Summary of Study ST000513

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 IDST000513
Study TitleInhibition of autophagy/proteasome degradation or inhibition of protein synthesis in models of muscle insulin resistance affect TCA cycle
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 TCA cycle in muscle tissue.
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 DetailGC-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:SU000535
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
SA026678Sample # 30Control/Colch Irlox
SA026679Sample # 29Control/Colch Irlox
SA026680Sample # 26Control/Colch Irlox IGFRlox
SA026681Sample # 27Control/Colch Irlox IGFRlox
SA026682Sample # 28Control/Colch Irlox IGFRlox
SA026683Sample # 25Control/Colch Irlox IGFRlox
SA026684Sample # 24Control/Colch Irlox IGFRlox
SA026685Sample # 6Control/Saline Irlox
SA026686Sample # 7Control/Saline Irlox
SA026687Sample # 5Control/Saline Irlox
SA026688Sample # 3Control/Saline Irlox IGFRlox
SA026689Sample # 2Control/Saline Irlox IGFRlox
SA026690Sample # 1Control/Saline Irlox IGFRlox
SA026691Sample # 4Control/Saline Irlox IGFRlox
SA026692Sample # 43HFD+Colch Irlox
SA026693Sample # 42HFD+Colch Irlox
SA026694Sample # 45HFD+Colch Irlox
SA026695Sample # 46HFD+Colch Irlox
SA026696Sample # 44HFD+Colch Irlox IGFRlox
SA026697Sample # 20HFD/Saline Irlox
SA026698Sample # 21HFD/Saline Irlox
SA026699Sample # 23HFD/Saline Irlox
SA026700Sample # 19HFD/Saline Irlox
SA026701Sample # 22HFD/Saline Irlox IGFRlox
SA026702Sample # 40IRKO/Colch IR -/-
SA026703Sample # 39IRKO/Colch IR -/-
SA026704Sample # 37IRKO/Colch IR -/-
SA026705Sample # 38IRKO/Colch IR -/-
SA026706Sample # 41IRKO/Colch IR -/-
SA026707Sample # 18IRKO/Saline IR -/-
SA026708Sample # 15IRKO/Saline IR -/-
SA026709Sample # 17IRKO/Saline IR -/-
SA026710Sample # 14IRKO/Saline IR -/-
SA026711Sample # 16IRKO/Saline IR -/-
SA026712Sample # 31MIGIRKO/Colch IR -/- IGFR -/-
SA026713Sample # 36MIGIRKO/Colch IR -/- IGFR -/-
SA026714Sample # 32MIGIRKO/Colch IR -/- IGFR -/-
SA026715Sample # 33MIGIRKO/Colch IR -/- IGFR -/-
SA026716Sample # 34MIGIRKO/Colch IR -/- IGFR -/-
SA026717Sample # 35MIGIRKO/Colch IR -/- IGFR -/-
SA026718Sample # 8MIGIRKO/Saline IR -/- IGFR -/-
SA026719Sample # 13MIGIRKO/Saline IR -/- IGFR -/-
SA026720Sample # 11MIGIRKO/Saline IR -/- IGFR -/-
SA026721Sample # 12MIGIRKO/Saline IR -/- IGFR -/-
SA026722Sample # 9MIGIRKO/Saline IR -/- IGFR -/-
SA026723Sample # 10MIGIRKO/Saline IR -/- IGFR -/-
Showing results 1 to 46 of 46

Collection:

Collection ID:CO000529
Collection Summary:mouse gastrocnemius muscle tissue
Sample Type:Muscle

Treatment:

Treatment ID:TR000549
Treatment Summary:Mice lacking insulin receptors (IR -/- genotype), or IGF-1 receptors (ICF-1 -/- genotype), or both were generated using Cre lox recombination. Controls were IR lox/lox, IGF-1 lox/lox, or both. Additional, 10 mice were included that were fed different diets for 8 weeks, chow or high fat diet.

Sample Preparation:

Sampleprep ID:SP000542
Sampleprep Summary:TCA concentrations in muscle tissue

Combined analysis:

Analysis ID AN000786
Analysis type MS
Chromatography type GC
Chromatography system Agilent 7890A
Column Agilent HP5-MS (30m × 0.25mm, 0.25 um)
MS Type EI
MS instrument type Single quadrupole
MS instrument name Agilent 5975
Ion Mode POSITIVE
Units nmol/mg tissue

Chromatography:

Chromatography ID:CH000563
Instrument Name:Agilent 7890A
Column Name:Agilent HP5-MS (30m × 0.25mm, 0.25 um)
Chromatography Type:GC

MS:

MS ID:MS000693
Analysis ID:AN000786
Instrument Name:Agilent 5975
Instrument Type:Single quadrupole
MS Type:EI
Ion Mode:POSITIVE
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