Evidence map›Paper›PMID 26694920›Full record

ArticleBMC biology2015

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

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 and 5 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in BMC biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed
3.8field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 51 citations in OpenAlex.

  1. Trial
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  8. Nonalcoholic Fatty Liver Disease and Staging of Hepatic Fibrosis.Advances in experimental medicine and biology · 2024
    Review
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  16. Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration-probing the role of PPARα.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019
    Article
  17. Review
  18. PPARα-independent effects of nitrate supplementation on skeletal muscle metabolism in hypoxia.Biochimica et biophysica acta. Molecular basis of disease · 2019
    Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 3 institutions in 1 country.

Tom AshmoreDepartment of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
Lee D RobertsDepartment of Biochemistry, University of Cambridge, Cambridge, UK.
Andrea J MorashDepartment of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
Aleksandra O KotwicaDepartment of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
John FinnertyDepartment of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
James A WestDepartment of Biochemistry, University of Cambridge, Cambridge, UK.
Steven A MurfittDepartment of Biochemistry, University of Cambridge, Cambridge, UK.
Bernadette O FernandezFaculty of Medicine, Clinical & Experimental Sciences, University of Southampton, Southampton, UK.
Cristina BrancoDepartment of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
Andrew S CowburnDepartment of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
Kieran ClarkeDepartment of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK.
Randall S JohnsonDepartment of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
Martin FeelischFaculty of Medicine, Clinical & Experimental Sciences, University of Southampton, Southampton, UK.
Julian L GriffinDepartment of Biochemistry, University of Cambridge, Cambridge, UK.
Andrew J MurrayDepartment of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK. ajm267@cam.ac.uk.
University of Cambridge · GBUniversity of Southampton · GBUniversity of Oxford · GB

Funding

Biotechnology and Biological Sciences Research Council BB/H013539/2British Heart Foundation FS/09/050Medical Research Council G1001536Medical Research Council MC_UP_A090_1006Wellcome Trust
6 · The paper itself

Abstract

backgroundInsulin 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.

resultsHerein, 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.

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

Indexed as

Animal FeedAnimalsCyclic GMPDietDose-Response Relationship, DrugFatty AcidsMaleMuscle, SkeletalNitratesNitric OxideOrganelle BiogenesisOxidation-ReductionPeroxisome Proliferator-Activated ReceptorsRatsRats, WistarCyclic GMPFatty AcidsNitratesNitric OxidePeroxisome Proliferator-Activated Receptors

Identifiers

PMID26694920
PMCPMC4688964
OpenAlexW2220428076

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.