Summary of Study ST003145

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 PR001956. The data can be accessed directly via it's Project DOI: 10.21228/M8WF0F This work is supported by NIH grant, U2C- DK119886.

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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 IDST003145
Study TitleMuscle-type specific stress responses explain the onset of external ophthalmoplegia in mitochondrial disease
Study SummaryMitochondrial dysfunctions elicit progressive tissue-specific stress responses that can be protective or deleterious. Here, we show that even different muscles of an individual react differently to mitochondrial disease. In mitochondrial myopathy (MM), the extraocular muscles (EOMs) are affected first, followed by exercise intolerance in the large lower limb muscles. Both muscle types show clear signs of respiratory chain deficiency. However, the limbs upregulate the mitochondrial integrated stress response (ISRmt) that drives glucose carbons to anabolic repair pathways, while EOMs present no signs of ISRmt. In contrast, in EOMs, Pdk4 activation inhibits pyruvate metabolism, while beta-oxidation of fatty acids is induced - despite the reliance of beta-oxidation on a functional respiratory chain for ATP production. The data suggest that the inability to upregulate ISRmt and consequent deleterious fuel choices sensitize EOMs to early weakness and atrophy, explaining ophthalmoplegia, the most common MM sign. The distinct responses to disease even in muscles of a single individual predict different responses to treatment, which is essential knowledge when designing interventions.
Institute
University of Helsinki
DepartmentFaculty of Medicine
LaboratoryAnu Wartiovaara Lab
Last NamePradhan
First NameSwagat
AddressC519b, Biomedicum 1, Haartmaninkatu 8, Helsinki
Emailswagat.pradhan@helsinki.fi
Phone+358465287359
Submit Date2024-02-21
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2025-01-02
Release Version1
Swagat Pradhan Swagat Pradhan
https://dx.doi.org/10.21228/M8WF0F
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR001956
Project DOI:doi: 10.21228/M8WF0F
Project Title:Muscle-type specific stress responses explain external ophthalmoplegia in mitochondrial disease
Project Summary:Mitochondrial dysfunctions elicit progressive tissue-specific stress responses that can be protective or deleterious. Here, we show that even different muscles of an individual react differently to mitochondrial disease. In mitochondrial myopathy (MM), the extraocular muscles (EOMs) are affected first, followed by exercise intolerance in the large lower limb muscles. Both muscle types show clear signs of respiratory chain deficiency. However, the limbs upregulate the mitochondrial integrated stress response (ISRmt) that drives glucose carbons to anabolic repair pathways, while EOMs present no signs of ISRmt. In contrast, in EOMs, Pdk4 activation inhibits pyruvate metabolism, while beta-oxidation of fatty acids is induced - despite the reliance of beta-oxidation on a functional respiratory chain for ATP production. The data suggest that the inability to upregulate ISRmt and consequent deleterious fuel choices sensitize EOMs to early weakness and atrophy, explaining ophthalmoplegia, the most common MM sign. The distinct responses to disease even in muscles of a single individual predict different responses to treatment, which is essential knowledge when designing interventions.
Institute:University of Helsinki
Laboratory:Anu Wartiovaara Lab
Last Name:Pradhan
First Name:Swagat
Address:C519b, Biomedicum 1, Haartmaninkatu 8, Helsinki, Uusimaa, 00290, Finland
Email:swagat.pradhan@helsinki.fi
Phone:+358465287359

Subject:

Subject ID:SU003262
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammals

Factors:

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

mb_sample_id local_sample_id Sample source Genotype
SA340691Del_2_EOMExtra-ocular muscle Deletor
SA340692Del_3_EOMExtra-ocular muscle Deletor
SA340693Del_5_EOMExtra-ocular muscle Deletor
SA340694Del_1_EOMExtra-ocular muscle Deletor
SA340695Del_4_EOMExtra-ocular muscle Deletor
SA340696Del_6_EOMExtra-ocular muscle Deletor
SA340697WT_1_EOMExtra-ocular muscle Wild type
SA340698WT_7_EOMExtra-ocular muscle Wild type
SA340699WT_3_EOMExtra-ocular muscle Wild type
SA340700WT_2_EOMExtra-ocular muscle Wild type
SA340701WT_6_EOMExtra-ocular muscle Wild type
SA340702WT_5_EOMExtra-ocular muscle Wild type
SA340703WT_4_EOMExtra-ocular muscle Wild type
SA340704Del_1_QFQuadriceps femoris Deletor
SA340705Del_4_QFQuadriceps femoris Deletor
SA340706Del_3_QFQuadriceps femoris Deletor
SA340707Del_5_QFQuadriceps femoris Deletor
SA340708Del_2_QFQuadriceps femoris Deletor
SA340709Del_6_QFQuadriceps femoris Deletor
SA340710WT_4_QFQuadriceps femoris Wild type
SA340711WT_1_QFQuadriceps femoris Wild type
SA340712WT_2_QFQuadriceps femoris Wild type
SA340713WT_3_QFQuadriceps femoris Wild type
SA340714WT_5_QFQuadriceps femoris Wild type
SA340715WT_6_QFQuadriceps femoris Wild type
Showing results 1 to 25 of 25

Collection:

Collection ID:CO003255
Collection Summary:Muscles were extracted by excision and snap frozen in liquid nitrogen
Sample Type:Muscle

Treatment:

Treatment ID:TR003271
Treatment Summary:The experimental mouse model used in this study (Deletor) are transgenic for Twnk, encoding Twinkle, a nuclear-encoded mtDNA helicase that carries a dominant mutation (homologous to a MM patient mutation, leading into a 13-amino acid duplication of amino acids p.353-365 in the protein). The controls were wild-type (WT) littermates of Deletor mice. WT mice are used as controls. The genotype and tissue specific differences were studied by analysing metabolites from Quadriceps femoris(QF) and extra-ocular muscles(EOM).

Sample Preparation:

Sampleprep ID:SP003269
Sampleprep Summary:The samples were added to 2 ml Precellys homogenization tube (Bertin Technologies, Montigny-le-Bretonneux, France) with 2.8 mm ceramic (zirconium oxide) beads with 500µl of cold extraction solvent (Acetonitrile:Methanol:Milli-Q Water; 40:40:20). Subsequently, samples were homogenized using a tissue homogenizer (Bertin Technologies, France) for 3 cycles (30sec at 5500rpm with 60sec pause at 4°C). It was then followed by centrifugation at 14000rpm at 4°C for 5 minutes. The supernatant was then loaded into a Phenomenex, Phree Phospholipid removal 96 well plate 30mg (Part No. 8E-S133-TGB) and passed through using a robotic vacuum. The resulting filtrate was then transferred into polypropylene tubes and placed into a Nitrogen gas evaporator to completely dry the solvent.

Chromatography:

Chromatography ID:CH003906
Instrument Name:Thermo Vanquish
Column Name:Merck SeQuant ZIC-pHILIC (100 x 2.1mm,5um)
Column Temperature:40 ± 3
Flow Gradient:gradient elution began with 20% mobile phase A and 80% mobile phase B and was maintained until 2 minutes. Then, mobile phase A was gradually increased from 20% to 80% until 17 minutes, followed by a decrease from 80% to 20% in mobile phase A from 17.1 minutes and maintained up to 24 minutes.
Flow Rate:0.100 mL/minute
Solvent A:100% water, 20mM Ammonium hydrogen carbonate, pH 9.4
Solvent B:100% acetonitrile
Chromatography Type:HILIC

Analysis:

Analysis ID:AN005161
Analysis Type:MS
Chromatography ID:CH003906
Num Factors:4
Num Metabolites:227
Units:Peak intensity
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