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 296: R1071-R1077, 2009. First published February 11, 2009 doi:10.1152/ajpregu.90925.2008.-Quercetin is one of a broad group of natural polyphenolic flavonoid substances that are being investigated for their widespread health benefits. These benefits have generally been ascribed to its combination of antioxidant and anti-inflammatory activity, but recent in vitro evidence suggests that improved mitochondrial biogenesis could play an important role. In addition, the in vivo effects of quercetin on mitochondrial biogenesis exercise tolerance are unknown. We examined the effects of 7 days of quercetin feedings in mice on markers of mitochondrial biogenesis in skeletal muscle and brain, and on endurance exercise tolerance. Mice were randomly assigned to one of the following three treatment groups: placebo, 12.5 mg/kg quercetin, or 25 mg/kg quercetin. Following 7 days of treatment, mice were killed, and soleus muscle and brain were analyzed for mRNA expression of peroxisome proliferator-activated receptor-␥ coactivator (PGC-1␣) and sirtuin 1 (SIRT1), and mitochondrial DNA (mtDNA) and cytochrome c. Additional mice underwent a treadmill performance run to fatigue or were placed in voluntary activity wheel cages, and their voluntary activity (distance, time, and peak speed) was recorded. Quercetin increased mRNA expression of PGC-1␣ and SIRT1 (P Ͻ 0.05), mtDNA (P Ͻ 0.05) and cytochrome c concentration (P Ͻ 0.05). These changes in markers of mitochondrial biogenesis were associated with an increase in both maximal endurance capacity (P Ͻ 0.05) and voluntary wheel-running activity (P Ͻ 0.05). These benefits of querectin on fitness without exercise training may have important implications for enhancement of athletic and military performance and may also extend to prevention and/or treatment of chronic diseases. flavonoid; mitochondria; endurance capacity MITOCHONDRIAL DYSFUNCTION in peripheral tissues and brain plays an important role in the etiology of many diseases, including neurodegenerative disorders, cancer, diabetes, and cardiovascular myopathies, as well as the aging process and poor exercise tolerance (3,28,32). Although poor exercise tolerance is clearly a problem for athletes and military personnel, it is also a risk factor for development of these disorders (28). Exercise training is generally thought to be the best strategy to increase muscle mitochondria number and function, although little is known about the effect of exercise on brain mitochondria (20,27). Given the difficulty in maintaining a regular exercise program, other strategies involving nutrition and drugs have received increasing attention. Among the most effective are caloric restriction, natural flavonoids like resveratrol, and drugs that have been shown to increase mitochondrial biogenesis via an increase in the transcriptional coactivators sirtuin 1 (SIRT1) and peroxisome prol...

Downhill running is associated with fiber damage, inflammation, delayed-onset muscle soreness, and various functional deficits. Curcumin, a constituent of the Indian spice turmeric has been investigated for its anti-inflammatory activity and may offset some of the damage and functional deficits associated with downhill running. This study examined the effects of curcumin on inflammation and recovery of running performance following downhill running in mice. Male mice were assigned to downhill placebo (Down-Plac), downhill curcumin (Down-Cur), uphill placebo (Up-Plac), or uphill curcumin (Up-Cur) groups and run on a treadmill at 22 m/min at -14% or +14% grade, for 150 min. At 48 h or 72 h after the up/downhill run, mice (experiment 1) underwent a treadmill performance run to fatigue. Another subset of mice was placed in voluntary activity wheel cages following the up/downhill run (experiment 2) and their voluntary activity (distance, time and peak speed) was recorded. Additional mice (experiment 3) were killed at 24 h and 48 h following the up/downhill run, and the soleus muscle was harvested for analysis of inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), and plasma was collected for creatine kinase analysis. Downhill running decreased both treadmill run time to fatigue (48 h and 72 h) and voluntary activity (24 h) (P < 0.05), and curcumin feedings offset these effects on running performance. Downhill running was also associated with an increase in inflammatory cytokines (24 h and 48 h) and creatine kinase (24 h) (P < 0.05) that were blunted by curcumin feedings. These results support the hypothesis that curcumin can reduce inflammation and offset some of the performance deficits associated with eccentric exercise-induced muscle damage.

Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions (n = 16-19/group). EX mice performed 8 wk of treadmill running for 1 h/day, 6 days/wk at 25 m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice (n = 9-11/group) were euthanized, and brain (brain stem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain) and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different subgroup of EX and SED mice (n = 7-8/group) performed a treadmill RTF test. Exercise training increased PGC-1α, SIRT1, and CS mRNA and mtDNA in most brain regions in addition to the soleus (P < 0.05). Mean treadmill RTF increased from 74.0 ± 9.6 min to 126.5 ± 16.1 min following training (P < 0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis, which 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.

Quercetin versus placebo ingestion did not alter exercise-induced changes in several measures of immune function, but it significantly reduced URTI incidence in cyclists during the 2-wk period after intensified exercise.

There is increased interest among such diverse groups as the military, athletes, and the aged for novel plant-derived dietary supplements to enhance performance and maintain/improve health. Quercetin, a flavonoid found in fruits and vegetables, has unique biological properties that are likely to improve mental/physical performance and reduce infection risk during intense exercise. These properties include antiinflammatory, antioxidant, and psychostimulant activity, as well as the ability to stimulate mitochondrial biogenesis, and they form the basis for potential benefits to overall health and disease resistance. However, most information regarding quercetin is based upon in vitro and animal studies. Therefore, there is a pressing need for well-designed clinical trials to evaluate this novel dietary supplement further. This article will examine the recent scientific literature concerning the role of quercetin in mental and physical performance and health.