Summary of Study ST000511

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 IDST000511
Study TitleDetermine how inhibition of autophagy/proteasome degradation or inhibition of protein synthesis in models of muscle insulin resistance affect amino acid metabolites
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 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 Date2016-11-18
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:SU000533
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 Treatment
SA026595ms5475-27Control Colch
SA026596ms5475-26Control Colch
SA026597ms5475-28Control Colch
SA026598ms5475-29Control Colch
SA026599ms5475-30Control Colch
SA026600ms5475-25Control Colch
SA026601ms5475-24Control Colch
SA026602ms5475-6Control Saline
SA026603ms5475-7Control Saline
SA026604ms5475-4Control Saline
SA026605ms5475-3Control Saline
SA026606ms5475-2Control Saline
SA026607ms5475-1Control Saline
SA026608ms5475-5Control Saline
SA026609ms5475-44HFD+Colch Colch
SA026610ms5475-43HFD+Colch Colch
SA026611ms5475-42HFD+Colch Colch
SA026612ms5475-45HFD+Colch Colch
SA026613ms5475-46HFD+Colch Colch
SA026614ms5475-21HFD Saline
SA026615ms5475-20HFD Saline
SA026616ms5475-19HFD Saline
SA026617ms5475-22HFD Saline
SA026618ms5475-23HFD Saline
SA026619ms5475-40IRKO Colch
SA026620ms5475-39IRKO Colch
SA026621ms5475-37IRKO Colch
SA026622ms5475-41IRKO Colch
SA026623ms5475-38IRKO Colch
SA026624ms5475-18IRKO Saline
SA026625ms5475-14IRKO Saline
SA026626ms5475-15IRKO Saline
SA026627ms5475-17IRKO Saline
SA026628ms5475-16IRKO Saline
SA026629ms5475-31MIGIRKO Colch
SA026630ms5475-36MIGIRKO Colch
SA026631ms5475-32MIGIRKO Colch
SA026632ms5475-33MIGIRKO Colch
SA026633ms5475-34MIGIRKO Colch
SA026634ms5475-35MIGIRKO Colch
SA026635ms5475-8MIGIRKO Saline
SA026636ms5475-10MIGIRKO Saline
SA026637ms5475-13MIGIRKO Saline
SA026638ms5475-11MIGIRKO Saline
SA026639ms5475-12MIGIRKO Saline
SA026640ms5475-9MIGIRKO Saline
Showing results 1 to 46 of 46

Collection:

Collection ID:CO000527
Collection Summary:mouse gastrocnemius muscle tissue
Sample Type:Muscle

Treatment:

Treatment ID:TR000547
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:SP000540
Sampleprep Summary:Concentration of amino acid metabolites in muscle tissue

Combined analysis:

Analysis ID AN000784
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 picomoles/mg

Chromatography:

Chromatography ID:CH000561
Instrument Name:Waters Acquity
Column Name:Waters Acquity BEH C18 (150 x 2.1mm,1.7um)
Chromatography Type:Reversed phase

MS:

MS ID:MS000691
Analysis ID:AN000784
Instrument Name:Thermo Quantum Ultra
Instrument Type:Triple quadrupole
MS Type:ESI
Ion Mode:POSITIVE
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