N-Acetylcysteine Hampers Adaptive Response To Exercise. 50% Reduction in JNK Phosphorylation Entail Reduced Expression of Genes Involved in Cell Proliferation, Apoptosis, Inflammation and DNA Repair.

Image 1: The "beneficial" bad guys under
the microscope: Reactive oxygen species
(green-yellow) within endosomes
of human smooth muscle cells
(Circulation Research. 09/2007)

If you listened to my dissertation on the sulfur-amino acids on Carl Lenore's Super Human Radio (cf. shownotes), you will be aware that I was and still am quite skeptical as far as the touted beneficial effects of n-acetylcysteine (NAC) supplementation on exercise performance are concerned. A very recent study that has been conducted by a team of Australian scientists from Deakin and Victoria University in Melbourne appears to warrant this skepticism.

In a 2006 study (McKennah. 2006) the same group had found that N-acetylcysteine can attenuate the decline in muscle Na+,K+-pump activity and thus delay fatigue during prolonged exercise in humans. But even then, the data on real-world and long-term benefits of n-acetylcysteine supplementation was conflictive and the authors' conclusion that NAC exerted it's effect mainly via the suppression of ROS (reactive oxygen species) generation, prompted questions on whether the suppression of exercise-induced ROS-generation would have any downstream effects on the hormetic (=positive adaptation / strengthening reaction after an insult) response scientists suspect to be the major driving force of the beneficial effects of exercise on perfmormance, as well as general and metablic health.

Illustration 1: Hypothetical dose-response curve of the hormetic response to reactive oxygen species inducing exercise (x-axis, arbitrary units); positive units on the y-axis indicate beneficial, negative units negative effects.

Indeed, a 2009 study by a group of scientists from the University of Jena (Ristow. 2009) was able to show that administration of an anti-oxidant supplement that contained 1,000mg vitamin C and 400 IU of vitamin E prevented the health-promoting effects of exercise on in trained, as well as untrained subjects.

Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.

In view of the latter results, the major news here is neither that an N-acetylcysteine infusion before a 45min. cylcing trial at 71% of the individual VO2max that was followed by a bout of all out sprinting to fatique partially blocked the release of reactive oxygen species in the eight male subjects (age, 27.1±5.6 years; height, 180.3±5.4 cm; body mass, 76.7±10.9 kg), nor the related prolongation in time to fatigue the scientists observed. What is new, however, is the data Petersen et al. obtained from sophisticated analyses of the activation of signaling pathways and genes, which have been implicated in exercise adaptation in human skeletal muscle (Petersen. 2011).

[...] NAC infusion blocked the exercise-induced increase in JNK phosphorylation, but not ERK1/2, or p38 MAPK.  Nuclear factor-κB p65 phosphorylation was unaffected by exercise; however it was reduced in NAC at fatigue by 14% (P<0.05) compared to pre-infusion.

This is an important finding, in so far, as it goes to show that the induction of JNK phosphorylation by exercise is ROS-dependent. Now, a -49% reduction in phosphorylation of JNK, a protein that has been shown to be activated as a consequence of strenuous aerobic and/or strength training, would not be a bad thing, if its activation would not play a significant role in the regulation of genes "involved in cell proliferation, apoptosis, inflammation and DNA repair (Karin and Gallagher. 2005) and thus [...] exercise adaptation."

It is difficult to say how the results of this short term study with intravenous n-acetylcysteine will translate into athletic practice. The (over-)consumption of large doses >>1-2g of oral NAC to facilitate exercise recovery, as it has been implicated by some of the advocates of the acetylated version of the sulfur-amino-acid cysteine, by all means, seems to be counter-indicated, as another dreaded foe, exercise-induced reactive oxygen specimen (ROS), eventually exhibits its complementary, hormetic face. The real challenge is thus not extinguish the fire, but to keep it burning at an optimal rate, or, metaphorically speaking, to generate and/or suppress ROS in a way which facilitates a precision landing on the maximum of the graph in illustration 1 ;-)

Short Bursts of High Intensity Circuit + Plyometric Training Keeps Blood Sugar "In the Zone" - No Matter If Your Parents Were Obese Diabetics, Or Lean Athletes!

Circuit Train Your Way Out of the Type II Diabetes Trap - High Intensity Resistance Training + Plyometrics Work Regardless of "Bad Genes" | It's your Lifestyle not your destiny that determines whether you'll become and insulin resistant lifestyle diabetic or not.

While many people still believe that "cardio" training was the only way to keep your blood sugar levels under control, anyone who knows something about exercise physiology will argue that a highly anaerobic exercise regimen, just like high intensity resistance training, for example, should be a way more powerful blood glucose normalizer than a 20-40 minute jog.

I guess this was what Ryan D. Russell, Arnold G. Nelson, and Robert R. Kraemer must have had on their minds, as well, when they planned their most recent experiment. An experiment that was designed to (1) determine the clinical benefits of "high intensity-resistance-focused" exercise training (HIRFT) in  healthy young people (age 23.5; BMI 24.25kf/m²) and (2) elucidate whether these effects would differ between young people with and without a family history (FH) of type II diabetes, if the baseline fasting glucose levels were identical (6.67 mmol/L in the study at hand).

Using HIIT you can achieve similar results as in the study at hand

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Making HIIT a Hit Part II/II

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The study consisted of three main parts: (A) a pre-training test day including fasting blood glucose measurement followed by determination of an estimated one-repetition maximum (1- RM) for bench press, squats, and dead-lift, and twopost-workout blood glucose measurements; (B) 7-weeks of short, HIRFT using fast-paced superset circuit training, body core, and plyometrics training; and, (C) a post-training test day including fasting and post-exercise blood glucose and re evaluation of calculated maximal strength. Participants were instructed not to perform strenuous exercise, nor consume alcohol or caffeine at least two days prior to either test day.

Table 1: Overview of the weekly training schedule (Russel. 2014)

Fasting blood glucose was measured in order to establish at baseline to ensure participants are evenly matched and not pre-diabetic. In order to determine if HIRFT is an effective means of resistance training, a sub-group was randomized to perform traditional multi-set resistance training instead of the fast-paced circuits, and strength gains was compared.

"Building the Jack-of-All-Traits Legs Workout With Squats, Jump Squats and Body Weight Plyometrics?" | more

"Individual resistance exercises were the same between both modes of training, and included: squat, bench-press, lateral pull down/seated row, shoulder press, push-up, bicep curl, triceps extension, and dead-lift exercises performed in that order.

Time to complete each session of multi-set training was 40-minutes, including 1-minute of rest between sets; while each circuit training session was limited to 10-minutes excluding warm-up and cool-down with no rest between exercises.

All subjects completed the same plyometric and body core exercises. Core and plyometrics continually changed with increased fitness. Core was performed in less than 15 minutes, using weighted/resistance techniques including, but not limited to: dumbbell sit-ups, medicine-ball toss, rolling on ab wheel (or barbell), and plank positions.

Plyometric workouts were completed in 50 minutes, and utilized short bouts of explosive movements with several minutes of rest between. Some workouts included: stadium sprints, clapping push-ups, box jumps, obstacle hops, ramp-runs, and various fast medicine ball and dumbbell movements.

The participants were encouraged to drink water ad-libitum before, during, and after workouts. Training progression was continuously monitored and load adjusted for all participants in both exercise groups to ensure continued progression, enabling all participants to continue to work out at 65-85% of 1RM (8-12 reps; to failure on last set) throughout training.

Figure 1: Strength gains (righ) and blood sugar reductions (left) correlate negatively (Russel. 2014)

While the specific HIRT circuit training showed significant reductions in fasting blood-glucose (p < 0.05), there were no differences in fasting, post-exercise, and 10-min recovery blood glucose concentrations between FH and CON.

Strength increased from pre to post training similarly in both groups, while fasting blood glucose concentrations decreased with training overall (p = 0.0054), with no differences between FH and CON groups (p = 0.7). Last but not least, the scientists found an inverse correlation between percent strength gains and decreased blood glucose concentrations from pre- to post-training (r= -0.519, p = 0.05), which indicates that the strength gains and thus eventually the training success determined the health improvements (measured as reductions in blood glucose levels).

Suggested read: "Isn't High Intensity Interval Training (HIIT) For Everyone? Study Puts "!" Behind "Personalized Training" - Fitness, Fatness, Age & More Determine Its Effective- & Usefulness" | read more

Bottom line: The study at hand demonstrates having a family history of type II diabetes is a lame excuse not to avoid having blame yourself for developing diabetes, when you are too lazy to go to gym to give your body a chance to burn off some of the sugary garbage you're shoveling down your piehole whole day, just like your sick relatives did.

Apropos "burning glucose", I am not sure why people still believe that it would always take endless, boring cardio sessions to ward off diabesity, when it's resistance training that depletes your intramuscular and hepatic glycogen stores to make room for the dietary glucose that would otherwise build up in your bloodstream until your organs are sugar-coated.

Reference:

• Russel, et al. "Short bouts of high-intensity resistance-style training produce similar reductions in fasting blood glucose of diabetic offspring and controls." Journal of Strength and Conditioning Research (2014). Publish Ahead of Print - DOI: 10.1519/JSC.0000000000000624

Exercise OR Calorie Restriction? Is This a Valid Question? Differential Epigenetics of Exercise and Calorie Restriction Suggest Otherwise.

It is beyond me, why the war between proponents of exercise based and calorie reduction based approaches to weight loss are still raging. As a faithful "student" of the SuppVersity, you know that I have always been recommending a combination of both for improved body composition, well-being and general health and was pretty angry, when Gary Taubes claimed in the course of Dr. Oz's ridiculous dissertation on the dangers of low carb diets, that exercise would only stimulate hunger and would thus fail to produce a beneficial effect on weight loss and related health problems (cf. video 1, below). A group of researchers (Karrie. 2011) from the Department of Nutritional Sciences at the University of Texas have now conducted a research study that may well shed some light onto what exactly (in this case this means on a epigenetic level) happens in the course of calorie restriction and/or exercise induced weight loss...

Video 1: Gary Taubes on Dr. Oz' show talking about the futility of exercise.
(Dr. Oz, official homepage)

Karrie, et al. had analyzed adipose gene expression in 48 female diet-induced obesity (DIO) mice in response to 8 weeks of either and ad-libitum fed CONTROL diet, a 30% calorically reduced regimen (CR), a treadmill exercise regimen (EX, with ad-libitum control diet), or  a continuation of the hypercaloric high fat diet (DIO) which made the mice fat in the first place (before the start of the experiment). What the scientists found is quite interesting and - at first sight - appear to rectify Taubes' skepticism with regards to exercise:

Relative to the DIO controls, both CR and EX reduced adiposity by 35–40% and serum leptin levels by 80%, but only CR increased adiponectin and insulin sensitivity.

Meaning visible improvements in terms of body fat were almost identical (cf. fig. 1), while favorable metabolic changes in the areas of  the hunger / satiety, insulin and leptin regulating peptide, as well as insulin sensitivity on the receptor level, occurred only in consequence to a reduction in caloric intake beyond maintenance.

Figure 1: Body weight and composition changes after 6 weeks on different diet / exercise protocols.
(data adapted from Karrie. 2011)

Only a few days ago I reported similar results, i.e. no effects of exercise alone on insulin sensitivity in the Layne study.  Other than Layne et al., whose primary focus was on m-TOR and AMPK responses in muscle tissue, the study at hand provides additional data on the differences in the epigenetic responses to calorie restriction, on the one, and exercise, on the other hand, which may well explain the (disappointing) observations:

Gene expression microarray analysis of visceral white adipose tissue revealed 209 genes responsive to both CR and EX, relative to the DIO group.  However, CR uniquely altered expression of an additional 496 genes, whereas only 20 were uniquely affected by EX.  Of the genes distinctly responsive to CR, 17 related to carbohydrate metabolism and glucose transport, including glucose transporter (GLUT) 4.

What this means is that both exercise, as well as calorie reduction, have 209 gene responses in common (probably responsible for the similar effects on weight loss); yet, additional 496 genes are modulated exclusively by calorie restriction and among these are 17, of which we already know that they are related to carbohydrate metabolism and glucose transport. It is thus suggesting itself to speculate that these genes are the ones, responsible for the beneficial effects on insulin sensitivity, which could not be observed in the exercise only group.

So, was Gary Taubes right, afterall? No. While it may be that exercise alone is not capable to upregulate insulin sensitivity its benefits on overall health, weight loss and above all weight maintenance have been so well established that it would be outrageous to question the advice any sensible nutritional counselor will provide his overweight clients with: Eat healthy (high protein, low / moderate carb, enough fat, whole foods, etc.), and moderately reduce your calorie intake, and begin an exercise regimen that is demanding, but not overcharging. Eventually, when this program has become a habit and the habit becomes a lifestyle, you can be certain that you are never going to be "the biggest loser" again.

Set to Be Obese? Epigenetic Programing in Utero - The Roles of Over- & Undernutrition, High & Low Protein, Fruits, Veggies, Zinc, Magnesium, Chromium, Vitamins & More

Image 1: Your mother's diet is not the sole cause of your love handles and health problems, but it could well have tipped the scale to your fat disadvantage. Don't be resentful, but don't repeat the same mistakes, either!

While it is certainly false to assume that anyone can't help but to get obese, it's similarly hard to deny that some people just have to cut back on the coke and sweets they eat to get back in shape, while others struggle with shedding superfluous weight (=fat) and regaining their health even if they are in a reasonable caloric deficit, eat a whole foods diet and exercise regularly. "It must be in my genes!" is what you will usually hear from people on both ends of the spectrum and while the former will smile at you and grab the next best snickers bar, just "to make sure that they don't lose too much weight", the unfortunate people on the other end of the spectrum are clutching to each and every straw, or, in these days of Internet quackery, "expert" advice to finally solve their life-long misery.

In today's blogpost I want to take a brief look at the leatest research into the epigenetic realities of obesity and how those nasty love-handles you have been carrying around for years, now, may actually have been "programmed" when what is now your body was still a bunch of constantly differentiating cells.

A fetus needs more than just adequate folate (let alone folic acid)

We have known for decades, that the consequences of fetal malnurishment, i.e. the insufficient provision of macro- and micronutrients, go well beyond an increase in infant morbidity and mortality. Van Assche et al. report as early as in 1977 that fetal growth retardation (due to malnurishment or other causes) was associated with reductions in both the size and the function of the pancreas (Assche. 1977); reductions, of which Hales et al. were able to show that they can lead to glucose intolerance and hypertension later in life (Hales. 1991).

Image 2: No, no, no! Juicing your fruits and downing 5-6 apples, oranges, peaches, lemons, grapefruits or whatever in one sitting is not healthy! Neither for you, nor for your offspring!

What can you do? As I said data from human studies is scarce and mostly observational, but if you are concerned about the beta-cell autoimmunity and subsequent increases in diabetes risk of your offspring, a study from the University of Tampare suggests that it may be a good idea to eat more berries (-10% risk) and to drink more coffee (-38% risk; Virtanen. 2011). If you are afraid that your offspring may be too small, you better eat fruit and veggies instead of pills, as the consumption of the former and not the total amount of micronutrients correlates with the size of a newborn (Loy. 2011). Thusly avoiding low intakes of (leafy) vegetables and (malaceous) fruits, all you need to reduce the incidence of allergic wheeze in your offspring is to make sure you get enough chocolate (low chocolate consumption = +36% increase; Erkkola. 2012) and avoid fruit and berry juices (+40% risk increase) and and you should be good to go ;-)

The overall message should yet be: Don't stuff or starve yourself and stick to the principles of healthy living I have been trying to piece together like a puzzle in the past 727 posts and the countless comments here at the SuppVersity. This will be good for you and for your offspring!

In the last decade more and more scientists have tried to elucidate the exact mechanisms behind this metabolic deteriorations. And while the increased awareness of the importance of dietary folate is probably the most prominent results of these efforts, vitamin B9 is by far not the only (micro-)nutrient in your diet which can exert far-reaching long-term effects on your offspring. And though much of the information we have is based on rodent or epidemiological human data, I believe that it is worth considering how what you eat today, may influence the health of your children in the future:

• Micronutrient deficiency and body fat % of the offspring: In a series of studies, Rao et al. were able to show that total (-50%) micronutrient deficiency, as well as an insufficient supply of magnesium, manganese, chromium, zinc, folic acid or vitamin B12 (summary in Rao. 2012) led to statistically significant increases in body fat levels in the offspring of rats. And while the effects of maternal chromium and manganese deficiency could be corrected later in life, those that were induced by a lack magnesium, zinc and vitamin A (Ribot. 2001) in the diet of the pregnant rat dams, were permanent.
   
• Exaggerated cortisol release due to high fat diet and insufficient chromium: Both a diet insufficient in the trace element chromium (Padmavathi. 2010), as well as one of the standard "high fat diets" (30% fat; 16% protein; 37% carbs; Bullo-Cioca. 2010) increased the corticosteroid (cortisol) response to stress and thusly increased the diabetes and obesity risk of the offspring of chromium deficient or HFD significantly. Unpublished results by Roa et al. suggest that a similar increase in 11-beta-HSD (the enzyme responsible for the formation of cortisol) exist for folate and vitamin B12, as well (Rao. 2012).
   
• Cholesterol, triglycerides and other lipids: While an insufficient intake of manganese during pregnancy appears to make the offspring more susceptible to diabetes, obesity and low-grade inflammation, a profound lack of magnesium and zinc reduced the levels of cholesterol and cholesterol and triglycerides, respectively (Venu. 2008; Padmavathi. 2009).
   
• Iron deficiency results in growth retardation and brain chemistry: Pubs born to rats on an iron-deficient diet were not only smaller and had altered lipid metabolisms, they also exhibited disturbances in brain dopamine metabolism and defects in the brain myelin (fatty layer that protects the neurons) fatty acid composition (Kwik-Uribe. 2000)
   
• Reduced and exaggerated salt intake predispose to hypertension: As of late the FDA has been going back on their recommendation to avoid salt like a plague and while their reasoning was a different one, the results of a 2011 study by Kaleganova et al. confirm that both a high and a low sodium intake during pregnancy can lead to pathological changes in the kidney morpholgy of the offspring and, subsequently, to hypertension (Kaleganova. 2011)
   
• Increased susceptibility to obesity in response to high-dose multi-vitamin supplementation: Although the overall message of the above effects of nutrient-depended epigenetic programming appears to be that you better make sure not to be deficient in any nutrient, the results of a 2009 study by scientists from the University of Toronto (Szeto. 2009), suggests doubling your already high-dose multivitamin "just to make sure", is probably the worst "prophylactic" measure you could resort to. After all the pubs that were born to rats who received the high dose (10x RDA) vitamin supplement in the Szeto study, were profoundly insulin resistance, hyperphagic and obese.

While some of these negative consequences of maternal and subsequent fetal mal-nutrishment are either reversible (by replenishing respective nutrients) or induced by developmental changes and consequent malfunction of organs or organ systems, it becomes increasingly clear that some of the changes are of epigenetic nature, which means that certain DNA strains are activated or deactivated via methylation in response to dietary restrictions or, as in the case of overall malnurishment or the so-called "high fat diet", an under-, respectively overabundance of energy.

Protein (mal-)nutrition during pregnancy and epigenetic consequences

Image 3: The effects of protein malnutrition on pediatric health are profound, at any age!

Of the macronutrients, dietary protein appears to exert the most profound epigenetic effects during the fetal period. The offspring of protein malnurished rats in a 2005 study from the University of Southhampton in the UK (Lillycrop. 2005), for example, had ~20% lower PPAR-alpha and glucocorticoid receptor methylation status than that of rats on a protein sufficient diet. The subsequent >10x higher PPAR-gamma and 2x higher glucocorticoid receptor mRNA expression render provide a "mechanistical" (obviously it is a physiological one, but if we think of the body as a epigenetically controlled machine, the expression "mechanistic" would be adequate) explanation for the increased susceptibility to dietary induced obesity in later life - an effect, by the way, which has only recently been shown to be sex-depended and more pronounced in female than male offspring of mice (van Straten. 2012).

A high protein content of an overall energy deficient diet, on the other hand, has recently been shown to correct the increased cardiovascular disease risk subsequent to fetal malnutrition in mouse offspring (Kavamura. 2012), which could in fact be related to a correction, or rather aversion of the detoriations in glucocorticoid receptor expression observed in the Lillycrop study (see above).

Note: A 2011 study from the Department of Nutritional Sciences at the University of Toronto suggests that even though soy may be less of a problem for women than men, you would be ill-advised to eat (or feed your pregnant wife) larger amounts of soy protein. After all, the scientists comparison of soy vs. casein based diets showed that the offspring of the soy-fed rodents exhibited increased body and fat pad weights and a statistically highly significant increase in systolic blood pressure - an effect that was, in this case, more pronounced in the male, than in the female pubs (Jahan-Milan. 2011).

Interestingly, we see very different effects with postnatal protein restrictions, only recently, a group of researchers from the Universidade do Estado do Rio de Janeiro, in Rio de Janeiro, Brazil (Lisboa. 2012), that the offspring of the dams received a low protein (8% vs. 23%) diet during the lactation period had lower adipocytes area, a higher leptin:visceral fat ratio, increased leptin receptor expression (and thusly sensitivity) and significantly higher levels of thyroid hormones (T3 and T4) at lower TSH levels than the adult offspring of mothers who had received the normal diet during lactation. These results emphasize the need for further research and confirm my repeatedly voiced concern about jumping to radical conclusions. After all, the same high protein diet that could decrease the CVD risk of your children could be one of a myriad of factors which contribute to the rampant rise of thyroid problems, these days.

Don't surrender, and outdo your well-meaning parents

If coupled with prenatal stress exposure, which has also been shown to induce profound negative effects on the glucocorticoid metabolism of the offspring (Brunton. 2010), protein malnutrition could form a "duo infernale", which would verify the initial statement that some people have an "epigenetic disadvantage" compared to others. It would yet be unfair and above all unproductive to lay the blame on your parents. After all, familial studies suggest that only 30%-50% of the weight gain could potentially be explained by (epi-)genetic factors (Lawin. 2009). This leaves a huge margin for you to intervene and still emphasizes the importance of watching your own diet - for your own, and the sake of your children and grandchildren (I guess, we forget about humanity for now ;-)