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

Overview of attention for article published in BMC Biology, December 2015
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Title
Nitrate enhances skeletal muscle fatty acid oxidation via a nitric oxide-cGMP-PPAR-mediated mechanism
Published in
BMC Biology, December 2015
DOI 10.1186/s12915-015-0221-6
Pubmed ID
Authors

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

Abstract

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 β-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. 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 PPARβ/δ- and PPARα-dependent mechanism. Enhanced PPARβ/δ and PPARα 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 PPARα(-/-) mice. In C2C12 myotubes, nitrate increased expression of the PPARα 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. Nitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.

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Mendeley readers

The data shown below were compiled from readership statistics for 76 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 2 3%
Unknown 74 97%

Demographic breakdown

Readers by professional status Count As %
Student > Master 14 18%
Researcher 12 16%
Student > Ph. D. Student 9 12%
Student > Bachelor 8 11%
Professor 5 7%
Other 10 13%
Unknown 18 24%
Readers by discipline Count As %
Agricultural and Biological Sciences 14 18%
Biochemistry, Genetics and Molecular Biology 13 17%
Medicine and Dentistry 9 12%
Sports and Recreations 5 7%
Pharmacology, Toxicology and Pharmaceutical Science 4 5%
Other 13 17%
Unknown 18 24%