Potentiating exercise training with resveratrol

In addition to improving health wellness and quality of life, exercise training exerts beneficial effects in chronic diseases like obesity, diabetes, and pulmonary and cardiovascular diseases, and possesses protective effects against ageing. This is why physical activity is recommended as an additional therapy in these diseases and is also beneficial to patients with cancer or neurodegenerative diseases. Regular exercise positively influences the cardiovascular system and improves heart and skeletal muscle, and vascular energy metabolism and function. Training based adaptations in the muscle are linked to an increase in the expression of genes involved in energy metabolism, mitochondrial respiration and fatty acid oxidation. The transcription cascade involved in the control of energy metabolism is mainly governed by the transcriptional co-activator PGC-1α and its target transcription factors like the PPARs. This is why it has been tempting to find oral compounds that would mimic or potentiate the effects of exercise to treat metabolic diseases and improve quality of life. Resveratrol is a polyphenol with antioxidant, anti-apoptotic and anti-inflammatory properties that was recently identified as an activator of one of the family member of sirtuins, SIRT1 (Lagouge et al. 2006). It is present in many plant-based foods commonly consumed in our diets, including peanuts, cocoa, rhubarb, cranberries, blueberries, blackberries and grapes. Many studies have provided evidence for neuroprotective, antiatherogenic, antithrombotic, antihypercholesterolemic, anti-inflammatory, anti-oxidant, proangiogenic, vasorelaxing and anti-cancer effects (for recent review see Brisdelli et al. 2009). Resveratrol is able to modulate energy metabolism and is now considered as a lead molecule for the development of drugs that treat metabolic disorders such as diabetes and obesity. Enhanced SIRT1 activity, as exercise training, decreases plasma glucose levels, improves insulin sensitivity, increases mitochondrial number and function, decreases adiposity, improves exercise tolerance and potentially lowers body weight (Elliott & Jirousek, 2008). Interestingly, SIRT1 acts in concert with PGC1α by inducing its deacetylation and thereby increasing its transcriptional activity (Rodgers et al. 2005). Resveratrol has been shown to induce mitochondrial biogenesis and improve fatty acid oxidation in many tissues by interplay between sirtuins and the AMP-activated protein kinase. In addition, resveratrol can modulate metabolic pathways and improve mitochondrial function, reduce oxidative stress and increase nitric oxide production that are involved in atherosclerosis prevention, blood pressure reduction, attenuation of left-ventricular hypertrophy, resistance to myocardial ischemic injury and heart failure prevention (Dolinsky & Dyck, 2011; Rimbaud et al. 2011). Interestingly, these effects mimic those of calorie restriction, another factor that activates sirtuin1 and mitochondrial biogenesis and results in increased longevity (Dali-Youcef et al. 2007). As resveratrol treatment mimics the benefits of exercise training, in a recent issue of The Journal of Physiology Dolinsky and colleagues (2012) asked whether resveratrol can enhance the physiological adaptations to physical training. It was found in this study that supplementing rats with resveratrol during exercise training could improve exercise performance, muscle strength and whole body oxidative metabolism. Moreover resveratrol treatment improved cardiac function and energy metabolism like mitochondrial activity and fatty acid oxidation, suggesting that resveratrol increases the ability of the heart to adapt to increased workloads as is induced by exercise. It is often emphasized that the beneficial effects of resveratrol may result from its pleiotropic effects via multiple signalling pathways acting on a variety of cellular targets. Nevertheless, metabolic effects on cardiac and skeletal muscles play an unquestionable role. Although the exact mechanisms are still debated, the beneficial effects of resveratrol are thought to depend in part on activation of the SIRT1/PGC1α/AMPK pathway which is involved in the control of energy metabolism in many tissues. Moreover, the exact target(s) of resveratrol are not precisely known. From the study by Dolinsky et al. (2012) and others (Rimbaud et al. 2011), it appears that resveratrol activates cardiac and skeletal muscle fatty acid metabolism by enhancing the activation of the nuclear receptor PPARα that modulates the expression of proteins involved in the transport and oxidation of fatty acids. Moreover, resveratrol may also indirectly improve cardiac and skeletal muscle energy metabolism, for example through its anti-oxidant properties and through its vasorelaxing effects which will improve cardiac and skeletal muscle perfusion, and enhance oxygen and substrate delivery to the heart and the periphery. Finally, beneficial cardiovascular and metabolic effects of resveratrol could also result from its phytooestrogenic properties (Mueller et al. 2004). Resveratrol treatment thus potentiates the effects of exercise. Interestingly, it was also shown that activation of the downstream targets of resveratrol with AMPK and PPARδ agonists, exerts similar potentiating effects to exercise training (Narkar et al. 2008). In addition, the vascular effects of resveratrol should not be neglected as it is able to activate angiogenesis and stimulate vasorelaxation through interaction with the vascular NO system (Brisdelli et al. 2009). Pharmacokinetic data indicate a poor bioavailability of resveratrol. A large range of doses has been used in animal studies that largely exceed food intake. Resveratrol even at the high dosage of 750 mg (kg body weight)−1 per day in 13-week developmental toxicity studies by the dietary route has been shown to have no adverse effects (Edwards et al. 2011). Pharmacological studies suggest that therapeutic doses of this molecule are non-toxic, easily absorbed and well tolerated by humans. A dose of ∼150 mg kg−1 day−1 has been used in the study of Dolinsky et al. (2012) while other studies have shown that lower doses of ∼20 mg kg−1 day−1 proved to be efficient in preventing cardiac dysfunction (Rimbaud et al. 2011) and pulmonary hypertension (Csiszar et al. 2009), and in vasoprotection (Ungvari et al. 2007). Dose–response studies are thus still needed to determine the lower effective dosage. An interesting question remains as to why and how resveratrol can mimic or potentiate the effects of exercise and of calorie restriction and what the common pathways are that are activated. From what has been described above, it appears that exercise training, calorie restriction and resveratrol activate energy metabolism and improve mitochondrial function. These findings and the abundant literature on the beneficial effects of resveratrol in a large number of diseases offers new and interesting therapeutic perspectives. Further studies are however needed to improve the bioavailability of resveratrol.