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.

Fat Content Per Energy Drink 0g, Body Fat Gain Per Energy Drink 18g! Human Trial Confirms: +1kg of Body Fat in 4 Weeks From Less than 2x Energy Drinks per Day!

Image 1 (NYC Dept. of Health & Mental Hygiene): The words on this poster from a 2009 campaign in the NY subway must be taken literally!

There is a reason for me to always begin my "dietary advice" with the statement "there is NO WAY that you ever again drink any soft, energy drinks or fruit juices on a daily basis". And though I would not have needed a study to confirm skipping, lemonade, coke & co is one of the simplest, for many people yet not easiest steps to a healthier and leaner physique, I must admit that I was pretty surprised how rapid both your health and body composition deteriorate, once you reintroduce this junk into your diet. +1kg of pure body fat in 4 weeks, that was the amount of weight the 11 healthy men and women in a recently published study by scientists from the UK, Italy and the US gained within just 4 weeks in the course of which they drank on average two more or less tasty Lucozade Energy drinks per day (Sartor. 2013).

Fat content of energy drink 0g, body fat gain per energy drink 18g!

Figure 1 (gsk): Nutritional information of the energy drink the subjects drank during the 4-week study period

Sartor et al. about whose study on the "habituation effects" of sweet beverage you may already have read in one of the installments of the Insulin Resistance Saga (cf. "Where Has All the Sweetness Gone? Plus: Bullied to Eat Twinkies") had recruited 11 healthy young men (n=5) and women (n=6) with a mean age of 26 years, who were handed a month's supply of GlaxoSmith Kline's yummy Lucozade Energy of which they had to drink ~2 bottles per day (2x 380ml; in fact the average intake was only 760ml and was matched to deliver 2g carbohydrates per kg body weight; for detailed "nutritional" information based see figure 1) - just to make that clear, I suspect the results would not have been much different if this had not been Lucozade, but plain Coke, if the daily consumption (1.2l) had delivered the same amount of sugary carbs.

Apropos effects, if you take a look at the actual data in figure 2 it is quite obvious that the increase in body fat did not occur in the absence of the rise of other characteristic features of the metabolic syndrome, i.e. changes in blood glucose and lipid metabolism.

Figure 2: Changes in body composition, HOMA markers of insulin resistance, sensitivity and pancreatic function, as well as blood lipids after 4 weeks of sugar-sweetened beverage consumption (based on Sartor. 2013)

A particular reason of concern - at least in my humble opinion - are the rapid (remember these deteriorations occurred within only 4 weeks!) reductions in HOMA measure insulin sensitivity / increases in HOMA based insulin resistance measures. Which would only exponentiate the detrimental effects of the daily glucose overload.

High blood glucose, high RER, high insulin, but no increase in energy intake

Together with the significantly increased fasting glucose (+6%) and fasting insulin levels (+25%) and the accompanying reversal of the fat-to-carbohydrate oxidation rates from 2:1 to 1:3 in the fasted state this does already suggest that this is once more not solely an effect of an increase in energy intake as conventional wisdom would have it!

Figure 3: Changes in macronutrient composition and non-existent changes in total caloric intake over the course of the 4 weeks of sugar-sweetened beverage consumption (based on Sartor. 2013)

If you take a closer look at the data in figure 3 you can even drop the "solely" from the previous sentence and state: "the obesogenic effect of sugary beverages has no relation whatsoever to an increase in overall energy intake!"

Its not so much about how much, its about what and which!

It stands to reason that this increasingly accepted "violation" of the rules of thermodynamics *rofl* did not go unnoticed by Sartor et al., who had also analyzed the expression of several genes in samples of the skeletal muscle tissue of their subjects and found that there were statistically significant

• increases in glyceraldehyde-3-phosphate dehydrogenase (GAPH), acetyl-CoA carboxylase alpha (ACC) and MonodA mRNA expression, which are indicative of increased glycolysis, decreased fatty acid oxidation and an increased cellular awareness of blood sugar abundance, respectively, as well as a significant
• decrease in peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1a), of which you have read in relation to Irisin in "If a High Fat Diet was a Pill, the Lay Press Would Celebrate it as Exercise in a Pill!" that it is responsible for increases in mitochondrial firepower and fatty oxidation capacity

Much more so than the 1kg of body fat, which should be relatively easy to shed by simply pouring energy-, soft-drinks & co down the sink, instead of downing them with a gulp, these transcriptional (epigenetic) changes and the previously reported deteriorations in taste perception in response to the consumption of sugar (not fructose!) sweetened beverages (Sartor. 2011), are the real alarming results of this 4-week trial. After all, they are the ones that predispose to future fat gain, diabetes and hyperlipidemia!

So, what can be done?

Image 2: OTC solution to the problem? Water + Workout

Luckily there is a tried and proven non-pharmacological solution to this problem, an OTC double-whammy, if you will that is not just free, but will actually save you truckloads of money! Initially for all the energy drinks and soft-drinks you are not buying anymore and for all the medication the medical bill's and the XXL coffin for your funeral in the weeks, months, years and decades to come. What? You want to know what this OTC double-whammy is? Plain water and regular exercise! While the former is equally if not more thirst-quenching than the differently colored sugar waters, the latter will help to gradually reverse the epigenitic changes and restore a healthy glucose and fatty acid metabolism.

References:

1. GlaxoSmithKline (gsk). Lucozade Official Shop. Lucozade Energy - Original. 2013 < http://www.lucozadeshop.com/lucozadeenergy/lucozadeenergyoriginal > Received on June 30, 2013.
2. Sartor F, Donaldson LF, Markland DA, Loveday H, Jackson MJ, Kubis HP. Taste perception and implicit attitude toward sweet related to body mass index and soft drink supplementation. Appetite. 2011 Aug;57(1):237-46. 
3. Sartor F, Jackson MJ, Squillace C, Shepherd A, Moore JP, Ayer DE, Kubis HP. Adaptive metabolic response to 4 weeks of sugar-sweetened beverage consumption in healthy, lightly active individuals and chronic high glucose availability in primary human myotubes. Eur J Nutr. 2013 Jun 26.