Sulforaphane from Cruciferous Vegetables Inhibits Myostatin and Increases Cell Viability in Skeletal Muscle Satellite Cells

Chicken Egg Rolls with Red Cabbage, Mango & Lime (CleanEatingMag); small inset shows sulforaphane content (µg/ml) of a juice made cauliflower, broccoli, red and white cabbage and brussel sprouts (based on Totušek. 2011).

When I am looking at the currently top-rated posts (see box "Most Popular (last 30 days)" on in the right navigation bar), it appears as if someone must have found my older article on the myostatin boosting effects of clenbuterol and told all his facebook friends about it.

Don't forget to check out and tell your friends about the latest SuppVersity Facebook News, as well!

In case this hypothesis is right, he (or she?) and all the friends will probably be happy to hear that there is a virtually side-effect free over-the-counter alternative that can suppress myostatin and thus make your muscles grow faster: Broccoli, cauliflower, cabbage and co (see image on the right and realize Red Cabbare, not broccoli is the King!) - the sulforaphane in these cruciferous vegetables appears to make that possible.

Muscle building veggies... yamyol!

Back in the day Popeye was invented to convince children that it would be worth eating their spinach (unfortunately this advise was based on the false assumption that it was a good source of iron and would thus help build the kids' stamina). I guess when the inventors of Popeye get wind of the soon to be published paper we are going to look at, today, we are soon going to see a digital avatar of Mr. O. munching broccoli in a 3D animated cartoon.

Sulforophane protects muscle against exercise induced damage: Although pertinent studies on the myostatin inhibiting effects of sulforophane outside of the petri dish have yet to be conducted, a rodent study from 2009 did already observe another, likely related effect of sulforophane  supplementation in intact animals. Administered at dose of 25mg/kg (human equivalent: 4mg/kg ~ 300-400mg for an average adult) it exerted significant ameliorative effects on exercise induced muscle damage (Malaguti. 2009). Against that background it does not seem to be exactly unlikely that chronic sulforophane supplementation or cruciferous vegetable consumption could give you a slight edge over those who don't eat their greens.

Whether the digital broccoli munching Mr. O Popey will be able to bring more scientifically sound arguments to the table than his predecessor, popeye does however still have to be determined. After all, the scientists from the Animal Breeding and Husbandry Group at the University of Bonn in Germany did not study the real-world effects of sulforaphane (SFN), but only the in vitro effects the exposition of porcine satellite cells to, of which every SuppVersity reader knows that they function as skeletal muscle stem cells and support muscle growth and regeneration following injury or disease, when they found that...

"[...] SFN treatment significantly represses MSTN expression, accompanied by strongly attenuated expression of negative feedback inhibitors of the MSTN signaling pathway. miRNAs targeting MSTN are not implicated in posttranscriptional regulation of MSTN." (Fan. 2013)

If you take a closer look at the data in figure you may notice that this increase in myostatin went hand in hand with a decrease in MyoD expression. With MyoD being a protein that is involved in the very first step of satellite cell recruitment (it stops the proliferation of stems cells and initiates their transformation to muscle cells) this may seem awkward at first.

In view of the MyoD promoting effects of trichostatin A, which basically stops cell development in its tracks it can however be explained by the fact that less new satellite cells are needed, because their survival is increased so that the proliferation rate does not actually suffer (figure 1, left).

Figure 1: Cell viability, proliferation, MyoD, Myostatin and (total) Follistatin mRNA expression in porcine stem cells (satellite cells) from semimembranosus muscles from 6 purebred Pietrain piglets after exposure to DMSO (control),  trichostatin A or different concentrations of sulforaphane (SFN; data based on Fan. 2013)

This explanation does not only stand in line with the previously reported increase in MyoD expression in aging muscle (in this case unfortunately in the absence of increased cell viability; Alway. 2013), but is also supported by the concomitant downregulation of the pro-apoptotic (=initiating cell death) caspase enzymes (not shown in figure 1) in the SFN treated satellite cells.

In conjunction with the decrease in myostatin, which is, as I am sure you all know the 'myocyte hypertrophy break' of your body, the data from this in vitro study clearly suggests that SFN treatment could well have a growth promoting effect on skeletal muscle, which is -- and this may be one of the most important messages here -- more prononce at lower concentration used in the study.

Figure 2: Appearance of SFN in serum (triangles) and its metabolite in the urin of one of 10 healthy, normal-weight adult (34 +/-13 y) male volunteers after the ingestion of 200g of raw (top) or cooked (bottom) as part of a warm meal (Vermeulen. 2008)

Bottom line: After you have read about the potent anti-adiposity effect of antibiotics which are used in poultry fattening, yesterday, and today's news about the myostatin inhibiting effects of cruciferous vegetables, or more precisely, their sulforphane content, the infamous 'chicken breast, broccoli and rice diet' does actually begin to shine in new splandor! I mean, if only 50% of the aforementioned in vitro effects could actually be achieved by eating like this day in and day out, these recent findings could well explain, why generations of bodybuilders thrived on these spartan foods. And in case you wondered why the guys get freakier year by year - that's simply the availability of broccoli extracts and the increased use of antibiotics in poultry fattening... ;-)

I am obviously just kidding. If we go by the bioavailability data of raw (figure 2, top) and cooked (figure 2, bottom) broccoli, 200g of broccoli served as part of a warm meal will get your blood SFN levels up to only 2.5% or 1.2% of the most effective dose (5µM) used in the study. So, it's pretty certain that you'd have to gobble copious amounts of red cabbage juice (see picture on top of the article) to get there.

In view of the fact that lower concentrations yielded greater effects, it is however not totally unlikely that even concentrations as low as 1µM would yield results. With additional supplements, it does therefore not appear to be unrealistic to achieve blood levels like that (although you should not expect the increase to be linear).... anyway, I will let you know as soon as the first pertinent rodent or even human trials are available.


References:

• Alway SE, Degens H, Lowe DA, Krishnamurthy G. Increased myogenic repressor Id mRNA and protein levels in hindlimb muscles of aged rats. Am J Physiol Regul Integr Comp Physiol. 2002 Feb;282(2):R411-22.
• Fan H, Zhang R, Tesfaye D, Tholen E, Looft C, Hölker M, Schellander K, Cinar MU. Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells. Epigenetics. 2013 Oct 23;7(12).
• Totušek J, Tříska J, Lefnerová D, et al. Contents of Sulforaphane and Total Isothiocyanates, Antimutagenic Activity, and Inhibition of Clastogenicity in Pulp Juices from Cruciferous Plants. Czech J. Food Sci. 2011; 29(5): 548–556.
• Vermeulen M, Klöpping-Ketelaars IW, van den Berg R, Vaes WH. Bioavailability and kinetics of sulforaphane in humans after consumption of cooked versus raw broccoli. J Agric Food Chem. 2008 Nov 26;56(22):10505-9.

Classic Beats Super Slow; Single 198 Second Sprint More Time Efficient Than Work-Matched HIIT; Exercise Better Than THC; Metformin + Cardio + Lifting = Anti-Obesity Triplet; Self-Efficiacy & Training Adherence - Plus: More!

This is just a random selection of the unlimited movement patterns your body has been designed to execute - don't make the mistake and rely on only one of them!

The amount of really interesting, let alone revolutionary new studies on the effects of different exercise modalities is not exactly high, to say the least. I am not quite sure, what the reasons are, but as I have stated before, part of it certainly is that you cannot monetize on the results by producing patentable drugs based on your findings and will thus have a hard time to find sponsors / get funding. It is therefore no wonder that many published papers are spin-offs of small scale trials that have been conducted as part of dissertations. Others simply use rodent models, which may provide relatively reliable data, when it comes to the effects of running on a treadmill, but are not exactly what I would want to see, when it comes to weight lifting or any other of the myriad complex movement patterns our bodies can, but these days way too often don't do.

I have nevertheless been able to compile another potpourri of studies of which I would hope that one or the other will enlighten or at least entertain you. That being said, let's get started with this weeks installment of the Exercise Science Special of "On Short Notice", here at the SuppVersity...

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HIT it short, hit it hard, hit the glucose and be smart! Yo, this awesome rhyme would be my advice to the very busy chubby manager-types with compromised insulin sensitivity out there and it's based on the results of a very recent study by scientists from the Institute of Cardiovascular and Medical Sciences at the College of Medical, Veterinary and Life Sciences of the University of Glasgow in the UK (Whyte. 2013)

Figure 1: Power, workload (top) and metabolic effects of SIT and ES regimen (vs. control; bottom)

When Laura J. Whyte and her colleagues compared the effects of the single bout of very high-intensity exercise (SIT: 4x 30-s maximal sprints w/ 4.5min recovery between each) to a single maximal extended sprint (ES) matched with SIT for work done, they found that the immediate advantage of higher insulin sensitivity (measured via oral glucose tolerance test) in the work-matched continuous sprint the shorter duration 190s (TOTAL!) as well as almost identical...

• decreases is RER and carbohydrate oxitation, and
• increases in fatty acid oxidation

on the day after the exercise bout, in the presence of statistically significant reductions in insulin sensitivity only after the ES trial.

In other words: A single all out sprint on a braked cycle ergometer (as fast as you can; with obviously decreasing power in the course o the sprint) elicits greater metabolic effects within a 85% shorter timespan (198s vs. 1360s!), than work-matched classic HIIT training, with allegedly very long periods of active recovery.

That being said, I strongly caution against taking the results of this study as an incentive to perform the classic "go as fast as you can, for as long as you can" HIT sessions on exercise bikes, treadmills or ellipticals - those SUCK! *full stop* Be smart and either perform that one 3min sprint (if you really have no more time), or modify your HIIT training to incorporate longer high intensity phases (45-90s) at a work to active recovery ratio of 1:3 - 1:2, so that a resulting workout could look like that 4x 60s sprints, interspersed by 120s of active recovery. I would bet money that this protocol outperforms a work-matched continuous sprint in terms of its immediate and long-term metabolic effects.

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Opioid-like effects of exercise depend on intensity I guess you will be familiar with the term "runner's high"? Now, while the latter is usually ascribed to the exercise induced release of serotonin, the improved affect, the sense of well-being, the anxiety lowering and calming effects of exercise are probably mediated by the release of endocannaboids, of which scientists from the University of Arizona, the University of Texas Health Science Center and the Eckert College in St. Petersburg, Florida, have recently shown that the levels of these endogenous THC-like compounds depends on the intensity of the workout (Raichlen. 2013).

Liar, liar, THC junkie on fire ;-) You don't need to smoke weed before a workout if you get the intensity right! But could exercise also help people who recover from major depression to battle their tendency to obsess with negative thoughts and feelings?

At least in the 10 healthy regular runners who participated in the study, the results of which have been published in the Journal of Applied Physiology the endocannaboid exercise induced increase in circulating anandamide was most pronounced (~2x), when the subjects exercised at ~72% of their maximal heart rate (the workout consisted of 30min of treadmill walking, jogging, running at 45, 72, 83, and 92% of their maximal heart rate). Moreover, the post hoc analysis of the blood samples that had been immediately before and after the workout revealed that exercising at both the lowest and highest intensities had the exact opposite effect, although the reductions in serum anandamide were - when considered in isolation - were not statistically significant.

In conjunction with the results of another recent study that has been conducted at the Stanford University, it becomes evident that these results could actually be more than just "scientific masturbation", so to say. The Stanford researchers compared the reactions of 41 female patients who had recovered from major depressive disorder (MDD) and those of 40 healthy control, both of whom had been randomly assigned to either exercise for 15 minutes or quiet rest, to two sad mood inductions (once before and once after exercise or rest) and found that

"[while r]ecovered depressed participants who had not exercised exhibited higher NA [neagtive affect] after the second sad mood induction [...], both recovered depressed participants who had engaged in acute exercise and healthy control participants showed no increase in NA in response to the repeated sad mood induction." (Hogan .2013)

A reaction that goes against the so-called sensitization effect, which describes the tendency of depressed people (or people with a propensity to develop depression) to react with an increased level of negative effect to a repeated negative stimulus (Eisenstein. 2001) and would thus predict an increase in negative affect in response to the second stimulus as it was observed in the non-exercise group (figure 2, red box).

Figure 2: Negative and positive affect after 1st and second sad mood induction (left) and before and after exercise (right), respectively, in 41 female patients who had recovered from major depressive disorder (data from Hogan. 2013)

Moreover, the 15 minutes of exercise at an intensity the participant felt comfortable with led to an increase in positive affect participants in the exercise groups after the exercise bout, but failed to produce the same beneficial effect on the positive affect in the subsequent double-exposure to the filmic sad mood stimuli:

"However, in contrast to our hypothesis, we did not find any interaction between exercise condition and diagnostic group in level of reported PA following the repeated sad mood inductions that would be consistent with the notion of sensitization or habituation." (Hogan. 2013)

And who knows, if the exercise intensity had been higher, so that there had been more anandamide and other endocannaboids floating around in the brains of the study participants, this could even have changed the positive affect trajectory from the first to the second filmic sad mood induction? "Yo, that's so sad... hahaha" ;-)

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Image 1: Otsuka Long-Evans Tokushima fatty rats (OLETF, right) have a  genetic disposition to develop type II diabetes.

When metformin is good for the obese (pre-)diabetic and exercise is good, as well, metformin + exercise cannot be bad, right? At least in OLETF rats, one of the common rodent models of the metabolic syndrome, this assumption appears to apply (Jenkins. 2013).

According to the recently published paper by Nathan T. Jenkins and his colleagues, metformin and exercise do in fact work synergistically - at least as far as the obesity induced inflammation is concerned. While metformin decreased the pro-inflammatory overexpression of leptin, the rodents that have been exposed to an endurance type exercise regimen exhibited higher levels of the anti-inflammatory cytokine IL-10, which limit and ultimately terminate inflammatory responses (Moore. 2001).

Not just in view of the fact that IL-10 has also been implicated in the prevention and even treatment of auto-immune diseases, such as lupus erythematosus and multiple sclerosis (Beebe. 2002), I would always choose exercise over metformin - this is all the more true, if you are not morbidly obese in the first place!

And if you want to go even one step further, you simply add couple of interval sprints to the equation as those have been shown - in the same rodent model, by the way - to elicit greater improvements in HbA1c, the long-term marker of glucose management that "classic" steady state endurance exercise (Martin. 2013). Since the latter were mediated via differential microvascular changes than those Martin et al. observed in endurance trained OLETF rats, it is furthermore almost certain that they will add up. Probably not 1+1, but 1.5 and even 1.1 would still be better than 1.0, wouldn't it?

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The lack of the feeling of  self-efficacy is one of the best predictors of not sticking to a workout routine. And you know what? Oftentimes it's not your your, Joe or Jane who is to blame, but simply their cookie-cutter trainer or unqualified cousin who's dragging them to the gym. Now, think about that... could it be that you are a cousin / trainer like that!? No way, right?

A feeling of accomplishment is one of the main determinants of exercise compliance Have you ever wanted why you really enjoy going to the gym, while your obese cousin will only drag his ass over there if you kick him into the latter? Well, according to the latest study from the Johns Hopkins University School of Nursing and Division of Cardiology at the The Johns Hopkins University School of Medicine in Baltimore, Maryland, it may in fact be you and not Joe or whatever his name is, who is to blame. Probably you are just having him copy what you do, with either way too much weight, or so little weigh that he does not just feel bad about it, but cannot make real progress either (Nam. 2013).

The scientists call that which Joe is lacking a feeling of "self-effiacy", when he is going to the gym training next to his 75lbs lighter cousin, lifting sissy weights and looking like a fat balloon.

No wonder he is falling off the wagon! Specifically, if you also take into consideration that in addition to the missing feeling of accomplishment, which increases his chance of non-compliancy by 19%, Joe also exhibits most of the other features Nam et al. have found to increase the chance of dropping out, specifically,

• low fitness - 26% increased chance of dropout and
• higher insulin resistance - 17% increased chance of dropout,

in the course of their experiment with 140 overweight, sedentary individuals with type II diabetes, who were randomly allocated to a 6-month, 3 times per week exercise intervention or a non-exercise control. And while bodyfatness, i.e. a higher total and subcutaneous abdominal fat percentage appeared to be indicators of higher compliance, when the scientists just looked at the raw data, these positive effects vanished, when they plied a multiple logical regression analysis.

So what's the take home message, here? Cousin or not, people won't do well on cookie cutter plans that won't allow them to make, see and feel progress.

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Isn't it astonishing how versatile and important these stem cells from the bone marrow are (image NIH. 2001)

1h of exercise thrice a week increases hematopoietic stem cell (HSC) count in the bone marrow With the almost magic effects of stem cell therapy being on everybody's lips, these days. You will probably be intrigued to hear that researcher from the McMaster University have recently established that a very reasonable amount of 3x 1h of exercise per week increased the quantity of hematopoietic stem cells in the bone marrow of exercised mice by +20% compared to their sedentary peers (de Lisio).

With it's likewise statistically significant effect on the proportion of whole BM cells in G(2)/M phase of cell cycle (p<0.05 and an increase in the number of spleen colonies (+48%, p<0.05) in those "model patients" who received transplants from the exercised compared to transplants from sedentary mice, it is thus likely that people who exercise regularly will benefit from both the quantitative increase, as as well as the qualitative improvements these multipotent stem cells, which  give rise to all the blood cell types from the myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (T-cells, B-cells, NK-cells), undergo in response to a moderate amount of exercise.

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Finally acknowledged: "[C]ombination exercise g[ives] greater benefits for weight loss, fat loss and cardio-respiratory fitness than aerobic and resistance training modalities", alone! And this is only the first part of the conclusion of a recently published paper by Suleen S Ho, Satvinder S Dhaliwal, Andrew P Hills and Sebely Pal, who explicitly suggest that

"Therefore, combination exercise training should be recommended for overweight and obese adults in National Physical Activity Guideline" (Ho. 2013)

How the scientists came to that conclusion? Well they could simply have read the SuppVersity news, but instead they conducted a 12-week trial, in the course of which 97 overweight or obese men (n = 16) and women (n = 81) (BMI >25 kg/m² or waist circumference >80 cm for women and 90 cm for men), aged 40 to 66 years, were randomly assigned to a either aerobic, resistance or combined training regimen (n=16 for each) or a sedentary control group (n=15). The results, spoke for themselves.

Figure 3: Changes in body fat (%; top) and VO2Max (bottom) in the course of the 12-week trial (based on Ho. 2013)

In the absence of statistically significant reduction in energy intake, or macronutient composition, the combination subjects in the combination group were the only ones to lose statistically significant amounts of

• body weight (-1.6kg),
• body fat (-1.9kg or 1% body fat), 
• android (=visceral) fat (-1.3kg),

had the most pronounced reduction in waist circumference (-2.6% vs. -2.5% in RT and -2.0 in AT) and were the only ones with statistically significant improvements in VO2Max, a marker of general cardiovascular fitness.

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Is there maybe more room in your training regimen for slow reps, than you may have thought? If you go by the statement "Slow speed-resistance training induced a greater adaptive response compared to training with a similar resistance at 'normal' speed" from a paper by Mark D. Schuenke and his colleagues from the University of New England, the Rocky Vista University, the College of Health Sciences and Profession and the Ohio-University that was published in the October Issue of the Journal of Applied Physiology (Schuenke. 2013), it would seem so.

If you do however take a closer look at the actual results you realize how important the adjoining qualificatory remark "However, training with a higher intensity at 'normal' speed resulted in the greatest overall muscle fiber response in each of the variables assessed" really is. After all, the "intensity" is per definitionem 20-45% higher in a classic strength training regimen compared to the often laughed at slow-speed resistance training (SS), which was - at least in the study at hand - defined as follows:

• SS: 6-10 reps, super-slow (10s) concentric (no typo!) and slow (4s) eccentric TUT, 40-60% of the individual 1-RM

Both the traditional strength training (TS) as well as the strength endurance regimen (TE) to which this protocol was compared used a TUT of 1-2s on the concentric and eccentric phase, but differed in terms of the weight and rep-numbers, which were

• TS: 6-10 reps at 80-85% 1-RM
• TE: 20-30 reps at 40-60% 1-RM

So, based on the qualificatory remark and a short glimpse on figure 4 you already know that the TS regimen yielded the best results during this 6-week resistance-training program that targeted the quadriceps femoris muscle group, in a total of 17 training sessions (only 2 in the first week), which were supervised to ensure that the 34 young, untrained female participants went to positive failure within the targeted repetition range on all three sets of the three exercises (leg press, squats, and knee extension) they performed after brief warm-up with ~2 min rest between sets and exercises.

Figure 4: Changes in body composition (left) and changes in muscle fiber cross-sectional area (all expressed relative to group baseline; data calculated based on Schuenke. 2013)

What's still missing though is the effect on overall body composition, where the super slow regimen did in fact produce almost identical results, while the "pump" workout ... ah, I mean the "strength endurance workout" sucked here just as it did as far as its effect on the increase in growth the number of hypertrophy-prone type II fibers is concerned.

So what's the take home message here? If you want some diversity, you can incorporate super slow sets into your regimen... but do you have to? At least based on the results of the study at hand, which was unfortunately conducted with untrained young women (who by the way love this alternative training styles) and is therefore not exactly representative for the average advanced trainee, the answer is "rather not, no!"

What neither the advanced nor the rookie who is striving to improve his or her body composition should do, however, is to train in the hilarious strength endurance range of 20-30 reps per set. If you want to build muscular endurance you either go out sprinting, beat the punching bag or do plyometrics.

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As I know you, you still want more, hah? Well, too much volume is not good for you and in case you cannot wait until next week, there will be some intriguing exercise news in the days to come, probably more on the SuppVersity Science Round-Up with Carl Lanore, on the Super Human Radio Network on Thursday, this week and obviously every day on the SuppVersity Facebook Wall @ www.facebook.com/SuppVersity - like it and always be the first to now!


References:

• Beebe AM, Cua DJ, de Waal Malefyt R. The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine Growth Factor Rev. 2002 Aug-Oct;13(4-5):403-12. 
• Eisenstein, E. M., Eisenstein, D., & Smith, J. C. The evolutionary significance of habituation and sensitization across phylogeny: A behavioral homeostasis model. Integrative Physiological & Behavioral Science. 2001; 36, 251–265.
• Ho SS, Dhaliwal SS, Hills AP, Pal S. The effect of 12 weeks of aerobic, resistance or combination exercise training on cardiovascular risk factors in the overweight and obese in a randomized trial. BMC Public Health. 2013 Aug 28;12(1):704.
• Jenkins NT, Padilla J, Arce-Esquivel AA, Bayless DS, Martin JS, Leidy HJ, Booth FW, Rector RS, Laughlin MH. Effects of Endurance Exercise Training, Metformin, and their Combination on Adipose Tissue Leptin and IL-10 Secretion in OLETF Rats. J Appl Physiol. 2013 Sep 27. 
• de Lisio M, Parise G. Characterization of the Effects of Exercise Training on Hematopoietic Stem Cell Quantity and Function. J Appl Physiol. 2013 Sep 27.
• Martin JS, Padilla J, Jenkins NT, Crissey JM, Bender SB, Rector RS, Thyfault JP, Laughlin MH. Functional adaptations in the skeletal muscle microvasculature to endurance and interval sprint training in the type 2 diabetic OLETF rat. J Appl Physiol. 2013 Aug 23.
• Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683-765.
• Nam S, Dobrosielski DA, Stewart KJ. Predictors of Exercise Intervention Dropout in Sedentary Individuals With Type 2 Diabetes. J Cardiopulm Rehabil Prev. 2013 Sep 24.
• National Institute of Health (NIH). Stem Cell Information Webpage. June 17, 2001. < https://stemcells.nih.gov/info/2001report/chapter4.asp > retrieved on Oct 01, 2013.
• Raichlen DA, Foster AD, Seillier A, Giuffrida A, Gerdeman GL. Exercise-induced endocannabinoid signaling is modulated by intensity. Eur J Appl Physiol. 2013 Sep 19.
• Whyte LJ, Ferguson C, Wilson J, Scott RA, Gill JM. Effects of single bout of very high-intensity exercise on metabolic health biomarkers in overweight/obese sedentary men. Metabolism. 2013 Sep 19.

How Working Out Changes the Morphology of Your Body Fat and Why This Explains that Intensity and Explosiveness Hold the Key to Getting and Staying Lean, Fit and Healthy

Can the guy on the right run away from the bloated macrophage coated fat cells on the left? Today's first post in the SuppVersity Exercise Science Week does hold the answer to this existential question.

Those of you who don't just read, but also think about the headlines of these posts will probably already have theorized about the remote possibility that I could have changed my mind and discarded the original plan to do an "exercise quickie" early this week (see SuppVersity post from Saturday). Now, before you are getting mad at me, let me give you the (as I would say good) reason for doing that: Some, if not almost all of the exercise related studies, I have piled up here are actually too interesting to end up as part of a mash-up. That's particularly true in view of the fact that my time budget during the week does not allow me to discuss them in appropriate detail. So, even if wanted to end up writing >10,000 word posts, this would only work on 48h days ;-)

The solution I came up with is easy and in my humble opinion actually quite cool: The world's first SuppVersity Exercise Science Week! In the course of the next days, I will serve you one or two of the latest studies from the realms of exercise science per day - with the rest (if there is one) being "mashed up" in the Short News on Saturday. Cool? No? Well, bad luck, then ;-)

We will kick off the week with the modulatory effect of exercise on adipose tissue

We all know that exercise is a good way to support and control diet induced weight loss. Specifically for those of us who are already on the lean(er) side of a "divide", where obese is soon going to be the new normal (see "Obese is Going About to Become the New Normal"), it's probably even obligatory, if it's not being skinny fat that's our diet goal. That being said, a recent review of Izawa et al. provides a couple of intriguing insights and links between physical activity and the structural changes our white adipose tissue is undergoing (Izawa . 2013). In this first post of the SuppVersity Exercise Science Week I am going to summarize and expand on some of these points and point towards the implications these more or less recent, in parts pretty geeky and abstract findings have on the way we could, should, or might train:

• Training can increase lypolysis: Compared to subcutaneous fat (SAT), visceral fat (VAT) has a higher lipid turnover. Interestingly, the same high lypolytic rates which render people with high VAT so vulnerable to high levels of blood fats, are also responsible for the comparable ease with which you can shake those unhealthy VAT depots melt away, when you're working out and/or dieting. The fat around the organs is not just the easiest to store, it's also the easiest to access and liberate (Ross. 2000). That this is not a location-specific characteristic, has already been proven. What does yet still have to be elucidated, is when and due to which complex mechanisms the genetic differences between the subcutaneous and visceral fat cells are getting programmed and whether there may be a way to reverse them.

• Training will modulate the growth environment: The maturation of stem cells into SAT, VAT, or BAT (brown adipose tissue) cells appears to be highly dependent the specific milieu in which they are in. The latter, in turn, is characterized by the presence of  various growth factors. The best known and allegedly most important ones belong to the transforming growth  factor (TGF) family. It is their presence that will control whether a stem cell turns into a "brown" = metabollically active fat cell with thermogenic abilities or a regular white one (SAT or VAT). While BMP2- and BMP-4 are responsible for the formation of white adipocytes, BMP-7 drives brown fat cell development. Together with FGF21 another of those growth factors, these proteins determine the fate of pre-adipocytes. Unfortunately, the research on the different ways by which exercise controls these factors is yet still in its infancy. We will take a closer look at what we know already in the next paragraph.

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  As you know from the "CLA Destroys Body Fat" post, PPAR-γ downregulation is also the main pathway by which conjugated linolic acid strips mice of almost all their body fat (read more). The exercise induced upregulation of the so-called hypoxia-inducible factor (HIF-1α) appears to do the exact same thing: Suppress PPAR-γ and thus hit the off switch on body fat storage.

  Training reduces WAT size and number: According to a 2004 review of the literature it appears as if exercise training (aerobic) specifically in early life reduces the number and size of WAT in rodent (Stallknecht. 2004). These results have been confirmed in a 5-week study designed that was conducted to elicit the underlying molecular mechanisms only recently (Sakurai. 2010); and the results of the Sakurai study suggest that it is one of our old acquaintances that is to "blame": The peroxisome proliferator-activated receptor-γ (PPAR-γ), a central regulator of adipogenesis! It's inhibition by physical activity is what does the trick. Now, as a diligent student of the SuppVersity you will certainly remember that this is also the main pathway by which CLA, rhein (from rhubarb) and other weight loss adjuvants work their "magic" - a blockade of the PPAR-γ receptor is like hitting the "off switch" on the body fat storage control panel. And who is it who hits that switch? Well, according to the current research it appears that this is the prerogative of the hypoxia-inducible factor (HIF-1α) which is in turn controlled by exercise induced WNT and AMPK signaling.

• Training improves angiogenesis in WAT: While you hear about angiogenesis, i.e. the physiological process through which new blood vessels form from pre-existing vessels, oftentimes in the context of various endothelial pathologies, its induction within the white adipose tissue is actually highly desirable. Scientists have long been speculating that the insufficient wiring of the adipose organ with blood vessels and the subsequent hypoxia are at least partly to blame for the constant inflammation in the ever-expanding fat depots of the obese (Ye. 2009). Since HIF-1α (see previous paragraph) also promotes the expression of vascular endothelial growth factors and their receptors (VEGFRs / VEGFs), its downstream activation by preferably intense physical activity should improve the endothelial wiring of the fat tissue and thus help sooth the chronic inflammation, that's at the heart of many, if not all of the key-features of the "metabolic syndrome".

• Training increases the adipocyte size depended release of adiponectin: In the past couple of months, the adipokine adiponectin turned out to do most of the good stuff (esp. improvements in glucose and fatty acid metabolism), of which scientists previously thought it was the prerogative of leptin. It is therefore important that exercise increases the rate at which a given increase in adipocyte size (obviously in response to fat storage) will increase the release of adiponectin (Miyazaki. 2010). If we use the classic notion of the adipokine as a signal the fat cells use to tell the brain and the rest of the body how much fat remains to fuel its energetic demands, you could say: Working out allows your body to see how much fat you actually got. The physiological consequences of this revelation are increases in lypolysis and fatty oxidation, as well as overall metabolic benefits.

So far for the stuff that will make you look smart, when you parrot it in front of your gymbros. In order to not just look smart, but also be smart -- and in this case train smart -- you will yet also have to know the implications of these revelations and this is exactly what the rest of this article is going to deal with:

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  Making HIIT a Hit! learn how in the SuppVersity  Special (read more) and use it to get lean & healthy and, more importantly, stay lean and healthy!

  HIF-1α <> PPAR-γ <> adipocyte crosstalk - an(-other) argument for high intensity exercise: Since the HIF-1α response to a given training stimulus decreases once the body has adapted to the stressor by increasing its exercise capacity (Lundby. 2005). The crosstalk between HIF-1α, PPAR-γ, and your fat cells provide another reason to work out in the higher range of the VO2max continuum and to never neglect the imperative of constant progression (even if it's only a progression of 0.1km/h during your sprints on the treadmill - adaptation means stagnation, if you don't raise the bar appropriately)

• Wnt10B response to stretching - an argument for heavy eccentrics and/or statics to revamp your body (less fat, more muscle!): The findings of Akimoto et al. point towards the existence of another rather strength-training specific contributer to the fat loss and leanness promoting effects of exercise - the stretch-induced activation of the wingless-type (WNT) MMV integration site family member WNT10b, the quasi cousin of an upstream mediator of HIF-1α (Akimoto. 2005). The activation of the WTNs does actually get down to the root of the trouble and will not just inhibit the formation of new fat cells from pre-adipocytes, it will also divert the mesenchymal and not yet specialized stem cells to turn into osteroblasts (bone) or myoblasts (muscle). In fact, research has shown that WNT signaling is a major contributer to both the recruitment of new muscle progenitor cells from the aforementioned pool of yet unspecific stem cells and skeletal muscle hypertrophy (Polesskaya. 2005; Armstrong. 2005).

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  You will also benefit from integrating plyometrics into your existing routine - build the Jack of All Traits Workout
  

  The greater WNT response to power vs. strength training points towards the superiority of a plyometrics to get and stay lea: In view of the results of Leal et al., who report a 3x greater WNT gene response to power compared to strength training in their 2011 paper on the effect of different resistance-training regimens on the WNT-signaling pathway, plyometrics, which have way more in common with the power training protocol in the Leal study (40% lighter weights; faster, explosive contractions) than whatever powerlifting routine you may have been thinking of, should be a superior means to stay lean (Leal. 2011)

• Exercise restores your body's fat gauge: If you wanted to pointedly summarize the exercise induced reductions in leptin expression, the associated restoration of leptin sensitivity in the obese, and the increased adiponectin release relative to the increase in fat cell diameter, you could actually say that exercise restores your body's fat gauge. It allows your brain and the other organs to see how much body fat you still got and have them react appropriately. Funnily this is also why you body will, clever as is is, pull the emergency break, whenever your body fat levels become too low (cf. "The Athlete Triad Series").

Did you know that 10% of the fat cells have to be renewed every year? I know this is speculative and we are not talking about ZERO adipocyte maturation here, but what do you think will happen when a fat cell is due and you just hit the off-switch on adipocyte maturation?

A final word of caution: I am well aware that some of you may take this article as justification for training themselves into the ground. So please(!) keep in mind that hypoxia induced WNT10 and stretch induced WNT10b signaling, as well as most of the other fancy stuff you have learned about in the previous paragraphs are stress responses that require adequate recovery periods for the metabolic and growth responses they induce to take effect. Sleep, Eat, Train, Rest, Sleep, Eat, Train, Rest, Sleep, Eat... do you notice something? Yeah, right that's a 3/1 ratio of non-stressful occupations, namely sleeping, eating and resting to a single stressor, i.e. training. In other words, 25% of your result are "made" in the gym, 75% in bed (don't make it too stressful there ;-), in the kitchen and even, when you spend time with friends and family or simply sprawl out on the couch. Think of that, when you're designing your next training routine.

References:

• Armstrong DD, Esser KA. Wnt/beta-catenin signaling activates growth-control genes during overload-induced skeletal muscle hypertrophy. Am J Physiol Cell Physiol. 2005 Oct;289(4):C853-9. Epub 2005 May 11.
• Akimoto T, Ushida T, Miyaki S, Akaogi H, Tsuchiya K, Yan Z, Williams RS, Tateishi T. Mechanical stretch inhibits myoblast-to-adipocyte differentiation through Wnt signal-ing. Biochem Biophys Res Commun. 2005; 329: 381-385
• Izawa T, Ogasawara J, Sakurai T, Nomura S, Kizaji T, Ohno H. Recent advances in the adaptations of adipose tissue to physical activity: Morphology and adipose tissue cellularity. J Phys Fitness Sports Med. 2013:1(3): 381-387. 
• Leal ML, Lamas L, Aoki MS, Ugrinowitsch C, Ramos MS,  Tricoli V, Moriscot AS. Effect of different resistance-training regimens on the WNT-signaling pathway. Eur J Appl  Physiol. 2011; 111: 2535-2545
• Miyazaki S, Izawa T, Ogasawara JE, Sakurai T, Nomura S, Kizaki T, Ohno H, Komabayashi T.  Effect of exercise training on adipocyte-size-dependent expression of leptin and adiponectin. Life Sci. 2010; 86: 691-698.
• Lundby C, Gassmann M, Pilegaard H. Regular endurance training reduces the exercise induced HIF-1alpha and HIF-2alpha mRNA expression in human skeletal muscle in normoxic conditions. Eur J Appl Physiol. 2006 Mar;96(4):363-9. Epub 2005 Nov 12.
• Polesskaya A, Seale P, Rudnicki MA. Wnt signaling induces the myogenic specification of resident CD45+ adult stem cells during muscle regeneration. Cell. 2003 Jun 27;113(7):841-52.
• Ross R, Dagnone D, Jones PJ, Smith H, Paddags A, Hudson R, Janssen I. Reduction in obesity and related comor-bid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med. 2000; 133: 92-103.
• Sakurai T, Endo S, Hatano D, Ogasawara J, Kizaki T, Oh-ishi S, Izawa T, Ishida H, Ohno H. Effects of exercise training on adipogenesis of stromal-vascular fraction cells in rat epididymal white adipose tissue. Acta Physiol (Oxf). 2010; 200: 325-338.
• Stallknecht B. 2004. Influence of physical training on adipose tissue metabolism -- with special focus on effects of insulin and epinephrine. Dan Med Bull. 2004; 51: 1-33.
• Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond). 2009 Jan;33(1):54-66.