Dietary Inorganic Nitrate Improves Mitochondrial Efficiency in Humans

Department of Physiology and Pharmacology, Karolinska Institutet, 11486 Stockholm, Sweden.
Cell metabolism (Impact Factor: 17.57). 02/2011; 13(2):149-59. DOI: 10.1016/j.cmet.2011.01.004
Source: PubMed


Nitrate, an inorganic anion abundant in vegetables, is converted in vivo to bioactive nitrogen oxides including NO. We recently demonstrated that dietary nitrate reduces oxygen cost during physical exercise, but the mechanism remains unknown. In a double-blind crossover trial we studied the effects of a dietary intervention with inorganic nitrate on basal mitochondrial function and whole-body oxygen consumption in healthy volunteers. Skeletal muscle mitochondria harvested after nitrate supplementation displayed an improvement in oxidative phosphorylation efficiency (P/O ratio) and a decrease in state 4 respiration with and without atractyloside and respiration without adenylates. The improved mitochondrial P/O ratio correlated to the reduction in oxygen cost during exercise. Mechanistically, nitrate reduced the expression of ATP/ADP translocase, a protein involved in proton conductance. We conclude that dietary nitrate has profound effects on basal mitochondrial function. These findings may have implications for exercise physiology- and lifestyle-related disorders that involve dysfunctional mitochondria.

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    • "Hypoxia facilitates the reduction of nitrite to NO (Millar et al., 1998; Maher et al., 2008), allowing more NO to be generated in tissues receiving less O 2 or that are more metabolically active (Thomas et al., 2001). Oral and dietary nitrate supplementation has been shown to reduce the O 2 cost of locomotion (Larsen et al., 2007, 2011; Bailey et al., 2009; Cermak et al., 2012a), which has been attributed to either improved efficiency of oxidative metabolic (Clerc et al., 2007; Larsen et al., 2011) or contractile processes (Bailey et al., 2010b). During exercise in moderate hypoxia, nitrate supplementation improves peripheral O 2 efficiency and phosphocreatine recovery kinetics (Vanhatalo et al., 2011; Masschelein et al., 2012). "
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    ABSTRACT: Background: Hypoxia-induced pulmonary vasoconstriction increases pulmonary arterial pressure (PAP) and may impede right heart function and exercise performance. This study examined the effects of oral nitrate supplementation on right heart function and performance during exercise in normoxia and hypoxia. We tested the hypothesis that nitrate supplementation would attenuate the increase in PAP at rest and during exercise in hypoxia, thereby improving exercise performance. Methods: Twelve trained male cyclists [age: 31 ± 7 year (mean ± SD)] performed 15 km time-trial cycling (TT) and steady-state submaximal cycling (50, 100, and 150 W) in normoxia and hypoxia (11% inspired O2) following 3-day oral supplementation with either placebo or sodium nitrate (0.1 mmol/kg/day). We measured TT time-to-completion, muscle tissue oxygenation during TT and systolic right ventricle to right atrium pressure gradient (RV-RA gradient: index of PAP) during steady state cycling. Results: During steady state exercise, hypoxia elevated RV-RA gradient (p > 0.05), while oral nitrate supplementation did not alter RV-RA gradient (p > 0.05). During 15 km TT, hypoxia lowered muscle tissue oxygenation (p < 0.05). Nitrate supplementation further decreased muscle tissue oxygenation during 15 km TT in hypoxia (p < 0.05). Hypoxia impaired time-to-completion during TT (p < 0.05), while no improvements were observed with nitrate supplementation in normoxia or hypoxia (p > 0.05). Conclusion: Our findings indicate that oral nitrate supplementation does not attenuate acute hypoxic pulmonary vasoconstriction nor improve performance during time trial cycling in normoxia and hypoxia.
    Frontiers in Physiology 11/2015; 6:288. DOI:10.3389/fphys.2015.00288 · 3.53 Impact Factor
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    • "Instead, we provide evidence that mitochondrial H 2 O 2 is increased, however it remains to be determined if this contributes to the observed reduction in VO 2 . This is in contrast to the results found following 3 days of sodium nitrate supplementation (Larsen et al. 2011). This is surprising given that nitrate appears to be the active ingredient in both supplements, as a nitrate-depleted beetroot juice placebo has been shown to have no effect on pulmonary responses to exercise in both moderate-and severe-intensity exercise, as well as blood pressure (Lansley et al. 2011). "
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    ABSTRACT: Ingestion of sodium nitrate (NO3 (-) ) simultaneously reduces whole-body oxygen consumption (VO2 ) during sub-maximal exercise while improving mitochondrial efficiency, suggesting a causal link. Consumption of beetroot juice (BRJ) elicits similar decreases in VO2 but potential effects on the mitochondria remain unknown. Therefore we examined the effects of 7-day supplementation with BRJ (280 ml d(-1) , ∼26 mmol NO3 (-) ) in young active males (n = 10) who had muscle biopsies taken before and after supplementation for assessments of mitochondrial bioenergetics. Subjects performed 20 min of cycling (10 min at 50% and 70% VO2peak ) 48 h before pre (baseline) and post (day 5 of supplementation) biopsies. Whole-body VO2 decreased (P < 0.05) by ∼3% at 70% VO2peak following supplementation. Mitochondrial respiration in permeabilized muscle fibres showed no change in leak respiration, the content of proteins associated with uncoupling (UCP3, ANT1, ANT2), maximal substrate-supported respiration, or ADP sensitivity (apparent Km ). In addition, isolated subsarcolemmal and intermyofibrillar mitochondria showed unaltered assessments of mitochondrial efficiency, including ADP consumed/oxygen consumed (P/O Ratio), respiratory control ratios (RCR) and membrane potential determined fluorometrically using Safranine-O. In contrast, rates of mitochondrial hydrogen peroxide (H2 O2 ) emission were increased following BRJ. Therefore, in contrast to sodium nitrate, BRJ supplementation does not alter key parameters of mitochondrial efficiency. This occurred despite a decrease in exercise VO2 , suggesting that the ergogenic effects of BRJ ingestion are not due to a change in mitochondrial coupling or efficiency. It remains to be determined if increased mitochondrial H2 O2 contributes to this response. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 10/2015; DOI:10.1113/JP270844 · 5.04 Impact Factor
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    • "ial respiration for O 2 , an effect that is reproduced in vitro—acutely and pH - dependently—by NO − 2 ( Larsen et al . , 2011 ) . Lowered affinity is attributed to an NO induced rise in the apparent K m of cytochrome c oxidase for O 2 ( Larsen et al . , 2011 ) but , inconsistently , NO − 2 does not affect mitochondrial respiration or efficiency ( Larsen et al . , 2011 ) like NO is expected to ( Brown and Borutaite , 2007 ) . Apparent mitochondrial respiratory affinity for O 2 depends strongly on the extent to which respiration is controlled by the enzyme reacting with O 2 ( Affourtit et al . , 2001 ) —control of cytochrome c oxidase over O 2 consumption may well have been affected by NO"
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    ABSTRACT: Inorganic nitrate is present at high levels in beetroot and celery, and in green leafy vegetables such as spinach and lettuce. Though long believed inert, nitrate can be reduced to nitrite in the human mouth and, further, under hypoxia and/or low pH, to nitric oxide. Dietary nitrate has thus been associated favorably with nitric-oxide-regulated processes including blood flow and energy metabolism. Indeed, the therapeutic potential of dietary nitrate in cardiovascular disease and metabolic syndrome-both aging-related medical disorders-has attracted considerable recent research interest. We and others have shown that dietary nitrate supplementation lowers the oxygen cost of human exercise, as less respiratory activity appears to be required for a set rate of skeletal muscle work. This striking observation predicts that nitrate benefits the energy metabolism of human muscle, increasing the efficiency of either mitochondrial ATP synthesis and/or of cellular ATP-consuming processes. In this mini-review, we evaluate experimental support for the dietary nitrate effects on muscle bioenergetics and we critically discuss the likelihood of nitric oxide as the molecular mediator of such effects.
    Frontiers in Physiology 08/2015; 6:211. DOI:10.3389/fphys.2015.00211 · 3.53 Impact Factor
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