), a molecule which has previously been shown to be able to cross the blood brain barrier (Bermann. 1994; Ohsumi. 2008) lead to an activation of the intra-cerebral mTOR cascade and the subsequent increase in protein synthesis. If you expand on that, you could even speculate about other GH mediated effect of GABA supplementation... I must yet forewarn you: GABA is not a proven ergogenic of any kind (doesn't build muscle, doesn't make you lean, etc.).

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Usually this would be the place to add some references to the latest Facebook news, but since the show is about to start in a couple of minutes (listen live), I'll just refer you directly to the SuppVersity Facebook Wall. With 6-9 studies you won't read about anywhere else every day, it's always worth visiting, anyway ;-) 

References: 

• Bentzinger CF, Lin S, Romanino K, Castets P, Guridi M, Summermatter S, Handschin C, Tintignac LA, Hall MN, Rüegg MA. Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy. Skelet Muscle. 2013 Mar 6;3(1):6.
• Bermann M, Jaffe CA, Tsai W, DeMott-Friberg R, Barkan AL. Negative feedback regulation of pulsatile growth hormone secretion by insulin-like growth factor I. Involvement of hypothalamic somatostatin. J Clin Invest. 1994 Jul;94(1):138-45.
• Ohsumi M, Tujioka K, Hayase K, Nagata S, Yokogoshi H. The growth hormone affects the brain protein synthesis rate in hypophysectomized aged rats. J Nutr Sci Vitaminol (Tokyo). 2008 Feb;54(1):76-81.
• Oliver J. Intra-Set Rest Intervals in Hypertrophic Training: Effects on Hypertrophy, Strength, Power, and Myosin Heavy Chain Composition.Doctoral dissertation, Texas A&M University. 2013.
• Thanapreedawat P, Ohsumi M, Hayase K, Yoshizawa F, Yokogoshi H. Influence of GABA on Brain Protein Synthesis Mediated by the Mammalian Target on the Rapamycin Pathway. Biosci Biotechnol Biochem. 2013 Mar 7.
• Vadiveloo M, Dixon LB, Parekh N. Associations between dietary variety and measures of body adiposity: a systematic review of epidemiological studies. Br J Nutr. 2013 Feb 27:1-16.