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Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans

Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans
Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans

BACKGROUND: Inorganic nitrate, abundant in leafy green vegetables and beetroot, is thought to have protective health benefits. Adherence to a Mediterranean diet reduces the incidence and severity of coronary artery disease, whereas supplementation with nitrate can improve submaximal exercise performance. Once ingested, oral commensal bacteria may reduce nitrate to nitrite, which may subsequently be reduced to nitric oxide during conditions of hypoxia and in the presence of "nitrite reductases" such as heme- and molybdenum-containing enzymes.

OBJECTIVE: We aimed to explore the putative effects of inorganic nitrate and nitrite on mitochondrial function in skeletal muscle.

METHODS: Mice were subjected to a nitrate/nitrite-depleted diet for 2 wk, then supplemented with sodium nitrate, sodium nitrite, or sodium chloride (1 g/L) in drinking water ad libitum for 7 d before killing. Skeletal muscle mitochondrial function and expression of uncoupling protein (UCP) 3, ADP/ATP carrier protein (AAC) 1 and AAC2, and pyruvate dehydrogenase (PDH) were assessed by respirometry and Western blotting. Studies were also undertaken in human skeletal muscle biopsies from a cohort of coronary artery bypass graft patients treated with either sodium nitrite (30-min infusion of 10 μmol/min) or vehicle [0.9% (wt:vol) saline] 24 h before surgery.

RESULTS: Neither sodium nitrate nor sodium nitrite supplementation altered mitochondrial coupling efficiency in murine skeletal muscle, and expression of UCP3, AAC1, or AAC2, and PDH phosphorylation status did not differ between the nitrite and saline groups. Similar results were observed in human samples.

CONCLUSIONS: Sodium nitrite failed to improve mitochondrial metabolic efficiency, rendering this mechanism implausible for the purported exercise benefits of dietary nitrate supplementation. This trial was registered at clinicaltrials.gov as NCT04001283.

0002-9165
Ntessalen, Maria
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Procter, Nathan E.K.
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Schwarz, Konstantin
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Loudon, Brodie L.
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Minnion, Magdalena
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Fernandez, Bernadette O.
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Vassiliou, Vassilios S.
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Vauzour, David
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Madhani, Melanie
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Constantin-Teodosiu, Dumitru
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Horowitz, John D.
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Feelisch, Martin
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Dawson, Dana
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Crichton, Paul G.
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Frenneaux, Michael P.
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Ntessalen, Maria
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Procter, Nathan E.K.
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Schwarz, Konstantin
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Loudon, Brodie L.
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Minnion, Magdalena
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Fernandez, Bernadette O.
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Vassiliou, Vassilios S.
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Vauzour, David
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Madhani, Melanie
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Constantin-Teodosiu, Dumitru
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Horowitz, John D.
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Feelisch, Martin
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Dawson, Dana
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Crichton, Paul G.
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Frenneaux, Michael P.
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Ntessalen, Maria, Procter, Nathan E.K., Schwarz, Konstantin, Loudon, Brodie L., Minnion, Magdalena, Fernandez, Bernadette O., Vassiliou, Vassilios S., Vauzour, David, Madhani, Melanie, Constantin-Teodosiu, Dumitru, Horowitz, John D., Feelisch, Martin, Dawson, Dana, Crichton, Paul G. and Frenneaux, Michael P. (2019) Inorganic nitrate and nitrite supplementation fails to improve skeletal muscle mitochondrial efficiency in mice and humans. The American Journal of Clinical Nutrition. (doi:10.1093/ajcn/nqz245).

Record type: Article

Abstract

BACKGROUND: Inorganic nitrate, abundant in leafy green vegetables and beetroot, is thought to have protective health benefits. Adherence to a Mediterranean diet reduces the incidence and severity of coronary artery disease, whereas supplementation with nitrate can improve submaximal exercise performance. Once ingested, oral commensal bacteria may reduce nitrate to nitrite, which may subsequently be reduced to nitric oxide during conditions of hypoxia and in the presence of "nitrite reductases" such as heme- and molybdenum-containing enzymes.

OBJECTIVE: We aimed to explore the putative effects of inorganic nitrate and nitrite on mitochondrial function in skeletal muscle.

METHODS: Mice were subjected to a nitrate/nitrite-depleted diet for 2 wk, then supplemented with sodium nitrate, sodium nitrite, or sodium chloride (1 g/L) in drinking water ad libitum for 7 d before killing. Skeletal muscle mitochondrial function and expression of uncoupling protein (UCP) 3, ADP/ATP carrier protein (AAC) 1 and AAC2, and pyruvate dehydrogenase (PDH) were assessed by respirometry and Western blotting. Studies were also undertaken in human skeletal muscle biopsies from a cohort of coronary artery bypass graft patients treated with either sodium nitrite (30-min infusion of 10 μmol/min) or vehicle [0.9% (wt:vol) saline] 24 h before surgery.

RESULTS: Neither sodium nitrate nor sodium nitrite supplementation altered mitochondrial coupling efficiency in murine skeletal muscle, and expression of UCP3, AAC1, or AAC2, and PDH phosphorylation status did not differ between the nitrite and saline groups. Similar results were observed in human samples.

CONCLUSIONS: Sodium nitrite failed to improve mitochondrial metabolic efficiency, rendering this mechanism implausible for the purported exercise benefits of dietary nitrate supplementation. This trial was registered at clinicaltrials.gov as NCT04001283.

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Accepted/In Press date: 3 September 2019
e-pub ahead of print date: 10 October 2019

Identifiers

Local EPrints ID: 436537
URI: http://eprints.soton.ac.uk/id/eprint/436537
ISSN: 0002-9165
PURE UUID: 34689b72-fb56-4f6a-a6b8-92d201234dae
ORCID for Bernadette O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 12 Dec 2019 17:30
Last modified: 26 Nov 2021 03:00

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Contributors

Author: Maria Ntessalen
Author: Nathan E.K. Procter
Author: Konstantin Schwarz
Author: Brodie L. Loudon
Author: Magdalena Minnion
Author: Bernadette O. Fernandez ORCID iD
Author: Vassilios S. Vassiliou
Author: David Vauzour
Author: Melanie Madhani
Author: Dumitru Constantin-Teodosiu
Author: John D. Horowitz
Author: Martin Feelisch ORCID iD
Author: Dana Dawson
Author: Paul G. Crichton
Author: Michael P. Frenneaux

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