• Exercise Mimetics And Mitochondrial Boosters


      By Monica Mollica BrinkZone

      Mitochondria are the ‘energy powerhouse of the cell’ that convert the foods we eat to usable energy our body uses to fuel life sustaining reactions within cells, our daily activities and athletic performance 1-4. While energy production capability and muscle performance might seem to be more relevant to sports, it also equally important for achievement and maintenance of health throughout the life span. In this article I will describe how chronological aging affects our mitochondria, its implications and the ins-and-outs of a new type of supplements marketed at “exercise mimetics”.

      Age related mitochondrial changes and implications

      Brain, heart, and skeletal muscle mitochondria are especially susceptible to age-induced declines in the capacity to produce energy (ATP), and ability to respond to increased energy demands 2-6. It is well documented that mitochondrial number, mass and function declines with aging 2-5, and that this decline plays an important role in the etiology of many disorders, including cardiovascular diseases, obesity, diabetes, neurodegenerative diseases, and cancer 7-15. Physical inactivity and poor exercise capacity is a risk factor not only for the development of these diseases 8 16-18, but also causes frailty, age-related physiologic functional declines 19-22, and accelerates secondary aging (i.e., aging caused by diseases and environmental factors) 15.

      The importance of exercise for mitochondrial function and prevention of age-related declines

      We all know that exercise training increases muscle mitochondria number, mass and function 23-26. Regular exercise counteracts the age-related decline in muscle mitochondrial expression and function 27-32 and protects against development of age-related metabolic diseases like the metabolic syndrome, obesity, and diabetes 9 28 29 33-36. Thus, regular exercise increases healthy life expectancy and prolongs life span through beneficial effects, in large part, at the level of the mitochondria 28.

      Muscle is the tissue with the largest capacity to increase caloric expenditure and energy production, and possesses the unique ability to increase metabolic rate nearly 100-fold during the transition from a basal resting state to maximal contractile activity 37. Being such a metabolic prowess, the importance of mitochondria in muscle tissue is obvious. However, exercise training also has beneficial effects on mitochondria in other tissues, especially the heart 38 39, and brain 40. In the resting state, these tissues actually consume more calories on a per gram basis than does muscle tissue 41 42. Several of the beneficial cardioprotective effects of exercise training can be traced to improved cardiac mitochondrial function 38, and regular exercise also increases brain mitochondrial biogenesis 40. This may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction 40.

      Recent advances in molecular biology have shed light on the mechanisms that regulate mitochondrial biogenesis (production of new mitochondria), and how exercise stimulates mitochondrial biogenesis. This is interesting not only from a physiological standpoint, but also from practical standpoint since it has allowed discovery of dietary substances (and potentially drugs) that could help us combat the age related mitochondrial decline. More on this in a bit. First, let’s take a quick look at what happens to our mitochondria when we exercise.

      Mitochondria at the molecular level – exercise induced signaling targets

      Energy stress from exercise triggers a host of signaling pathways in muscle cells 43-47. One of the identified exercise-induced signals is AMPK (AMP-activated protein kinase) 48-50. AMPK functions as a metabolic “fuel sensor” in muscle cells because it becomes activated in response to decreased energy levels (like for ex. during muscle contractions), and in turn activates catabolic processes that generate and restore ATP levels 48 51 52.

      Another energy sensor is SIRT1 (Sirtuin-1) 51 53 54. There are actually seven sirtuins 55; they have generated a lot of scientific interest after the discovery that sitruins partly mediate the increase in longevity with calorie restriction that has been seen in lower organism and animals 56-60. But sirtuins regulate a wide range of important biological processes 61. One of them is muscle precursor cell (MPC) proliferation. The finding that SIRT1 increases muscle precursor cell proliferation is very interesting since MPC proliferation has important implications in regulating muscle growth, maintenance, repair, and the aging-related loss of skeletal muscle mass 62.

      Adult muscle stem cells, also called satellite cells or muscle precursor cells (MPCs), play an important role in the remarkable ability of muscle fibers to grow in size, repair and regenerate 63 64. A hallmark of aging is diminished regenerative ability of muscle tissues, which is in large part due to age-related changes in tissue-specific stem cells 65. Muscle precursor cells are important not only for regeneration after tissue damage, but also for maintenance. Age-related muscle loss (sarcopenia) is caused in large part by atrophy of type II muscle fibers 66, which is associated with a fiber type-specific decline in muscle precursor cell content 66. Thus, SIRT1 is an attractive target for dietary/exercise interventions to prevent the loss of muscle mass and function with aging 66.

      SIRT1 also works jointly with AMPK in regulating cellular fuel metabolism, inflammation, and mitochondrial function 51. In addition, SIRT1 activates and increases the activity of PGC-1 (peroxisome proliferator-activated receptor-γ coactivator, a transcriptional coactivator), which finally activates transcription factors that turn on genes in our DNA that produce new mitochondria 23-25 54 67. One such transcription factor is PPAR-gamma, which also contributes to mitochondrial biogenesis 68.

      Of the mentioned “control points” (AMPK, SIRT1, PPAR-gamma and PGC-1), PGC-1 is considered the “master regulator” of mitochondrial biogenesis 69-71. It also increases oxidative phosphorylation and ATP (energy) production 71. As a result, increased expression of PGC-1 has been shown to increase peak oxygen uptake and delay fatigue during prolonged exercise 69. In addition to its stimulatory effect on mitochondrial biogenesis and function, PGC-1 also regulates muscle fueling stores by increasing muscle glucose uptake, augmenting muscle glycogen storage, and preventing muscle glycogen depletion during exercise 72.

      Ok, now you know enough molecular biology to understand the rationale behind exercise mimetics, which we will focus on next.

      Exercise Mimetics

      Elucidation of the molecular mechanisms behind mitochondrial biogenesis and function, coupled with the identification of dietary substances that seem to increase the expression of PGC-1, SIRT1, AMPK etc. and/or their regulators, has led to great interest in developing drugs and dietary supplements to target the SIRT1-PGC-1 complex and related signaling pathways 47 50 73-75.

      Because these supplements and drugs activate some of the signaling pathways that are activated by exercise, they have been labeled as “exercise mimetics” 47 74. Here’s a rundown of some dietary bioactive substances that are currently in the scientific spotlight for their potential exercise mimetic effects.

      PQQ

      PQQ (short for Pyrroloquinoline Quinone, and also called methoxatin) is a less well known dietary compound that was discovered 1979 76-78. PQQ is present in tissues and body fluids, including human milk 79-81 and in foods. The richest dietary sources are 82:

      Natto (fermented soybeans) 61 ng PQQ/g

      Parsley 34 ng PQQ/g

      Green tea 30 ng PQQ/g

      Green pepper 28 ng PQQ/g

      Kiwi 27 ng PQQ/g

      Papaya 27 ng PQQ/g

      Tofu (soybean curd) 24 ng PQQ/g

      Spinach 22 ng PQQ/g

      Carrot 17 ng PQQ/g

      When you read supplement labels, remember that 1 milligram (mg) = 1,000,000 nanogram (ng)

      PQQ acts as an antioxidant 83, enzyme cofactor 84-91, nero-protectant 92-95, cardio-protectant 96-98, and may have an important role in cell signaling 92 99-101. In this context, the most interesting function of PQQ is that it affects the expression of genes involved in mithochondrial functions and biogenesis (most notably, PGC-1) 99 102.

      The nutritional importance of PQQ has been demonstrated by feeding rats and mice a diet that is devoid of PQQ; the animals show growth retardation, reproductive failure, compromised immune responses, skeletal deformities aortic aneurysms, and fragile skin 91 103 104. This strongly suggests that PQQ is necessary for normal body functions and health. It is actually being debated whether PQQ might become the “next vitamin” 78 88.

      What’s more interesting is that varying the amount of PQQ in diets causes modulation in mitochondrial content, alters lipid metabolism, and reverses inhibition elicited by classical mitochondrial function inhibitors 97 104-106. PQQ deficiency decreases both mitochondrial function and number 106. The most recent study on PQQ fed rats a nutritionally complete diet either with or without PQQ 105. The rats that got the PQQ diet not only exhibited lower blood triglycerides but also showed increased energy expenditure, hepatic (liver) mitochondrial content. In contrast, the rats that were fed the PQQ deficient diet instead exhibited deterioration in mitochondrial function, a lowered energy expenditure and reduced capacity to oxidize fat for energy (that is, reduced fat burning) 105. However, at the time of this writing, no human study has investigated the effect(s) of PQQ on metabolic, muscular and mitochondrial parameters. PQQ can already be found on the supplement market, but for now we will have to be our own lab rats.

      Quercetin

      A natural polyphenolic flavonoid, quercetin is present in a wide variety of food plants, including red onions, apples, and berries 107 108. Known for its multiple health benefits 109-118, it has recently been shown that quercetin also beneficially affects mitochondrial energetics 119 120 and stimulates mitochondrial biogenesis (by increasing expression of PGC-1alpha and SIRT1) 121. The quercetin-induced increase in mitochondrial biogenesis was accompanied 121 with both maximal endurance capacity and voluntary wheel-running activity in mice 121.

      However, findings from the few research studies on the ergogenic (i.e. performance enhancing) effects of quercetin supplementation in humans are equivocal 122-127. A small preliminary study showed that when given in combination with other antioxidants for 6 weeks, quercetin improved endurance time-trial performance on a bicycle ergometer in humans 126. Another study, conducted by the same research team that showed performance enhancing effects in mice, gave healthy but untrained participants 500 mg of quercetin twice daily. After 7 days it was shown that the quercetin supplementation resulted in a modest increase in VO2max along with a substantial (13.2%) increase in ride time to fatigue 125. It was concluded that quercetin supplementation can increase endurance without previous exercise training in untrained participants 125. In contrast, another controlled study conducted by another research team, which gave young healthy recreationally active men 1 g/day of quercetin in a sports hydration for 16 days failed to show any benefits over placebo; the quercetin supplementation did not improve neither muscle oxidative capacity or performance in a 10 min maximal-effort cycling test 124. Also, supplementing with 1 g/day of quercetin for 3 weeks in trained cyclists failed to show a performance benefits 127.

      A recently published meta-analysis of human studies on quercetin and performance concluded that quercetin supplementation significantly endurance performance, but that the effect is very small 128. The computed effect size for the performance enhancement was 3-5% over placebo 128. This can be compared to the effect size for the performance enhancement with caffeine, which is in the range of 12% over placebo 129. If at all, people with low fitness levels will probably most likely experience a performance benefit of quercetin supplementation, since highly fit individuals already have an elevated mitochondrial density and function.

      There is a possibility that a longer supplementation duration is necessary for quercetin to exert a performance enhancing effect, and/or that it could be ergogenic in elderly. Hopefully, future studies will address that. Thus, while quercetin is a prudent supplement to take for its beneficial health effect, if you’re looking for a boost in mitochondrial function and/or performance, don’t expect too much.

      Resveratrol

      Resveratrol is the most well known SIRT1 activator 130-132. A natural compound present in grapes (especially grape skin) 133 134, resveratrol has been in the spotlight since it was found to be one major factor explaining the French paradox and conferring the cardioprotective effect of red wine 135-140. Fresh grape skin contains about 0.05-0.1 mg resveratrol per gram, while red wine is a concentrated source of resveratrol providing up to 14 mg per liter. Resveratrol also protects against cancer 135, and induces several signaling pathways that are also seen with calorie restriction (I will cover this more in an upcoming article on calorie restriction mimetics).

      More recently, it has been shown that resveratrol also might improve mitochondrial function and stimulate mothochondrial biogenesis 131 141. In mice, intake of resveratrol together with habitual exercise, suppresses the aging-related decline in physical performance 141. This effect was attributable, at least in part, to improved muscle mitochondrial function 141. Another mice study showed that resveratrol increases aerobic capacity, as evidenced by an increased running time to exhaustion 131. On a molecular level, this effect was paralleled by an induction of genes for oxidative phosphorylation, increase in PGC-1alpha activity and enhanced mitochondrial biogenesis 131. Resveratrol also seems to be able to counteract muscle atrophy during periods of physical inactivity (mechanical unloading) in rats 142.

      However, while there is ample of human data on the health promoting effects of resveratrol, at the time of this writing there are no human studies on its potential mitochondrial, metabolic and/or performance enhancing effects.

      Nootkatone

      A new kid on the block, nootkatone is another bioactive naturally occurring dietary compound that is found primarily in grapefruit (a whole grapefruit contains about 100 mg of nootkatone, mainly in the rind)143.

      It was recently shown in mice that nootkatone potently activates the AMPK signaling pathway in both muscle and liver, increases energy expenditure, endurance performance, and also suppresses diet-induced development of obesity, abdominal fat accumulation, and insulin resistance 143. Body weight in nootkatone-fed mice was significantly decreased despite no significant decrease in energy intake 143. It was concluded that activation of AMPK and subsequent induction of PGC-1α, with a possibly enhanced oxidative energy metabolism and stimulation of energy expenditure, is an underlying mechanism of the antiobesity effects of nootkatone 143. This study supports the idea that AMPK activators could be useful as exercise mimetics or exercise-supporting supplements in preventing/treating obesity and/or metabolic syndrome, and for improving physical performance.

      Nootkatone has a pleasant, citrusy grapefruit aroma, and is GRAS approved 144 for use as a food flavoring agent, and as a fragrance in perfumes and essential oils 145. You can even use it as a non-toxic effective repellent/insecticide against mosquitos and other insects 146. Being this multi-functional, we will most likely hear more about nootkatone, in one way or the other, it in the near future. It is interesting to speculate whether the nootkatone-induced AMPK activation is part of the mechanism underlying the weight loss and increased insulin sensitivity that has been reported after grapefruit supplementation 147. Even though nootkatone is currently not available as a dietary supplement in isolated form, you can always add some grapefruit to your regimen (remember that whole fruits are better than juice). However, if you are taking any medications, talk to your doctor first because grapefruit interferes with the enzymes that metabolize medications, and can cause a lethal buildup of medication in the body 148-151.

      Downsides…

      The potential of exercise mimetics certainly appeals to the huge mass of lazy folks who cannot get their butts off the couch, and the pharmaceutical and supplement industry that sees the tremendous market potential. So we’ll most certainly be hearing a lot about these “exercise pills” in the near future. However, I want to emphasize that an “exercise pill” will never ever be a substitute for actual exercise training. Why? For several reasons:

      Firstly, mimicking activation of exercise signaling pathways could result in a chronic catabolic state. For example, activation of AMPK could inhibit protein synthesis 152 and stimulate autophagy (cell cannibalism, that is, degradation of a cell’s own components through the lysosomal machinery) 153. Also, while augmenting oxidative capacity in mice, overproduction of PGC-1α in muscle has been shown to result in severe muscle atrophy as mice aged 154. These effects would clearly be detrimental, especially for aging people. This underscores the importance of striking an optimum balance between continuous compared with transient activation of exercise signaling pathways.

      Secondly, intense exercise bouts induce significant temporary stress on various organ systems. With an over 15-fold increase in whole body oxygen consumption when transitioning from complete rest to intense exercise, it is no surprise that a complex myriad of signaling pathways are activated in multiple tissues, of which we only know a few. Even though science is making progress in elucidating the exercise response on a molecular level, we are still barely just scraping the tip of the iceberg.

      Thirdly, exercise training has multiple health benefits that do not, at least directly or entirely, relate to the muscle-specific adaptations. For example, cardiovascular adaptations like blood pressure reduction and improved blood lipid profile are not completely (albeit partly) due to muscle-specific adaptations 155 156. This is further underscored by the finding that beneficial effects of regular exercise are even seen in arteries of non-exercise-trained limbs 157-160. Additionally, regular exercise results in a host of other health benefits; it prevents or reduces the severity of dementia and other neurological disorders, osteoarthritis, osteoporosis, fall-related injuries, depression, certain cancers and cardiovascular diseases 16 18 161-165. Exercise also improves cardiac function and enhances stroke volume, increases VO2max (the maximal oxygen uptake, or aerobic capacity, which is the maximum capacity of the body to transport and use oxygen during exercise), increases nitric oxide levels in vascular endothelial cells, increases bone mass and strength, enhances the immune system, lowers TNF-α and other inflammatory markers, improves insulin sensitivity and blood lipid profiles, and increases muscle capillarization, muscle size and muscle strength 161 166. Obviously, no single pharmaceutical or dietary agent could mimic this multifaceted response.

      Fourthly, in order for an “exercise mimetic” to mimic the effect of exercise on obesity, it would have to result in an increase in energy expenditure to the same degree as exercise. Even though PQQ increases energy expenditure in rats (see above), this increase is nowhere near the increase that is seen with exercise. An increase in muscle mitochondria enhances exercise capacity and endurance, making it possible to expend more total energy, or the same amount of energy in a shorter time. So, an increase in mitochondria enhances the capacity to expend calories by means of exercise, and thereby could make exercise more effective in preventing and/or treating obesity. However, an increase in mitochondria per se has no major independent effect (in the absence of exercise) on energy expenditure.

      Finally, regular exercise has psychological effects on constructs like self-mastery 167, self-esteem 167, self-perception 167, self-efficacy 168 self-regulation 168 and also social engagement 167, which no “magic” mimetic pill ever will be able to reproduce. The psychological effects of exercise might actually be at least as important as the physiological effects in the achievement of fat loss 154. This is an areas that I think deserves more attention.

      A poly-pill containing a number of agents aimed at selected targets could theoretically address the second and third objection. However, as indicated in objection one, it is likely to be associated with multiple unwanted effects, and to be of questionable long-term efficacy. Thus, with the discovery and development of tissue-specific targets, only limited aspects of the exercise response can be mimicked. The term ‘exercise mimetic’ is therefore misleading, and could lull a false sense of security and give lazy folk another excuse not to exercise “I took this exercise pill so I don’t have to go to the gym”…. These days, unfortunately the general tendency is to look for a pill to solve our problems anytime we face obstacles. This fact is aptly highlighted by a comment from one of the most prominent researchers on the health benefits of regular physical activity “When will we treat physical activity as a legitimate medical therapy…even though it does not come in a pill?” 169.

      Conclusion

      Exercise mimetics work by stimulating some of the molecular pathways that are also activated by actual exercise. Pharmacological stimulation of AMPK and PGC-1 in sedentary mice has been shown to induce metabolic genes and enhanced running endurance even without exercise 50. Similarly, SIRT1 activation could protect against metabolic disorders by stimulating fat burning (oxidation). Also, the question remains as to what extent data from cell culture and rodent studies can be extrapolated to humans.

      However, the terms “exercise mimetic”, and its synonym “exercise pill”, are very misleading. I prefer the term “mitochondrial booster”, since it doesn’t erroneously imply that these types of pills can substitute for the real thing. A mitochondrial booster (or exercise mimetic, if you wish) supplement could be a great adjunct to exercise, but never ever a substitute.

      Bearing all the caveats in mind, since actual exercise and exercise mimetics at least partly target the same molecular pathways at potentially complementary control points, it is extremely interesting to speculate on the possible synergistic effects between exercise and exercise mimetics on muscle, mitochondrial function, performance, and in preventing the age-related declines in muscular function…indeed, there are preliminary data pointing towards promising synergistic effects 50. Rest assured I will be keeping you posted here on BrinkZone.com.

      However, exercise is and always will be necessary. Sorry folks, there are no magic bullets. There’s simply no way around it. Amen!!!

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