Summary of Study ST003784

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 PR002361. The data can be accessed directly via it's Project DOI: 10.21228/M8FN8H This work is supported by NIH grant, U2C- DK119886. See: https://www.metabolomicsworkbench.org/about/howtocite.php

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Study IDST003784
Study TitleMuscle-specific Ryanodine Receptor 1 Properties Underlie Limb-Girdle Muscular Dystrophy 2B/R2 Progression
Study SummaryRyanodine receptor 1 Ca2+ leak is a signal in skeletal muscle, but chronic leak can underlie pathology. Here we show that in healthy male mouse, limb-girdle muscle presents higher sympathetic input, elevated ryanodine receptor 1 basal phosphorylation, Ca2+ leak and mitochondrial Ca2+ content compared to distal leg muscles. These regional differences are consistent with heat generation in resting muscle to maintain core temperature. The dysferlin-null mouse develops severe pathology in the limb-girdle but not leg muscles. Absence of dysferlin disrupts dihydropyridine receptors’ inhibitory control over ryanodine receptor 1 leak, synergistically increasing leak through the already phosphorylated receptor of limb-girdle muscle, altering Ca2+ handling and distribution leading to reactive oxygen species production prior to disease onset. With age, oxidation of Ca2+ -handling proteins in dysferlin-null limb-girdle muscle exacerbated basal Ca2+ movements. Our results show that muscle-specific pathology in dysferlin-null mice is triggered by increased ryanodine receptor 1 Ca2+ leak.
Institute
University of Queensland
DepartmentSchool of Biomedical Sciences
Last NameLaunikonis
First NameBradley
AddressSchool of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
Emailb.launikonis@uq.edu.au
Phone61 7 3365 4301
Submit Date2025-02-16
Raw Data AvailableYes
Raw Data File Type(s)mzML, d
Analysis Type DetailLC-MS
Release Date2025-03-31
Release Version1
Bradley Launikonis Bradley Launikonis
https://dx.doi.org/10.21228/M8FN8H
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR002361
Project DOI:doi: 10.21228/M8FN8H
Project Title:Muscle-specific Ryanodine Receptor 1 Properties Underlie Limb-Girdle Muscular Dystrophy 2B/R2 Progression
Project Summary:Ryanodine receptor 1 Ca2+ leak is a signal in skeletal muscle, but chronic leak can underlie pathology. Here we show that in healthy male mouse, limb-girdle muscle presents higher sympathetic input, elevated ryanodine receptor 1 basal phosphorylation, Ca2+ leak and mitochondrial Ca2+ content compared to distal leg muscles. These regional differences are consistent with heat generation in resting muscle to maintain core temperature. The dysferlin-null mouse develops severe pathology in the limb-girdle but not leg muscles. Absence of dysferlin disrupts dihydropyridine receptors’ inhibitory control over ryanodine receptor 1 leak, synergistically increasing leak through the already phosphorylated receptor of limb-girdle muscle, altering Ca2+ handling and distribution leading to reactive oxygen species production prior to disease onset. With age, oxidation of Ca2+ -handling proteins in dysferlin-null limb-girdle muscle exacerbated basal Ca2+ movements. Our results show that muscle-specific pathology in dysferlin-null mice is triggered by increased ryanodine receptor 1 Ca2+ leak.
Institute:University of Queensland
Department:School of Biomedical Sciences
Last Name:Launikonis
First Name:Bradley
Address:School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia
Email:b.launikonis@uq.edu.au
Phone:61 7 3365 4301

Subject:

Subject ID:SU003918
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Genotype Strain:Wildtype

Factors:

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

mb_sample_id local_sample_id Sample source Muscle type (Ps psoas TA tibialis anterior)
SA410995RunA_dil01Mouse tissue Ps
SA410996RunA_02Mouse tissue Ps
SA410997RunB_Dil50-05Mouse tissue Ps
SA410998RunB_Dil50-04Mouse tissue Ps
SA410999RunB_Dil50-03Mouse tissue Ps
SA411000RunB_Dil50-02Mouse tissue Ps
SA411001RunB_Dil50-01Mouse tissue Ps
SA411002RunA_dil05Mouse tissue Ps
SA411003RunA_dil04Mouse tissue Ps
SA411004RunA_dil03Mouse tissue Ps
SA411005RunA_dil02Mouse tissue Ps
SA411006RunA_01Mouse tissue Ps
SA411007RunA_03Mouse tissue Ps
SA411008RunA_04Mouse tissue Ps
SA411009RunA_05Mouse tissue Ps
SA411010RunB_Dil50-13Mouse tissue TA
SA411011RunA_12Mouse tissue TA
SA411012RunA_dil11Mouse tissue TA
SA411013RunA_14Mouse tissue TA
SA411014RunA_15Mouse tissue TA
SA411015RunA_dil14Mouse tissue TA
SA411016RunA_dil15Mouse tissue TA
SA411017RunA_dil13Mouse tissue TA
SA411018RunA_13Mouse tissue TA
SA411019RunA_11Mouse tissue TA
SA411020RunB_Dil50-11Mouse tissue TA
SA411021RunB_Dil50-12Mouse tissue TA
SA411022RunB_Dil50-14Mouse tissue TA
SA411023RunB_Dil50-15Mouse tissue TA
SA411024RunA_dil12Mouse tissue TA
SA411025RunA_dil22Naïve lysis buffer -
SA411026RunA_dil21Naïve lysis buffer -
SA411027RunA_22Naïve lysis buffer -
SA411028RunA_21Naïve lysis buffer -
SA411029RunB_Dil50-21Naïve lysis buffer -
SA411030RunB_Dil50-22Naïve lysis buffer -
SA411031RunA_32STD-10 -
SA411032RunA_32repSTD-10 -
SA411033RunA_23repSTD-1 -
SA411034RunA_23STD-1 -
SA411035RunA_24repSTD-2 -
SA411036RunA_24STD-2 -
SA411037RunA_25STD-3 -
SA411038RunA_25repSTD-3 -
SA411039RunA_26STD-4 -
SA411040RunA_26repSTD-4 -
SA411041RunA_27repSTD-5 -
SA411042RunA_27STD-5 -
SA411043RunA_28STD-6 -
SA411044RunA_28repSTD-6 -
SA411045RunA_29STD-7 -
SA411046RunA_29repSTD-7 -
SA411047RunA_30STD-8 -
SA411048RunA_30repSTD-8 -
SA411049RunA_31STD-9 -
SA411050RunA_31repSTD-9 -
SA411051RunB_STDA01-repSTDA01 -
SA411052RunB_STDA01-rep2STDA01 -
SA411053RunB_STDA01STDA01 -
SA411054RunB_STDA02STDA02 -
SA411055RunB_STDA02-repSTDA02 -
SA411056RunB_STDA02-rep2STDA02 -
SA411057RunB_STDA03STDA03 -
SA411058RunB_STDA03-repSTDA03 -
SA411059RunB_STDA03-rep2STDA03 -
SA411060RunB_STDA04STDA04 -
SA411061RunB_STDA04-repSTDA04 -
SA411062RunB_STDA04-rep2STDA04 -
SA411063RunB_STDA05STDA05 -
SA411064RunB_STDA05-repSTDA05 -
SA411065RunB_STDA05-rep2STDA05 -
SA411066RunB_STDA06STDA06 -
SA411067RunB_STDA06-rep2STDA06 -
SA411068RunB_STDA06-repSTDA06 -
SA411069RunB_STDA07STDA07 -
SA411070RunB_STDA07-repSTDA07 -
SA411071RunB_STDA07-rep2STDA07 -
SA411072RunB_STDA08STDA08 -
SA411073RunB_STDA08-repSTDA08 -
SA411074RunB_STDA08-rep2STDA08 -
SA411075RunB_STDA09STDA09 -
SA411076RunB_STDA09-rep2STDA09 -
SA411077RunB_STDA09-repSTDA09 -
SA411078RunB_STDB01STDB01 -
SA411079RunB_STDB01-repSTDB01 -
SA411080RunB_STDB02STDB02 -
SA411081RunB_STDB02-repSTDB02 -
SA411082RunB_STDB03STDB03 -
SA411083RunB_STDB03-repSTDB03 -
SA411084RunB_STDB04STDB04 -
SA411085RunB_STDB04-repSTDB04 -
SA411086RunB_STDB05STDB05 -
SA411087RunB_STDB05-repSTDB05 -
SA411088RunB_STDB06STDB06 -
SA411089RunB_STDB06-repSTDB06 -
SA411090RunB_STDB07STDB07 -
SA411091RunB_STDB07-repSTDB07 -
SA411092RunB_STDB08STDB08 -
SA411093RunB_STDB08-repSTDB08 -
SA411094RunB_STDB09STDB09 -
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Collection:

Collection ID:CO003911
Collection Summary:Male C57Bl/6J mice were housed with standard chow food and water ad libitum. Mice were euthanised by cervical dislocation and skeletal muscle samples (psoas and tibialis anterior) were rapidly excised and frozen.
Sample Type:Muscle

Treatment:

Treatment ID:TR003927
Treatment Summary:No treatment. Skeletal muscle obtained from two distinct sites of male C57BL/6J mice (Ps=psoas; TA=tibialis anterior).

Sample Preparation:

Sampleprep ID:SP003924
Sampleprep Summary:~50 mg tissue samples were cryoground, homogenised with zirconium oxide beads in MeOH/water (1:1), extracted with CHCl3, and aqueous phase lyophilised (GeneVac MiVac Duo, max temp 35 *C). Samples were stored at -80 *C prior to analysis. Samples were resuspended in 60 uL of ACN/H2O (1:1) and clarified prior to LC/MS. Samples were ran either as is ('neat'), or further diluted in ACN/H2O, with the fold-dilution specified in the Study Design table.

Combined analysis:

Analysis ID AN006217 AN006218
Chromatography ID CH004714 CH004714
MS ID MS005921 MS005922
Analysis type MS MS
Chromatography type HILIC HILIC
Chromatography system Agilent 1290 Infinity II Agilent 1290 Infinity II
Column Agilent InfinityLab Poroshell 120 HILIC-Z (100 x 2.1mm,2.7um) Agilent InfinityLab Poroshell 120 HILIC-Z (100 x 2.1mm,2.7um)
MS Type ESI ESI
MS instrument type Triple quadrupole Triple quadrupole
MS instrument name Agilent 6470 QQQ Agilent 6470 QQQ
Ion Mode POSITIVE NEGATIVE
Units pmol/mg tissue pmol/mg tissue

Chromatography:

Chromatography ID:CH004714
Chromatography Summary:Agilent InfinityLab Poroshell 120 HILIC-Z column (100 x 2.1 mm,2.7µm,stainless-steel lined); Variable flow rate was used as specified in the flow gradient.
Instrument Name:Agilent 1290 Infinity II
Column Name:Agilent InfinityLab Poroshell 120 HILIC-Z (100 x 2.1mm,2.7um)
Column Temperature:30
Flow Gradient:0 min, 0% B, 250 μL/min; 2 min, 0% B, 250 μL/min; 12 min, 40% B, 250 μL/min; 14 min, 40% B, 250 μL/min; 14.5 min, 0% B, 500 μL/min; 18.4 min, 0% B, 500 μL/min; 18.5 min, 0% B, 250 μL/min
Flow Rate:250-500uL/min
Solvent A:80% acetonitrile/20% water; 10mM ammonium acetate (pH 9); 5µM medronic acid
Solvent B:10% acetonitrile/90% water; 10mM ammonium acetate (pH 9); 5µM medronic acid
Chromatography Type:HILIC

MS:

MS ID:MS005921
Analysis ID:AN006217
Instrument Name:Agilent 6470 QQQ
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:ESI = Jet Stream Technology Ion Source MS acquisition was performed in dMRM mode, with acquisition parameters (e.g. collision energy, fragmentation voltage) for each precursor/product transition optimised using neat metabolite standards. Run A was dMRM analysis, with glutamate and alpha-ketoglutarate being quantified. Run B was a standard MRM-mode analysis, with lactate and pyruvate being quantified. Metabolites were identified by their transition and retention time. For dMRM mode, retention times updated using a neat standard mix injected immediately prior to performing the dMRM analysis. For MRM mode, retention times were confirmed using neat standards. Data processing, peak identification, and quantification was performed using Skyline, with the MRM parameters inputted prior to file import.
Ion Mode:POSITIVE
  
MS ID:MS005922
Analysis ID:AN006218
Instrument Name:Agilent 6470 QQQ
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:ESI = Jet Stream Technology Ion Source MS acquisition was performed in dMRM mode, with acquisition parameters (e.g. collision energy, fragmentation voltage) for each precursor/product transition optimised using neat metabolite standards. Run A was dMRM analysis, with glutamate and alpha-ketoglutarate being quantified. Run B was a standard MRM-mode analysis, with lactate and pyruvate being quantified. Metabolites were identified by their transition and retention time. For dMRM mode, retention times updated using a neat standard mix injected immediately prior to performing the dMRM analysis. For MRM mode, retention times were confirmed using neat standards. Data processing, peak identification, and quantification was performed using Skyline, with the MRM parameters inputted prior to file import.
Ion Mode:NEGATIVE
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