Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release

Roberts, Lee D.; Ashmore, Tom; McNally, Ben D.; Murfitt, Steven A.; Fernandez, Bernadette; Feelisch, Martin; Lindsay, Ross T; Siervo, Mario; Williams, Elizabeth A.; Murray, Andrew J.; Griffin, Julian L.

doi:10.2337/db16-0843

Cited by 40 publications

(28 citation statements)

References 47 publications

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“…Simultaneous administration of oral nitrate could improve aerobic exercise training and subsequent outcomes. This hypothesis is supported by recent work showing that dietary nitrate results in similar physiological responses as exercise therapy in a diabetic rat model [36]. We tested our hypothesis in two separate studies: patients with HFpEF and individuals with controlled hypertension.…”

Section: Introductionmentioning

confidence: 55%

Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction

et al. 2017

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Aerobic exercise training is an effective therapy to improve peak aerobic power (peak VO2) in individuals with hypertension (HTN, AHA/ACC class A) and heart failure patients with preserved ejection fraction (HFpEF). High nitrate containing beetroot juice (BRJ) also improves sub-maximal endurance and decreases blood pressure in both HTN and HFpEF. We hypothesized that combining an aerobic exercise and dietary nitrate intervention would result in additive or even synergistic positive effects on exercise tolerance and blood pressure in HTN or HFpEF. We report results from two pilot studies examining the effects of supervised aerobic exercise combined with dietary nitrate in patients with controlled HTN (n=26, average age 65 ± 5 years) and in patients with HFpEF (n = 20, average age 69 ± 7 years). All patients underwent an aerobic exercise training regimen; half were randomly assigned to consume a high nitrate-containing beet juice beverage (BRJ containing 6.1 mmol nitrate for the HFpEF study consumed three times a week and 8 mmol nitrate for the HTN study consumed daily) while the other half consumed a beet juice beverage with the nitrate removed (placebo). The main result was that there was no added benefit observed for any outcomes when comparing BRJ to placebo in either HTN or HFpEF patients undergoing exercise training (p ≥ 0.14). There were within-group benefits. In the pilot study in patients with HFpEF, aerobic endurance (primary outcome), defined as the exercise time to volitional exhaustion during submaximal cycling at 75% of maximal power output, improved during exercise training within each group from baseline to end of study, 369 ± 149 sec vs 520 ± 257 sec (p = 0.04) for the placebo group and 384 ± 129 sec vs 483 ± 258 sec for the BRJ group (p = 0.15). Resting systolic blood pressure in patients with HFpEF also improved during exercise training in both groups, 136 ± 16 mm Hg vs 122 ± 3 mm Hg for the placebo group (p < 0.05) and 132 ± 12 mm Hg vs 119 ± 9 mm Hg for the BRJ group (p < 0.05). In the HTN pilot study, during a treadmill graded exercise test, peak oxygen consumption (primary outcome) did not change significantly, but time to exhaustion (also a primary outcome) improved in both groups, 504 ± 32 sec vs 601 ± 38 sec (p < 0.05) for the placebo group and 690 ± 38 sec vs 772 ± 95 sec for the BRJ group (p < 0.05) which was associated with a reduction in supine resting systolic blood pressure in BRJ group. Arterial compliance also improved during aerobic exercise training in both the HFpEF and the HTN patients for both BRJ and placebo groups. Future work is needed to determine if larger nitrate doses would provide an added benefit to supervised aerobic exercise in HTN and HFpEF patients.

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Section: Introductionmentioning

confidence: 55%

Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction

et al. 2017

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“…Moreover, we only used male mice in this study, which may be a limitation because, for example, gender dimorphic differences in the antiplatelet response to NO 3 − supplementation have been observed in humans (48). As with our previous studies, we were able to precisely control NO 3 − intake using a standardized quality-controlled diet and deionized water (23, 33–35, 49, 50). Although the anorexic effects in the early stages of hypoxic exposure may have confounded our findings, the long duration of the hypoxic exposure proved to be a strength because water intake and therefore NO 3 − intake stabilized in hypoxic mice by wk 2, matching that of their normoxic counterparts for the remainder of the study.…”

Section: Discussionmentioning

confidence: 93%

Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration—probing the role of PPARα

et al. 2019

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Dietary inorganic nitrate prevents aspects of cardiac mitochondrial dysfunction induced by hypoxia, although the mechanism is not completely understood. In both heart and skeletal muscle, nitrate increases fatty acid oxidation capacity, and in the latter case, this involves up-regulation of peroxisome proliferator-activated receptor (PPAR)α expression. Here, we investigated whether dietary nitrate modifies mitochondrial function in the hypoxic heart in a PPARα-dependent manner. Wild-type (WT) mice and mice without PPARα ( Ppara −/− ) were given water containing 0.7 mM NaCl (control) or 0.7 mM NaNO 3 for 35 d. After 7 d, mice were exposed to normoxia or hypoxia (10% O 2 ) for the remainder of the study. Mitochondrial respiratory function and metabolism were assessed in saponin-permeabilized cardiac muscle fibers. Environmental hypoxia suppressed mass-specific mitochondrial respiration and additionally lowered the proportion of respiration supported by fatty acid oxidation by 18% ( P < 0.001). This switch away from fatty acid oxidation was reversed by nitrate treatment in hypoxic WT but not Ppara −/− mice, indicating a PPARα-dependent effect. Hypoxia increased hexokinase activity by 33% in all mice, whereas lactate dehydrogenase activity increased by 71% in hypoxic WT but not Ppara −/− mice. Our findings indicate that PPARα plays a key role in mediating cardiac metabolic remodeling in response to both hypoxia and dietary nitrate supplementation.—Horscroft, J. A., O’Brien, K. A., Clark, A. D., Lindsay, R. T., Steel, A. S., Procter, N. E. K., Devaux, J., Frenneaux, M., Harridge, S. D. R., Murray, A. J. Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration—probing the role of PPARα.

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“…irisin and beta-aminoisobutyric acid). Such observations have led authors to conclude that NaNO 3 induces responses that mimic exercise [103].…”

Section: Other Pharmacological Compoundsmentioning

confidence: 99%

In vitro experimental models for examining the skeletal muscle cell biology of exercise: the possibilities, challenges and future developments

Carter

Solomon

2018

Pflugers Arch - Eur J Physiol

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Exercise provides a cornerstone in the prevention and treatment of several chronic diseases. The use of in vivo exercise models alone cannot fully establish the skeletal muscle-specific mechanisms involved in such health-promoting effects. As such, models that replicate exercise-like effects in vitro provide useful tools to allow investigations that are not otherwise possible in vivo. In this review, we provide an overview of experimental models currently used to induce exercise-like effects in skeletal muscle in vitro. In particular, the appropriateness of electrical pulse stimulation and several pharmacological compounds to resemble exercise, as well as important technical considerations, are addressed. Each model covered herein provides a useful tool to investigate different aspects of exercise with a level of abstraction not possible in vivo. That said, none of these models are perfect under all circumstances, and the choice of model (and terminology) used should be informed by the specific research question whilst accounting for the several inherent limitations of each model. Further work is required to develop and optimise the current experimental models used, such as combination with complementary techniques during treatment, and thereby improve their overall utility and impact within muscle biology research.

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Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release

Cited by 40 publications

References 47 publications

Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction

Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction

Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration—probing the role of PPARα

In vitro experimental models for examining the skeletal muscle cell biology of exercise: the possibilities, challenges and future developments

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