Summary of study ST000514

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 PR000383. The data can be accessed directly via it's Project DOI: 10.21228/M8JG7B This work is supported by NIH grant, U2C- DK119886.

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Study IDST000514
Study TitleInhibition of autophagy/proteasome degradation or inhibition of protein synthesis in models of muscle insulin resistance affect amino acids metabolites in serum
Study SummaryTo determine which protein degradation pathways downstream of IR and IGF1R contribute to changes in amino acid and mitochondrial metabolite pools, we will treat control, M-IR-/-, MIGIRKO, and HFD obese mice with inhibitors of autophagy or proteasome. We will treat 5 animals each of control, M-IR-/-, MIGIRKO, and HFD mice with vehicle, colchicine to inhibit autophagy, or MG132 to inhibit proteasome activity, then measure amino acid metabolites in serum.
Institute
Mayo Clinic
Last NameO'Neill
First NameBrian
AddressOne Joslin Place, Boston, MA 02215
Emailbrian.o'neill@joslin.harvard.edu
Phone617-309-2400
Submit Date2016-12-02
Analysis Type DetailLC-MS
Release Date2018-12-11
Release Version1
Brian O'Neill Brian O'Neill
https://dx.doi.org/10.21228/M8JG7B
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000383
Project DOI:doi: 10.21228/M8JG7B
Project Title:Mayo Metabolomics Pilot and Feasibility Award: Role of muscle insulin and IGF-1 signaling on serum and muscle metabolite profiles
Project Summary:Skeletal muscle insulin resistance is a cardinal feature of the pathogenesis of type 2 diabetes. Insulin and IGF-1 signal through their highly related receptors to impact on many aspects of muscle physiology including glucose homeostasis, protein metabolism, and mitochondrial function. Early physiological studies, as well as recent large scale metabolomic studies, have shown that changes in specific pools of circulating amino acid metabolites, such as branched chain amino acids (BCAAs), are associated with insulin resistance and can predict future diabetes, but the source and impact of these changes in amino acids are not fully understood. We have recently generated mice which lack insulin receptors (IR) or IGF-1 receptors (IGF1R) or both in muscle using Cre lox recombination. We find that mice which lack only IR or only IGF1R in muscle show minimal changes in muscle mass, but do display increases in proteasomal activity and autophagy in muscle. On the other hand, mice with combined loss of both IR and IGF1R display markedly decreased muscle mass and enhanced degradation pathways, associated with increased protein synthesis, and display changes in mitochondrial gene regulation, indicating that both receptors can compensate to some extent for loss of the other. We hypothesize that IR and IGF1R signaling in muscle coordinate amino acid metabolite turnover and fuel substrate/mitochondrial metabolism, and that in insulin resistant states, changes in protein metabolism and mitochondrial function disrupt relative proportions of amino acid metabolites, which in turn contribute to diabetes risk and/or muscle pathology. We propose to test this hypothesis by performing large scale metabolomics on serum and muscle from mice lacking IR, IGF1R or both in muscle, and we will compare these changes to both insulin deficient streptozotocin-treated and insulin resistant diet-induced obese mouse models. To gain insight into which pathways are critical for metabolite changes, we will also treat mice with specific inhibitors of mTOR, a common protein synthesis pathway, as well as inhibitors of autophagy or proteasomal degradation and determine metabolite concentrations in muscle and serum. These studies will identify specific pathways that impact amino acid and mitochondrial metabolite flux which are perturbed in insulin resistant states, and potentially provide insights into how changes in amino acid metabolites contribute to diabetes risk.
Institute:Mayo Clinic
Last Name:O'Neill
First Name:Brian
Address:One Joslin Place, Boston, MA 02215
Email:brian.o'neill@joslin.harvard.edu
Phone:617-309-2400

Subject:

Subject ID:SU000536
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 Genotype Treatment
SA026725ms5629-21Control colch Irlox IGFRlox Colch
SA026726ms5629-22Control colch Irlox IGFRlox Colch
SA026727ms5629-20Control colch Irlox IGFRlox Colch
SA026728ms5629-19Control colch Irlox IGFRlox Colch
SA026729ms5629-25Control colch Irlox Colch
SA026730ms5629-24Control colch Irlox Colch
SA026724ms5629-23Control colch - Colch
SA026753ms5629-7control IR -/- IGFR -/- saline
SA026754ms5629-2control Irlox IGFRlox saline
SA026755ms5629-1control Irlox IGFRlox saline
SA026756ms5629-3control Irlox IGFRlox saline
SA026757ms5629-4control Irlox saline
SA026758ms5629-6control Irlox saline
SA026759ms5629-5control Irlox saline
SA026731ms5629-34HFD + Colch Irlox IGFRlox Colch
SA026732ms5629-36HFD + Colch Irlox Colch
SA026733ms5629-33HFD + Colch Irlox Colch
SA026734ms5629-32HFD + Colch Irlox Colch
SA026735ms5629-35HFD + Colch Irlox Colch
SA026736ms5629-17HFD Irlox IGFRlox saline
SA026737ms5629-18HFD Irlox saline
SA026738ms5629-14HFD Irlox saline
SA026739ms5629-16HFD Irlox saline
SA026740ms5629-15HFD Irlox saline
SA026741ms5629-31MIGIRKO colch IR -/- IGFR -/- Colch
SA026742ms5629-27MIGIRKO colch IR -/- IGFR -/- Colch
SA026743ms5629-29MIGIRKO colch IR -/- IGFR -/- Colch
SA026744ms5629-30MIGIRKO colch IR -/- IGFR -/- Colch
SA026745ms5629-26MIGIRKO colch IR -/- IGFR -/- Colch
SA026746ms5629-28MIGIRKO colch IR -/- IGFR -/- Colch
SA026747ms5629-11MIGIRKO IR -/- IGFR -/- saline
SA026748ms5629-13MIGIRKO IR -/- IGFR -/- saline
SA026749ms5629-10MIGIRKO IR -/- IGFR -/- saline
SA026750ms5629-12MIGIRKO IR -/- IGFR -/- saline
SA026751ms5629-9MIGIRKO IR -/- IGFR -/- saline
SA026752ms5629-8MIGIRKO IR -/- IGFR -/- saline
Showing results 1 to 36 of 36

Collection:

Collection ID:CO000530
Collection Summary:mouse serum
Sample Type:Muscle

Treatment:

Treatment ID:TR000550
Treatment Summary:To determine which protein degradation pathways downstream of IR and IGF1R contribute to changes in amino acid and mitochondrial metabolite pools, we will treat control, M-IR-/-, MIGIRKO, and HFD obese mice with inhibitors of autophagy or proteasome. We will treat 5 animals each of control, M-IR-/-, MIGIRKO, and HFD mice with vehicle, colchicine to inhibit autophagy, or MG132 to inhibit proteasome activity, then measure amino acid metabolites in serum as well as TCA cycle and amino acid metabolites in muscle tissue.

Sample Preparation:

Sampleprep ID:SP000543
Sampleprep Summary:Concentration of amino acid metabolites in serum

Combined analysis:

Analysis ID AN000787
Analysis type MS
Chromatography type Reversed phase
Chromatography system Waters Acquity
Column Waters Acquity BEH C18 (150 x 2.1mm, 1.7um)
MS Type ESI
MS instrument type Triple quadrupole
MS instrument name Thermo Quantum Ultra
Ion Mode POSITIVE
Units uM

Chromatography:

Chromatography ID:CH000564
Instrument Name:Waters Acquity
Column Name:Waters Acquity BEH C18 (150 x 2.1mm, 1.7um)
Chromatography Type:Reversed phase

MS:

MS ID:MS000694
Analysis ID:AN000787
Instrument Name:Thermo Quantum Ultra
Instrument Type:Triple quadrupole
MS Type:ESI
Ion Mode:POSITIVE
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