Quercetin's Influence on Exercise Performance and Muscle Mitochondrial Biogenesis

Purpose: To determine the influence of 2 wk of quercetin (Q; 1000 mg·d) compared with placebo (P) supplementation on exercise performance and skeletal muscle mitochondrial biogenesis in untrained, young adult males (N = 26, age = 20.2 ± 0.4 yr, V·O2max = 46.3 ± 1.2 mL·kg·min). Methods: Using a randomized, crossover design with a 2-wk washout period, subjects provided blood and muscle biopsy samples presupplementation and postsupplementation periods and were given 12-min time trials on 15% graded treadmills after 60 min of moderate exercise preloads at 60% V·O2max. Results: Plasma Q levels rose significantly in Q versus P during the 2-wk supplementation period (interaction P value <0.001). During the 12-min trial, the net change in distance achieved was significantly greater during Q (2.9%) compared with P (-1.2%; 29.5 ± 11.5 vs 11.9 ± 16.0 m, respectively, P = 0.038). Skeletal muscle messenger RNA expression tended to increase (range = 16-25%) during Q versus P for sirtuin 1 (interaction effect, P = 0.152), peroxisome proliferator-activated receptor [gamma] coactivator-1[alpha] (P = 0.192), cytochrome c oxidase (P = 0.081), and citrate synthase (P = 0.166). Muscle mitochondrial DNA (relative copy number per diploid nuclear genome) increased 140 ± 154 (4.1%) with Q compared with -225 ± 157 (6.0% decrease) with P (P = 0.098). Conclusions: In summary, 1000 mg·d Q versus P for 2 wk by untrained males was associated with a small but significant improvement in 12-min treadmill time trial performance and modest but insignificant increases in the relative copy number of mitochondrial DNA and messenger RNA levels of four genes related to mitochondrial biogenesis. Polyphenolic compounds, or polyphenols, are polyhydroxylated phytochemicals, of which the two main classes include flavonoids and phenolic acids. Flavonoids are a large family of secondary plant phenolic of low molecular weight, derivatives of benzo-[gamma]-pyrone, and present in most edible fruits and vegetables (2,12,23). Flavonoid consumption has been associated with a lower incidence of heart disease and certain types of cancers, and mechanisms may include flavonoid-related antioxidant, anti-inflammatory, and gene regulatory effects (12,23). The influence of flavonoid supplementation on exercise-induced physiologic stress and performance has been a focus of our research team during the past several years (31-33). Cardiorespiratory endurance exercise increases active skeletal muscle mitochondrial density by 20%-100%, depending on the initial fitness level and duration, frequency, and intensity of training (4,13,15). Exercise-induced mitochondrial biogenesis is mediated by the increase in intracellular calcium levels during muscle fiber contraction and is a multifaceted process involving the coordinated expression of mitochondrial and nuclear genes (7,11,14). In particular, the transcriptional coactivator peroxisome proliferator-activated receptor [gamma] coactivator-1[alpha] (PGC-1[alpha]) plays a key role in regulating skeletal muscle mitochondrial adaptive responses to regular endurance exercise (7). Recent evidence in animal models indicates that some of the adaptations in muscle phenotype elicited by exercise can be mimicked by energy restriction, genetic manipulation, drug treatment, and certain types of polyphenols (3,6,20,28,29,34). Few human studies, however, have been conducted to determine whether nonexercise methods can increase mitochondrial density in skeletal muscle. Soy isoflavone derivatives (34), resveratrol (20), and tea catechins including epigallocatechin gallate (EGCG) (25,28) are associated with induction of genes for mitochondrial biogenesis and oxidative phosphorylation. Treatment of mice with large quantities of resveratrol (200-400 mg·kg·d) for 15 wk induced PGC-1[alpha] with activation from sirtuin 1 (SIRT1), resulting in a significant increase in mitochondrial density and endurance running capacity (20). Tea catechin intake improved physical performance and mitochondrial function in the skeletal muscle of aged mice, especially when combined with exercise (27,28). Cell culture studies show that isoflavone derivatives induce the activation of PGC-1[alpha], SIRT1, and mitochondrial biogenesis (34). Other studies show that EGCG accumulates in mitochondria and exerts anti-apoptotic effects (37) and that specific flavonoids induce a mild uncoupling of mitochondrial oxidative phosphorylation and inhibit mitochondrial membrane lipid peroxidation (8,9,19,36). Recent evidence indicates that quercetin supplementation induces a strong increase in mitochondrial biogenesis and endurance performance in mice (6). Quercetin is a flavonol that constitutes the aglycone of the plant glycosides rutin and quercetrin. Of all flavonoids, quercetin is among the most widespread, with broad spectrum bioactive effects (5,12,23). Two reports support the safety of quercetin as a nutritional supplement (12,40). Human subjects can absorb significant amounts of quercetin, with a reported half-life ranging from 3.5 to 28 h (23,26). A few recent studies have investigated quercetin's effects on endurance performance and mitochondrial biogenesis. One study of 11 elite male cyclists reported a 1.7% 30-km time trial performance enhancement above placebo after 6 wk of quercetin supplementation (24). Another study using sedentary mice showed that 7-d quercetin feeding (both 12.5 and 25 mg·kg) increased soleus muscle PGC-1[alpha] and SIRT1 messenger RNA (mRNA) levels twoto threefold, cytochrome c concentration by 18%32%, and treadmill run time to fatigue by 37% (6). A study of 40 trained cyclists randomized to 1000 mg·d quercetin or placebo for 3 wk failed, however, to show any group differences in skeletal muscle mRNA expression for PGC-1[alpha] or SIRT1 (31,32). Another study of 39 trained cyclists also showed no effect of 1000 mg of quercetin a day compared with placebo on mRNA expression for mitochondrial biogenesis or cycling time trial performance (33). Quercetin supplementation may have a larger effect on mitochondrial biogenesis and endurance performance in untrained compared with trained subjects due to differences in prestudy muscle mitochondrial density. The purpose of this study was to determine the influence of 2 wk of quercetin supplementation (1000 mg·d) compared with placebo ingestion on skeletal muscle mitochondrial biogenesis in untrained males and the ability to perform during a 12-min time trial on a graded treadmill after a 60-min moderate exercise preload.