By increasing mitochondrial biogenesis in brain and muscle . . .

Quercetin Improves
Exercise Tolerance

In a surprise conclusion, quercetin has been found to
enhance the motivation and willingness to exercise
By Will Block

magine that you’re a recent college graduate who is worried about your future, but you don’t simply want to follow the commercial path of your affluent family and their friends. At a gathering to celebrate your graduation at your parent’s home, you’re cornered by a friend of the family, who asks whether you’re off to graduate school and, when you shrug, says, “I want to offer you just two words.” Cringingly, you wait for the expected. But instead, you hear, “Mitochondrial biogenesis!”

Sound familiar and unfamiliar at the same time? Well it certainly is not the 1960’s and not the dilemma of “The Graduate” same old, same old, all over again—giving homage to things that are “plastic.” Instead, in fundamental ways, it’s plasticity—a measure of neural adaptivity—and that gets your blood flowing … taking you into the realm of organic, rather than industrial, products … into the sphere of more powerful and durable shapes and forms … into the sustainability of building better brains and stronger muscles. Isn’t the first decade of the 21st Century great, you think to yourself! Yes, we have a lot to look forward to in the way of exciting health biotechnology.

Quercetin as Mitochondrial Protector and Progenitor

We have previously reported that quercetin operates within mitochondria as an inhibitor of the mitochondrial membrane permeability transition, the opening of an unselective pore elicited by calcium or pro-oxidants. Thus quercetin helps prevent mitochondrial damage.1 And now a new report finds that quercetin also increases brain and muscle mitochondrial biogenesis and exercise tolerance.2

As we have recently written (See “Enhance Your Cellular Power” in the July issue), mitochondrial dysfunction in peripheral tissues and the brain is complicit in the causality of many diseases, including neurodegenerative disorders, cancer, diabetes, and cardiovascular myopathies, as well as the aging process and poor exercise tolerance.

Therefore, any scientific report that a nutrient can maintain, restore, or improve mitochondrial function is welcome indeed. If it can enhance mitochondrial production, so much the better!


A new report finds that quercetin
also increases brain and muscle
mitochondrial biogenesis and
exercise tolerance.


What is Quercetin?

Quercetin is not a new nutrient on the block, but one member of a subgroup of natural polyphenolic flavonoid substances that are under investigation for a cornucopia of health benefits. Found widely in nature, flavonoids are categorized by their chemical structure into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins, and chalcones. To date, more than 4,000 flavonoids have been identified in vegetables, fruits, vegetables, and beverages (tea, coffee, wine, beer, and fruit drinks). Scientists have been investigating the flavonoids, in particular, because of their recognized and further potential beneficial effects on human health. Among these benefits are antioxidant, antiviral, anti-allergic, antiplatelet, anti-inflammatory, and antitumor activities. Quercetin may be the most important of the flavonoids, as we shall see.


The in vivo evidence for quercetin’s
effects on mitochondrial biogenesis
exercise tolerance has not been
investigated … until now.


The bulk of quercetin’s benefits have been attributed to its combination of antioxidant and anti-inflammatory activity, yet recent in vitro evidence points to its ability to enhance mitochondrial biogenesis as central to its protective role. Yet the in vivo evidence for quercetin’s effects on mitochondrial biogenesis exercise tolerance has not been investigated … until now.

More Muscle and Brain Power

The new study, conducted at the University of South Carolina’s Arnold School of Public Health by a team of physiologists and exercise scientists led by J. Mark Davis, PhD, examined the effects of quercetin feedings in mice for 7 days. They paid special attention to markers of mitochondrial biogenesis in skeletal muscle and brain, and on endurance exercise tolerance. The mice were randomly assigned to three treatment groups: placebo, 12.5 mg/kg quercetin, or 25 mg/kg quercetin per day. The flavonoid was mixed with orange-flavored Tang® (“OJ for Astronauts”) or placebo (Tang only) daily via gavage for 7 days. Tang masks the taste of quercetin very well and contains vitamins (especially B3 and C), which may increase bioavailability. The human equivalence of the doses given the mice would be 76 mg and 152 mg per day, respectively, for a 75 kg (165 lb) person.

Following 7 days of treatment, the soleus muscle and brain tissues were analyzed for expression of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) and sirtuin 1 (SIRT1), and mitochondrial DNA (mtDNA) and cytochrome c (a marker for apoptotic cell death). (See “The Antidiabetes Trigger” in the March issue and “The Universal Cause of Aging” in the February issue.) As another measure of quercetin’s effects, some of the mice were given a treadmill performance run to fatigue test or were placed in activity wheel cages, where their voluntary activity (distance, time, and peak speed) was recorded. Interestingly, treadmill running is thought to be a better indicator of maximal running capacity as opposed to wheel running, which is greatly influenced by behavioral factors. Significantly, both treadmill and wheel running are strongly influenced by an increase in both muscle and brain mitochondria, although the brain is seldom mentioned in this context.

Just as resveratrol has been shown to increase expression of PGC-1α, so too did quercetin. Moreover, so too did quercetin increase the expressions of SIRT1 and mtDNA (mitochondrial DNA). Cytochrome c concentration was also increased. And all of these benefits occurred in skeletal muscle and brain tissue. Importantly, these marker changes of mitochondrial biogenesis were associated with an increase in both maximal endurance capacity (in which the mice were “forced” to go on) and wheel-running activity (in which the mice “volunteered” to go on).


Crucially, although often ignored,
the brain’s role in
exercise tolerance is paramount.


The Effect of Brain on Brawn

As we have previously written, PGC-1α plays an important role in stimulating mitochondrial biogenesis after physiological demands such as exercise or nutrients such as the flavonoid resveratrol. (See “Resveratrol Mimics Caloric Restriction,” in the April 2008 issue.) PGC-1α expression is emphatic in high-capacity mitochondrial systems, such as muscle fibers, where it helps regulate skeletal muscle fuel stores, an essential mechanism for endurance exercise capacity. Crucially, although often ignored, the brain’s role in exercise tolerance is paramount. According to Davis et al., what goes on in the metabolism of your brain has “important consequences for motivation, mood (e.g., vigor, fatigue, anxiety, depression), and central motor drive from the cortex, and increased brain mitochondrial activity could certainly enhance cerebral metabolism.”

PGC-1α activates mitochondrial biogenesis which increases production of ATP, the universal energy molecule, and this in turn allows for greater physiological demands caused by exercise and energy deprivation. When this happens, peak oxygen uptake increases and fatigue is diminished or is delayed during prolonged exercise.


In mice, the motivation and
willingness to exercise were found to
be driven more by brain factors.
Presumably, this is true for
humans too.


It is important to stress that no prior studies have focused on the mitochondrial biogenesis effect in the brain, but after just 7 days of quercetin feeding in the current study both PGC-1α and SIRT1 expression increased significantly in both skeletal muscle and brain (for both doses). However, while increases in muscle mtDNA (achieved in only the higher dose of quercetin), have been well-documented to enhance exercise tolerance, there is far less knowledge about the impact of these changes in the brain. The fact that the 12.5 mg/day quercetin feeding did not increase mtDNA may be attributed to the short feeding duration (more on this below). So while muscle mitochondrial biogenesis increases may be the most important factor responsible for increased endurance exercise tolerance in response to exercise training, the data of the researchers show that the brain also plays an important role.

Human Exercise is Dominated by the Brain

The stimuli of the two paradigms of exercise (treadmill running and voluntary wheel running) are very different. Treadmill running is “forced” because, when the mice can no longer maintain the pace necessary to keep up with the moving belt, they are gently prodded by hand or mild electrical shock. Their fatigue arises primarily from peripheral limitations (e.g., cardiovascular system and muscle). On the other hand, voluntary wheel-running behavior is more centrally (i.e., involving the brain) influenced. This is more conducive to our own volitional exercise programs. Thus, while treadmill running is a better indicator of a mouse’s maximal running capacity, wheel running is strongly influenced by behavioral factors, as is the case for humans. Once again, while brain and muscle mitochondria are influential in exercise, rarely is the brain considered for the distinct role that it plays.

Suppressing the Neuroinhibitor Adenosine

A further point that the researchers made is that the benefits of the quercetin feedings increased voluntary activity during the feeding period as well as for 7 days after feeding was stopped. This extended respond was probably due to the combined effects of quercetin and exercise on mitochondrial biogenesis, but with the plasma half-life of quercetin at 6–12 h, there may be a supplementary explanation. That is—and this is especially important for humans—the motivation and willingness to exercise is driven more by brain factors.

Contributing to these brain factors—given that the quercetin-induced increase in maximum speed found on days 2–3 was far too short a time for sufficient change in mitochondrial capacity—may be the caffeine-like quality of quercetin. This entails quercetin’s ability to block the effect of the neuroinhibitor adenosine, the antagonism of which is partially responsible for caffeine’s psychostimulant and ergogenic effects. Consequently, in addition to enhancing mitochondrial biogenesis, quercetin may increase exercise tolerance through its activity as an adenosine receptor blocker in the brain.


Anything that safely increases
our ability to stay strong
is of major importance.


Maintaining and Avoiding Loss of Strength

One of the most pervasive aspects of aging is the loss of strength. So anything that safely increases our ability to stay strong is of major importance. With this study, quercetin has entered a new arena of health benefits. Its apparent ability to enhance the value of exercise on fitness, even without explicit training, may have important implication for not only athletic and military performance, but also for all “graduates” to greater knowledge. These benefits of quercetin may also extend to the prevention and treatment of chronic diseases, thereby extending the quality and perhaps quantity of our lives.

References

  1. Fiorani M, Guidarelli A, Blasa M, Azzolini C, Candiracci M, Piatti E, Cantoni O. Mitochondria accumulate large amounts of quercetin: prevention of mitochondrial damage and release upon oxidation of the extramitochondrial fraction of the flavonoid. J Nutr Biochem 2009 Mar 17. [Epub ahead of print]
  2. Davis JM, Murphy EA, Carmichael MD, Davis B. Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul Integr Comp Physiol 2009 Apr;296(4):R1071-7. Epub 2009 Feb 11.

The Coactivation Connection

In the field of longevity, one member of a group of nuclear receptor coactivator proteins has created quite a stir. That’s the protein with the formidable name peroxisome proliferator-activated receptor gamma coactivator-1α (abbreviated PGC-1α, where the P stands for PPAR). PGC-1α is a transcriptional master regulator, which recently has been discovered to be activated by the sirtuin SIRT1, which in turn is activated by the phytonutrient resveratrol. In effect, resveratrol exerts pharmacological preconditioning by activating PGC-1α. In a recent paper, cinnamon has been found to be a PPAR activator, opening the doors of coactivation yet wider.

The reason for all the excitement is that PGC-1α induces mitochondrial biogenesis, a process whereby mitochondria, the energy agents of the cell, are increased. When more energy is produced, the result is less oxidative damage, improved energy efficiency, and an increase in overall health, and perhaps longer life. Resveratrol is a mitochondrial turbocharger.

What is the interconnection between coactivators, such as PGC-1α and the PPARs? Although certain relationships have been established—for example, PGC-1α and PPARα cooperate to activate genes encoding enzymes involved in cardiac fatty oxidation—there is a paucity of knowledge at this time. Answering these questions should help in the design of studies that investigate these relationships. In time, they may lead to the creation of nutrient cocktails—such as perhaps a quercetin-resveratrol-cinnamon combination—for a spectrum of health benefits unforeseeable at this time.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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