Summary of Study ST003126
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 PR001944. The data can be accessed directly via it's Project DOI: 10.21228/M8FD9G 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.
| Study ID | ST003126 |
| Study Title | Effect of high fat diet on heart metabolome of CHCHD10 mutant mice |
| Study Summary | Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress. |
| Institute | Weill Cornell Medicine |
| Last Name | Southwell |
| First Name | Nneka |
| Address | 407 E 61st St |
| nns4001@med.cornell.edu | |
| Phone | 646-962-8172 |
| Submit Date | 2024-03-03 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | raw(Thermo) |
| Analysis Type Detail | LC-MS |
| Release Date | 2024-03-26 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Project:
| Project ID: | PR001944 |
| Project DOI: | doi: 10.21228/M8FD9G |
| Project Title: | High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice |
| Project Summary: | Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress. |
| Institute: | Weill Cornell Medicine |
| Last Name: | Southwell |
| First Name: | Nneka |
| Address: | 407 E 61st St |
| Email: | nns4001@med.cornell.edu |
| Phone: | 646-962-8172 |
Subject:
| Subject ID: | SU003243 |
| Subject Type: | Mammal |
| Subject Species: | Mus musculus |
| Taxonomy ID: | 10090 |
Factors:
Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)
| mb_sample_id | local_sample_id | Sample source | Genotype | Sex | Diet |
|---|---|---|---|---|---|
| SA338887 | H_HetCD_1 | Heart | CHCHD10 S55L Het | F | Control Diet |
| SA338888 | H_HetCD_4 | Heart | CHCHD10 S55L Het | F | Control Diet |
| SA338889 | H_HetCD_5 | Heart | CHCHD10 S55L Het | F | Control Diet |
| SA338890 | H_HetCD_3 | Heart | CHCHD10 S55L Het | F | Control Diet |
| SA338891 | H_HetCD_2 | Heart | CHCHD10 S55L Het | F | Control Diet |
| SA338892 | H_HetHFD_2 | Heart | CHCHD10 S55L Het | F | High Fat Diet |
| SA338893 | H_HetHFD_3 | Heart | CHCHD10 S55L Het | F | High Fat Diet |
| SA338894 | H_HetHFD_5 | Heart | CHCHD10 S55L Het | F | High Fat Diet |
| SA338895 | H_HetHFD_4 | Heart | CHCHD10 S55L Het | F | High Fat Diet |
| SA338896 | H_HetHFD_1 | Heart | CHCHD10 S55L Het | F | High Fat Diet |
| SA338897 | H_HetCD_10 | Heart | CHCHD10 S55L Het | M | Control Diet |
| SA338898 | H_HetCD_8 | Heart | CHCHD10 S55L Het | M | Control Diet |
| SA338899 | H_HetCD_9 | Heart | CHCHD10 S55L Het | M | Control Diet |
| SA338900 | H_HetCD_6 | Heart | CHCHD10 S55L Het | M | Control Diet |
| SA338901 | H_HetCD_7 | Heart | CHCHD10 S55L Het | M | Control Diet |
| SA338902 | H_HetHFD_8 | Heart | CHCHD10 S55L Het | M | High Fat Diet |
| SA338903 | H_HetHFD_10 | Heart | CHCHD10 S55L Het | M | High Fat Diet |
| SA338904 | H_HetHFD_9 | Heart | CHCHD10 S55L Het | M | High Fat Diet |
| SA338905 | H_HetHFD_7 | Heart | CHCHD10 S55L Het | M | High Fat Diet |
| SA338906 | H_HetHFD_6 | Heart | CHCHD10 S55L Het | M | High Fat Diet |
| SA338907 | H_WTCD_5 | Heart | WT | F | Control Diet |
| SA338908 | H_WTCD_4 | Heart | WT | F | Control Diet |
| SA338909 | H_WTCD_1 | Heart | WT | F | Control Diet |
| SA338910 | H_WTCD_2 | Heart | WT | F | Control Diet |
| SA338911 | H_WTCD_3 | Heart | WT | F | Control Diet |
| SA338912 | H_WTHFD_5 | Heart | WT | F | High Fat Diet |
| SA338913 | H_WTHFD_2 | Heart | WT | F | High Fat Diet |
| SA338914 | H_WTHFD_3 | Heart | WT | F | High Fat Diet |
| SA338915 | H_WTHFD_4 | Heart | WT | F | High Fat Diet |
| SA338916 | H_WTHFD_1 | Heart | WT | F | High Fat Diet |
| SA338917 | H_WTCD_10 | Heart | WT | M | Control Diet |
| SA338918 | H_WTCD_6 | Heart | WT | M | Control Diet |
| SA338919 | H_WTCD_9 | Heart | WT | M | Control Diet |
| SA338920 | H_WTCD_7 | Heart | WT | M | Control Diet |
| SA338921 | H_WTCD_8 | Heart | WT | M | Control Diet |
| SA338922 | H_WTHFD_10 | Heart | WT | M | High Fat Diet |
| SA338923 | H_WTHFD_9 | Heart | WT | M | High Fat Diet |
| SA338924 | H_WTHFD_6 | Heart | WT | M | High Fat Diet |
| SA338925 | H_WTHFD_7 | Heart | WT | M | High Fat Diet |
| SA338926 | H_WTHFD_8 | Heart | WT | M | High Fat Diet |
| Showing results 1 to 40 of 40 |
Collection:
| Collection ID: | CO003236 |
| Collection Summary: | Murine cardiac tissue was excised, then snap frozen in liquid nitrogen. |
| Sample Type: | Cardiac tissue |
Treatment:
| Treatment ID: | TR003252 |
| Treatment Summary: | CHCHD10 WT and CHCHD10 S55L heterozygous mice were treated with either a control diet (70% Carbohydrate, 20% Protein, 10% Fat) or High Fat Diet (60% Fat, 20% Protein, 20% Carbohydrate) in utero until 75 days of age. |
Sample Preparation:
| Sampleprep ID: | SP003250 |
| Sampleprep Summary: | 15 mg of cardiac tissue was homogenized in 80% methanol (Sigma) using Tissue Tearer (BioSpec) on dry ice. Samples were incubated at -80ºC for 4 hours. Homogenates were then centrifuged at 14,000 rfc for 20 min at 4ºC. The supernatant was extracted and stored at -80ºC for mass spectroscopy with the Weill Cornell Medicine Meyer Cancer Center Proteomics & Metabolomics Core Facility. |
Combined analysis:
| Analysis ID | AN005125 |
|---|---|
| Analysis type | MS |
| Chromatography type | HILIC |
| Chromatography system | Thermo Vanquish |
| Column | Merck SeQuant ZIC-pHILIC (150 x 2.1mm,5um) |
| MS Type | ESI |
| MS instrument type | Orbitrap |
| MS instrument name | Thermo Q Exactive Orbitrap |
| Ion Mode | UNSPECIFIED |
| Units | Peak Intensity |
Chromatography:
| Chromatography ID: | CH003878 |
| Methods Filename: | Protocol_HeartMetabolomics.pdf |
| Instrument Name: | Thermo Vanquish |
| Column Name: | Merck SeQuant ZIC-pHILIC (150 x 2.1mm,5um) |
| Column Temperature: | 30 |
| Flow Gradient: | 85% to 30% A in 20 min followed by a wash with 30% A and re-equilibration at 85% A |
| Flow Rate: | 150 μL/min |
| Solvent A: | 100% acetonitrile |
| Solvent B: | 100% water; 0.1% NH4OH; 20 mM CH3COONH4 |
| Chromatography Type: | HILIC |
MS:
| MS ID: | MS004861 |
| Analysis ID: | AN005125 |
| Instrument Name: | Thermo Q Exactive Orbitrap |
| Instrument Type: | Orbitrap |
| MS Type: | ESI |
| MS Comments: | The MS data was processed using XCalibur 4.1 (Thermo Scientific) to obtain the metabolite signal intensity for relative quantitation. Targeted identification was available for 205 metabolites based on an in-house library established using known chemical standards. Identification required exact mass (within 5ppm) and standard retention times. For untargeted metabolomics, metabolites were identified by mass matching of the MS signal to metabolites in the HMDB database. If multiple metabolites in the database were matched to a certain MS signal, all matched metabolites were grouped into a single identification, and ordered based on the number of references included in the HMDB database (high to low). We used the first ranked metabolite in the downstream analyses. When multiple values with the same metabolite attribution occurred (different metabolites with same mass and retention time), we opted to use all values in the analyses to avoid biases on which intensities/attributions to consider. Peak intensities for metabolites were screened for missing values and relative metabolite abundance data was analyzed by using MetaboAnalyst software version 5.0 (Pang et al, 2021). Metabolite significance was determined with one-way ANOVA with post-hoc t-tests, with the cutoff being a raw p value < 0.05, and the pathway significance cutoff was FDR corrected p value < 0.05. |
| Ion Mode: | UNSPECIFIED |
| Analysis Protocol File: | Protocol_HeartMetabolomics.pdf |
