Downloaded from http://journals.lww.com/acsm-msse by BhDMf5ePHKbH4TTImqenVHSKDBWmBJlG8K4iIgxcVJWS3n+wBtENNa6DUPnjeL+x on 10/20/2020 Synergetic Effect of NO Precursor Supplementation and Exercise Training THIBAULT LE ROUX-MALLOUF 1 , ANGELA VALLEJO 1 , FELIX PELEN 1 , IDIR HALIMAOUI 1 , STÉPHANE DOUTRELEAU 1,2 , and SAMUEL VERGES 1,2 1 HP2 Laboratory INSERM U1042, Faculty of Medicine, Université Grenoble Alpes, Grenoble, FRANCE; and 2 Sport and Pathologies Unit, Grenoble Alpes University Hospital, Hôpital Michallon, Grenoble, FRANCE ABSTRACT LE ROUX-MALLOUF, T., A. VALLEJO, F. PELEN, I. HALIMAOUI, S. DOUTRELEAU, and S. VERGES. Synergetic Effect of NO Pre- cursor Supplementation and Exercise Training. Med. Sci. Sports Exerc., Vol. 52, No. 11, pp. 2437–2447, 2020. Introduction: Nitric oxide (NO) precursor supplementation has been shown to increase NO bioavailability and can potentially improve vascular function and exercise performance. It remains unclear whether the combination of NO precursor supplementation and exercise training has synergic effects on ex- ercise performance. This study aims to assess the effect of chronic nitrate and citrulline intake on exercise training adaptations in healthy young individuals. Methods: In this randomized, double-bind trial, 24 healthy young (12 females) subjects performed vascular function assessment (blood pressure, pulse wave velocity, postischemia vasodilation, and cerebrovascular reactivity) and both local (submaximal isometric unilat- eral knee extension) and whole-body (incremental cycling) exercise tests to exhaustion before and after a 2-month exercise training program and daily intake of a placebo or a nitrate-rich salad and citrulline (N + C, 520 mg nitrate and 6 g citrulline) drink. Prefrontal cortex and quad- riceps oxygenation was monitored continuously during exercise by near-infrared spectroscopy. Results: N + C supplementation had no effect on vascular function and muscle and cerebral oxygenation during both local and whole-body exercise. N + C supplementation induced a sig- nificantly larger increase in maximal knee extensor strength (+5.1 ± 3.5 vs +0.2 ± 5.5 kg, P = 0.008) as well as a trend toward a larger increase in knee extensor endurance (+35.2 ± 26.1 vs +24.0 ± 10.4 contractions, P = 0.092) than placebo, but no effect on exercise training-induced maximal aerobic performance improvement. Conclusion: These results suggest that chronic nitrate and citrulline supplementation enhances the effect of exercise training on quadriceps muscle function in healthy active young individuals, but this does not translate into improved max- imal aerobic performances. Key Words: CITRULLINE, NITRATE, HEALTHY, YOUNG, STRENGTH, ENDURANCE N itric oxide (NO) is a gaseous signaling molecule in- volved in a variety of physiological functions throughout the body (1). The first pathway for NO production is endogenous via the citrulline–arginine–NO pathway and requires the activity of the nitric oxide synthase (NOS) enzymes. The second pathway is partially exogenous because it uses nitrate and nitrite brought by water and food to produce NO based on the simple one-electron reduction of nitrite. Systemic NO bioavailability can be enhanced by NO precursors supplementation such as citrulline (2,3) and nitrate (4). In the peripheral vessels, NO regulates vascular tone by ac- tivating soluble guanylate cyclase in the vascular smooth mus- cle. During physical activities, NO bioavailability is important to match blood flow to oxygen demand in the brain and contracting muscles. For instance, although NOS inhibition (via N G -monomethyl-arginine) during intermittent handgrip exercise reduces muscle blood flow (5), several studies sug- gest that nitrate supplementation may improve performance in a variety of exercises (6). NO also seems to have an effect specifically on muscle metabolism. It has recently been shown that chronic nitrate supplementation may favorably affect the contractile properties of skeletal muscle by increasing NO bio- availability (7). Specifically, the improvements in exercise ef- ficiency and performance may be related to an improvement in the oxygen or adenosine triphosphate (ATP) cost of muscle force or power production (7). In turn, this might be related to an increased perfusion, mitochondrial (8), and contractile function (9). Regarding citrulline, besides its ability to increase plasma arginine bioavailability as a substrate for NO synthesis (2), it could enhance muscle protein resynthesis (10) and re- duce fatigue during exercise by improving ammonia liver elimination (11). Recently, we showed that acute nitrate and citrulline supplementation increases postischemic hyperemic response in healthy young subjects (12), whereas 1 month of daily nitrate and citrulline supplementation increases cycling performance in healthy older individuals (13). However, al- though the effects of NO precursor intake have been widely in- vestigated on acute exercise responses, it is less clear how Address for correspondence: Samuel Verges, Ph.D., Laboratoire HP2 (U1042 INSERM), UM Sports Pathologies, Hôpital Sud, Université Grenoble Alpes, Avenue Kimberley, 38434 Echirolles, France; E-mail: sverges@chu-grenoble.fr. Submitted for publication September 2019. Accepted for publication April 2020. 0195-9131/20/5211-2437/0 MEDICINE & SCIENCE IN SPORTS & EXERCISE ® Copyright © 2020 by the American College of Sports Medicine DOI: 10.1249/MSS.0000000000002387 2437 APPLIED SCIENCES Copyright © 2020 by the American College of Sports Medicine. 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