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Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism

Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism
Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism
Background: Insulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of ?-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms.

Results: Herein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPAR?/?- and PPAR?-dependent mechanism. Enhanced PPAR?/? and PPAR? expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPAR??/? mice. In C2C12 myotubes, nitrate increased expression of the PPAR? targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate supplementation.

Conclusions: Nitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.
fatty acid oxidation, metabolism, mitochondria, muscle, nitrate, nitric oxide
1471-2180
1-17
Ashmore, Tom
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Roberts, Lee D.
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Morash, Andrea J.
d07b352f-3e0c-432e-9352-67facd351ff1
Kotwica, Aleksandra O.
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Finnerty, John
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West, James A.
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Murfitt, Steven A.
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Fernandez, Bernadette O.
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Branco, Cristina
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Cowburn, Andrew S.
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Clarke, Kieran
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Johnson, Randall S.
f76ee722-08df-4010-b5c9-684689e9872c
Feelisch, Martin
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Griffin, Julian L.
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Murray, Andrew J.
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Ashmore, Tom
3c15ded2-cdd0-4ca1-966e-39dd8dd7f80d
Roberts, Lee D.
b88baf39-097a-4cb5-a448-f39381229837
Morash, Andrea J.
d07b352f-3e0c-432e-9352-67facd351ff1
Kotwica, Aleksandra O.
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Finnerty, John
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West, James A.
acf1532e-266d-487c-bbe5-87bba31f6c44
Murfitt, Steven A.
d84e66cd-3bfa-478d-9e80-2f42d78219de
Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Branco, Cristina
a2c49c1c-b7c3-410d-91e9-334513afaf6d
Cowburn, Andrew S.
265baf1a-3607-403d-9e09-46f0fb193a0c
Clarke, Kieran
983493ef-1b8f-4ad8-bcdf-f288f87e3a12
Johnson, Randall S.
f76ee722-08df-4010-b5c9-684689e9872c
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Griffin, Julian L.
efbf2925-ee1c-4e28-8e89-c1a70d143928
Murray, Andrew J.
cec08ce8-91ec-42c6-9746-c4a0d9306e7b

Ashmore, Tom, Roberts, Lee D., Morash, Andrea J., Kotwica, Aleksandra O., Finnerty, John, West, James A., Murfitt, Steven A., Fernandez, Bernadette O., Branco, Cristina, Cowburn, Andrew S., Clarke, Kieran, Johnson, Randall S., Feelisch, Martin, Griffin, Julian L. and Murray, Andrew J. (2015) Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism. BMC Biology, 13 (110), 1-17. (PMID:26694920)

Record type: Article

Abstract

Background: Insulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of ?-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms.

Results: Herein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPAR?/?- and PPAR?-dependent mechanism. Enhanced PPAR?/? and PPAR? expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPAR??/? mice. In C2C12 myotubes, nitrate increased expression of the PPAR? targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate supplementation.

Conclusions: Nitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.

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Accepted/In Press date: 10 December 2015
Published date: 22 December 2015
Keywords: fatty acid oxidation, metabolism, mitochondria, muscle, nitrate, nitric oxide
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 390056
URI: https://eprints.soton.ac.uk/id/eprint/390056
ISSN: 1471-2180
PURE UUID: 2f994272-a6c3-4204-a1a3-11d066b5384e
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: 17 Mar 2016 14:45
Last modified: 25 Apr 2019 00:31

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Contributors

Author: Tom Ashmore
Author: Lee D. Roberts
Author: Andrea J. Morash
Author: Aleksandra O. Kotwica
Author: John Finnerty
Author: James A. West
Author: Steven A. Murfitt
Author: Bernadette O. Fernandez ORCID iD
Author: Cristina Branco
Author: Andrew S. Cowburn
Author: Kieran Clarke
Author: Randall S. Johnson
Author: Martin Feelisch ORCID iD
Author: Julian L. Griffin
Author: Andrew J. Murray

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