Summary of Study ST000651

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000460. The data can be accessed directly via it's Project DOI: 10.21228/M8M027 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST000651
Study TitleEffects of NO Donor Therapy on the Dystrophic Mouse Heart Metabolome (part VII)
Study SummaryFor this aim, we will only use male mdx mice. We will study three groups treated for 7 days with vehicle, naproxcinod (i.e., NO-naproxen), or naproxen (n = 10 each group). Two hours after the final treatment, half the mice in each group will be run to exhaustion on a treadmill. The heart and gastrocnemius, soleus, and quadriceps muscles of one hindlimb will be sent to the Mayo Clinic Metabolomics Resource Core. The heart and quadriceps muscle will be used for untargeted metabolomics profiling (LC/MS).
Institute
Mayo Clinic
Last NameThomas
First NameGail
AddressPenn State Hershey Heart and Vascular Institute Penn State College of Medicine 500 University Drive, MC H047 Hershey, PA 17033
Emailgthomas4@hmc.psu.edu
Phone717-531-0003, ext. 287087
Submit Date2017-06-23
Analysis Type DetailLC-MS
Release Date2019-07-17
Release Version1
Gail Thomas Gail Thomas
https://dx.doi.org/10.21228/M8M027
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR000460
Project DOI:doi: 10.21228/M8M027
Project Title:The dystrophic muscle metabolome: effects of exercise and NO donor therapy
Project Summary:In Duchenne and Becker muscular dystrophy (DMD, BMD), loss of the cytoskeletal protein dystrophin weakens the sarcolemma and disrupts cellular signaling, rendering the diseased muscles susceptible to contractioninduced damage. We and others have shown that loss of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma of dystrophin-deficient muscle causes functional muscle ischemia during exercise due to unopposed sympathetic vasoconstriction, thereby exacerbating fatigue and injury of the diseased muscles. Genetic and pharmacologic strategies targeting nNOSμ-NO signaling ameliorate functional muscle ischemia, as well as many other features of the dystrophic phenotype in the mdx mouse model of DMD/BMD. These findings suggest that the therapeutic benefit of NO likely extends beyond its vascular effects. A growing body of evidence indicates that NO directly influences muscle metabolism through effects on glucose transport as well as mitochondrial biogenesis and function. Both nNOS-/- mice and mdx mice exhibit muscle mitochondrial dysfunction, decreased resistance to fatigue, and exercise-induced muscle injury, suggesting a causal role of nNOSμ-NO deficiency. However, the specific metabolic changes resulting from reduced NO signaling that might render dystrophic muscle susceptible to fatigue and use-dependent injury remain poorly defined. Therefore, the goal of this pilot metabolomics study is to identify the unique biochemical profiles of skeletal and cardiac muscles of mdx mice to gain further mechanistic insight into the pathophysiological role of NO deficiency in muscular dystrophy. In Aim 1, we will characterize the skeletal and cardiac muscle metabolomes of mdx and nNOS-/- mice at rest and following a single bout of treadmill exercise with the goal of discovering common metabolic signatures caused by loss of NO signaling. In Aim 2, we will evaluate the potential of a NO donor drug that is under development as a therapeutic for DMD/BMD to improve the skeletal and cardiac muscle metabolomes in mdx mice. As a result of this pilot study, we hope to gain new understanding of the metabolic derangements in dystrophin-deficient muscle, insight into the therapeutic effects of NO replacement, and to identify new pathogenic mechanisms and putative therapeutic targets that will form the basis of future grant applications.
Institute:Mayo Clinic
Last Name:Thomas
First Name:Gail
Address:Penn State Hershey Heart and Vascular Institute Penn State College of Medicine 500 University Drive, MC H047 Hershey, PA 17033
Email:gthomas4@hmc.psu.edu
Phone:717-531-0003, ext. 287087

Subject:

Subject ID:SU000674
Subject Type:Mouse
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammal

Factors:

Subject type: Mouse; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Group rep
SA036619nC18-01may16-012-r001RUN-Naproxcinod 1
SA036620pC18-29apr16-022-r001RUN-Naproxcinod 1
SA036621philic-29apr16-022-r001RUN-Naproxcinod 1
SA036622nhilic-01may16-008-r001RUN-Naproxcinod 1
SA036623nhilic-01may16-012-r001RUN-Naproxcinod 1
SA036624pC18-29apr16-019-r001RUN-Naproxcinod 1
SA036625nC18-01may16-016-r001RUN-Naproxcinod 1
SA036626nC18-01may16-022-r001RUN-Naproxcinod 1
SA036627nC18-01may16-019-r001RUN-Naproxcinod 1
SA036628pC18-29apr16-008-r001RUN-Naproxcinod 1
SA036629pC18-29apr16-012-r001RUN-Naproxcinod 1
SA036630nC18-01may16-008-r001RUN-Naproxcinod 1
SA036631pC18-29apr16-016-r001RUN-Naproxcinod 1
SA036632philic-29apr16-019-r001RUN-Naproxcinod 1
SA036633philic-29apr16-016-r001RUN-Naproxcinod 1
SA036634nhilic-01may16-022-r001RUN-Naproxcinod 1
SA036635nhilic-01may16-019-r001RUN-Naproxcinod 1
SA036636philic-29apr16-008-r001RUN-Naproxcinod 1
SA036637nhilic-01may16-016-r001RUN-Naproxcinod 1
SA036638philic-29apr16-012-r001RUN-Naproxcinod 1
SA036639philic-29apr16-016-r002RUN-Naproxcinod 2
SA036640pC18-29apr16-012-r002RUN-Naproxcinod 2
SA036641philic-29apr16-008-r002RUN-Naproxcinod 2
SA036642nhilic-01may16-022-r002RUN-Naproxcinod 2
SA036643pC18-29apr16-008-r002RUN-Naproxcinod 2
SA036644nC18-01may16-022-r002RUN-Naproxcinod 2
SA036645pC18-29apr16-019-r002RUN-Naproxcinod 2
SA036646philic-29apr16-019-r002RUN-Naproxcinod 2
SA036647nC18-01may16-019-r002RUN-Naproxcinod 2
SA036648nhilic-01may16-008-r002RUN-Naproxcinod 2
SA036649nhilic-01may16-016-r002RUN-Naproxcinod 2
SA036650pC18-29apr16-022-r002RUN-Naproxcinod 2
SA036651nhilic-01may16-012-r002RUN-Naproxcinod 2
SA036652philic-29apr16-012-r002RUN-Naproxcinod 2
SA036653nhilic-01may16-019-r002RUN-Naproxcinod 2
SA036654pC18-29apr16-016-r002RUN-Naproxcinod 2
SA036655philic-29apr16-022-r002RUN-Naproxcinod 2
SA036656nC18-01may16-016-r002RUN-Naproxcinod 2
SA036657nC18-01may16-012-r002RUN-Naproxcinod 2
SA036658nC18-01may16-008-r002RUN-Naproxcinod 2
SA036659nC18-01may16-004-r001RUN-Naproxen 1
SA036660philic-29apr16-002-r001RUN-Naproxen 1
SA036661philic-29apr16-024-r001RUN-Naproxen 1
SA036662pC18-29apr16-004-r001RUN-Naproxen 1
SA036663nhilic-01may16-004-r001RUN-Naproxen 1
SA036664nhilic-01may16-024-r001RUN-Naproxen 1
SA036665nC18-01may16-011-r001RUN-Naproxen 1
SA036666pC18-29apr16-002-r001RUN-Naproxen 1
SA036667pC18-29apr16-011-r001RUN-Naproxen 1
SA036668nC18-01may16-013-r001RUN-Naproxen 1
SA036669philic-29apr16-004-r001RUN-Naproxen 1
SA036670philic-29apr16-013-r001RUN-Naproxen 1
SA036671philic-29apr16-011-r001RUN-Naproxen 1
SA036672nhilic-01may16-011-r001RUN-Naproxen 1
SA036673nC18-01may16-002-r001RUN-Naproxen 1
SA036674pC18-29apr16-013-r001RUN-Naproxen 1
SA036675nC18-01may16-024-r001RUN-Naproxen 1
SA036676pC18-29apr16-024-r001RUN-Naproxen 1
SA036677nhilic-01may16-002-r001RUN-Naproxen 1
SA036678nhilic-01may16-013-r001RUN-Naproxen 1
SA036679nC18-01may16-004-r002RUN-Naproxen 2
SA036680nC18-01may16-013-r002RUN-Naproxen 2
SA036681philic-29apr16-024-r002RUN-Naproxen 2
SA036682nhilic-01may16-013-r002RUN-Naproxen 2
SA036683pC18-29apr16-013-r002RUN-Naproxen 2
SA036684nhilic-01may16-011-r002RUN-Naproxen 2
SA036685nhilic-01may16-004-r002RUN-Naproxen 2
SA036686pC18-29apr16-011-r002RUN-Naproxen 2
SA036687pC18-29apr16-002-r002RUN-Naproxen 2
SA036688nC18-01may16-024-r002RUN-Naproxen 2
SA036689philic-29apr16-002-r002RUN-Naproxen 2
SA036690nhilic-01may16-002-r002RUN-Naproxen 2
SA036691philic-29apr16-004-r002RUN-Naproxen 2
SA036692pC18-29apr16-024-r002RUN-Naproxen 2
SA036693nC18-01may16-011-r002RUN-Naproxen 2
SA036694philic-29apr16-013-r002RUN-Naproxen 2
SA036695pC18-29apr16-004-r002RUN-Naproxen 2
SA036696nC18-01may16-002-r002RUN-Naproxen 2
SA036697nhilic-01may16-024-r002RUN-Naproxen 2
SA036698philic-29apr16-011-r002RUN-Naproxen 2
SA036699philic-29apr16-020-r001RUN-Vehicle 1
SA036700nC18-01may16-020-r001RUN-Vehicle 1
SA036701pC18-29apr16-023-r001RUN-Vehicle 1
SA036702pC18-29apr16-020-r001RUN-Vehicle 1
SA036703philic-29apr16-023-r001RUN-Vehicle 1
SA036704nhilic-01may16-006-r001RUN-Vehicle 1
SA036705pC18-29apr16-018-r001RUN-Vehicle 1
SA036706nhilic-01may16-003-r001RUN-Vehicle 1
SA036707nC18-01may16-006-r001RUN-Vehicle 1
SA036708philic-29apr16-003-r001RUN-Vehicle 1
SA036709pC18-29apr16-003-r001RUN-Vehicle 1
SA036710philic-29apr16-006-r001RUN-Vehicle 1
SA036711nC18-01may16-003-r001RUN-Vehicle 1
SA036712nC18-01may16-018-r001RUN-Vehicle 1
SA036713nC18-01may16-023-r001RUN-Vehicle 1
SA036714pC18-29apr16-006-r001RUN-Vehicle 1
SA036715nhilic-01may16-023-r001RUN-Vehicle 1
SA036716nhilic-01may16-018-r001RUN-Vehicle 1
SA036717philic-29apr16-018-r001RUN-Vehicle 1
SA036718nhilic-01may16-020-r001RUN-Vehicle 1
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Collection:

Collection ID:CO000668
Collection Summary:Blood and Tissue Harvesting: Mice will be euthanized and blood will be taken by cardiac puncture, centrifuged, and the plasma will be stored at -80ºC. The heart, diaphragm, and muscles of both hindlimbs (gastrocnemius, soleus, quadriceps) will be dissected and snap frozen in liquid nitrogen. Tibialis anterior and plantaris muscles from both hindlimbs also will be dissected and one set will be snap frozen in liquid nitrogen while the other set will be mounted in OCT and frozen in isopentane cooled by liquid nitrogen. Cryosections will be used to evaluate disease activity and exercise-induced muscle injury by staining with: (a) hematoxylin and eosin to assess gross morphology, cellular infiltration, and necrosis, (b) anti-F4/80 to label macrophages, and (c) anti-IgG or IgM to label damaged muscle fibers.
Sample Type:Heart tissue

Treatment:

Treatment ID:TR000688
Treatment Summary:Studies will be performed in 12-16 week old male mdx mice, C57BL10 control mice, and nNOS-/- mice obtained from Jackson Laboratory. All protocols will be approved by the Penn State College of Medicine Institutional Animal Care and Use Committee. Drug Treatment: Mice will be treated with vehicle, naproxcinod (20 mg/kg/day) or equimolar naproxen (12.5mg/kg/day) once a day for 7 consecutive days. To avoid the stress of oral gavage or ip injections in mdx mice, drug or vehicle will be administered in a small volume of peanut butter. Most mice readily consume the dosed peanut butter within 30 min. Terminal experiments will be performed 2 hours after the final dose is consumed.

Sample Preparation:

Sampleprep ID:SP000681
Sampleprep Summary:mouse heart untarged metabolomics profiling

Combined analysis:

Analysis ID AN000983 AN000984 AN000985 AN000986
Analysis type MS MS MS MS
Chromatography type HILIC HILIC Reversed phase Reversed phase
Chromatography system Agilent 1290 Infinity Agilent 1290 Infinity Agilent 1290 Infinity Agilent 1290 Infinity
Column Waters Acquity BEH Amide (150 x 2.1mm,1.7um) Waters Acquity BEH Amide (150 x 2.1mm,1.7um) Waters Acquity HSS C18 (150 x 2.1mm,1.8um) Waters Acquity HSS C18 (150 x 2.1mm,1.8um)
MS Type ESI ESI ESI ESI
MS instrument type QTOF QTOF QTOF QTOF
MS instrument name Agilent 6550 QTOF Agilent 6550 QTOF Agilent 6550 QTOF Agilent 6550 QTOF
Ion Mode POSITIVE NEGATIVE POSITIVE NEGATIVE
Units intensity intensity intensity intensity

Chromatography:

Chromatography ID:CH000708
Instrument Name:Agilent 1290 Infinity
Column Name:Waters Acquity BEH Amide (150 x 2.1mm,1.7um)
Chromatography Type:HILIC
  
Chromatography ID:CH000709
Instrument Name:Agilent 1290 Infinity
Column Name:Waters Acquity HSS C18 (150 x 2.1mm,1.8um)
Chromatography Type:Reversed phase

MS:

MS ID:MS000878
Analysis ID:AN000983
Instrument Name:Agilent 6550 QTOF
Instrument Type:QTOF
MS Type:ESI
Ion Mode:POSITIVE
  
MS ID:MS000879
Analysis ID:AN000984
Instrument Name:Agilent 6550 QTOF
Instrument Type:QTOF
MS Type:ESI
Ion Mode:NEGATIVE
  
MS ID:MS000880
Analysis ID:AN000985
Instrument Name:Agilent 6550 QTOF
Instrument Type:QTOF
MS Type:ESI
Ion Mode:POSITIVE
  
MS ID:MS000881
Analysis ID:AN000986
Instrument Name:Agilent 6550 QTOF
Instrument Type:QTOF
MS Type:ESI
Ion Mode:NEGATIVE
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