#METABOLOMICS WORKBENCH hormel101_20161118_115525_mwtab.txt DATATRACK_ID:778 STUDY_ID:ST000512 ANALYSIS_ID:AN000785 PROJECT_ID:PR000383
VERSION             	1
CREATED_ON             	December 8, 2016, 3:10 pm
#PROJECT
PR:PROJECT_TITLE                 	Mayo Metabolomics Pilot and Feasibility Award: Role of muscle insulin and IGF-1
PR:PROJECT_TITLE                 	signaling on serum and muscle metabolite profiles
PR:PROJECT_SUMMARY               	Skeletal muscle insulin resistance is a cardinal feature of the pathogenesis of
PR:PROJECT_SUMMARY               	type 2 diabetes. Insulin and IGF-1 signal through their highly related receptors
PR:PROJECT_SUMMARY               	to impact on many aspects of muscle physiology including glucose homeostasis,
PR:PROJECT_SUMMARY               	protein metabolism, and mitochondrial function. Early physiological studies, as
PR:PROJECT_SUMMARY               	well as recent large scale metabolomic studies, have shown that changes in
PR:PROJECT_SUMMARY               	specific pools of circulating amino acid metabolites, such as branched chain
PR:PROJECT_SUMMARY               	amino acids (BCAAs), are associated with insulin resistance and can predict
PR:PROJECT_SUMMARY               	future diabetes, but the source and impact of these changes in amino acids are
PR:PROJECT_SUMMARY               	not fully understood. We have recently generated mice which lack insulin
PR:PROJECT_SUMMARY               	receptors (IR) or IGF-1 receptors (IGF1R) or both in muscle using Cre lox
PR:PROJECT_SUMMARY               	recombination. We find that mice which lack only IR or only IGF1R in muscle show
PR:PROJECT_SUMMARY               	minimal changes in muscle mass, but do display increases in proteasomal activity
PR:PROJECT_SUMMARY               	and autophagy in muscle. On the other hand, mice with combined loss of both IR
PR:PROJECT_SUMMARY               	and IGF1R display markedly decreased muscle mass and enhanced degradation
PR:PROJECT_SUMMARY               	pathways, associated with increased protein synthesis, and display changes in
PR:PROJECT_SUMMARY               	mitochondrial gene regulation, indicating that both receptors can compensate to
PR:PROJECT_SUMMARY               	some extent for loss of the other. We hypothesize that IR and IGF1R signaling in
PR:PROJECT_SUMMARY               	muscle coordinate amino acid metabolite turnover and fuel
PR:PROJECT_SUMMARY               	substrate/mitochondrial metabolism, and that in insulin resistant states,
PR:PROJECT_SUMMARY               	changes in protein metabolism and mitochondrial function disrupt relative
PR:PROJECT_SUMMARY               	proportions of amino acid metabolites, which in turn contribute to diabetes risk
PR:PROJECT_SUMMARY               	and/or muscle pathology. We propose to test this hypothesis by performing large
PR:PROJECT_SUMMARY               	scale metabolomics on serum and muscle from mice lacking IR, IGF1R or both in
PR:PROJECT_SUMMARY               	muscle, and we will compare these changes to both insulin deficient
PR:PROJECT_SUMMARY               	streptozotocin-treated and insulin resistant diet-induced obese mouse models. To
PR:PROJECT_SUMMARY               	gain insight into which pathways are critical for metabolite changes, we will
PR:PROJECT_SUMMARY               	also treat mice with specific inhibitors of mTOR, a common protein synthesis
PR:PROJECT_SUMMARY               	pathway, as well as inhibitors of autophagy or proteasomal degradation and
PR:PROJECT_SUMMARY               	determine metabolite concentrations in muscle and serum. These studies will
PR:PROJECT_SUMMARY               	identify specific pathways that impact amino acid and mitochondrial metabolite
PR:PROJECT_SUMMARY               	flux which are perturbed in insulin resistant states, and potentially provide
PR:PROJECT_SUMMARY               	insights into how changes in amino acid metabolites contribute to diabetes risk.
PR:INSTITUTE                     	Mayo Clinic
PR:LAST_NAME                     	O'Neill
PR:FIRST_NAME                    	Brian
PR:ADDRESS                       	One Joslin Place, Boston, MA 02215
PR:EMAIL                         	brian.o'neill@joslin.harvard.edu
PR:PHONE                         	617-309-2400
#STUDY
ST:STUDY_TITLE                   	Investigating TCA concentrations in mice muscle tissue lacking insulin receptors
ST:STUDY_TITLE                   	and IGF-1 receptors
ST:STUDY_SUMMARY                 	Quantitative measures of TCA cycle metabolites from control, M-IR-/-, M-IGF1R-/-
ST:STUDY_SUMMARY                 	, and MIGIRKO mice. Also compare mice on a chow diet to mice on a high fat diet
ST:STUDY_SUMMARY                 	(HFD).
ST:INSTITUTE                     	Mayo Clinic
ST:LAST_NAME                     	O'Neill
ST:FIRST_NAME                    	Brian
ST:ADDRESS                       	One Joslin Place, Boston, MA 02215
ST:EMAIL                         	brian.o'neill@joslin.harvard.edu
ST:PHONE                         	617-309-2400
#SUBJECT
SU:SUBJECT_TYPE                  	Mouse
SU:SUBJECT_SPECIES               	Mus musculus
SU:TAXONOMY_ID                   	10090
#SUBJECT_SAMPLE_FACTORS:         	SUBJECT(optional)[tab]SAMPLE[tab]FACTORS(NAME:VALUE pairs separated by |)[tab]Additional sample data
SUBJECT_SAMPLE_FACTORS           	185	Sample # 1	Group:Control | Genotype:IRlox IGFR lox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1226	Sample # 2	Group:Control | Genotype:IRlox IGFR lox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1228	Sample # 3	Group:Control | Genotype:IRlox IGFR lox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	191	Sample # 4	Group:Control | Genotype:IRlox IGFR lox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	189	Sample # 5	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1221	Sample # 6	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1227	Sample # 7	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1236	Sample # 8	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1238	Sample # 9	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	193	Sample # 10	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	719	Sample # 11	Group:Control | Genotype:Irlox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	721	Sample # 12	Group:Control | Genotype:Irlox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	813	Sample # 13	Group:Control | Genotype:Irlox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	546	Sample # 14	Group:Control | Genotype:Irlox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	822	Sample # 15	Group:IRKO | Genotype:IR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	723	Sample # 16	Group:IRKO | Genotype:IR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	814	Sample # 17	Group:IRKO | Genotype:IR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	817	Sample # 18	Group:IRKO | Genotype:IR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	549	Sample # 19	Group:IRKO | Genotype:IR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	551	Sample # 20	Group:IRKO | Genotype:IR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	743	Sample # 21	Group:Control | Genotype:IGFR lox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	747	Sample # 22	Group:Control | Genotype:IGFR lox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	783	Sample # 23	Group:Control | Genotype:IGFR lox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	740	Sample # 24	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	741	Sample # 25	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	742	Sample # 26	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	780	Sample # 27	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	781	Sample # 28	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1191	Sample # 29	Group:CD | Genotype:Irlox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1192	Sample # 30	Group:CD | Genotype:Irlox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1193	Sample # 31	Group:CD | Genotype:Irlox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	1195	Sample # 32	Group:CD | Genotype:Irlox | Diet:Chow	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	850	Sample # 33	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	864	Sample # 34	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	865	Sample # 35	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	867	Sample # 36	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
SUBJECT_SAMPLE_FACTORS           	869	Sample # 37	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Tissue/Serum=Gastrocnemius; array=TCA concentrations in muscle tissue
#COLLECTION
CO:COLLECTION_SUMMARY            	mouse gastrocnemius muscle tissue
#TREATMENT
TR:TREATMENT_SUMMARY             	Mice lacking insulin receptors (IR -/- genotype), or IGF-1 receptors (ICF-1 -/-
TR:TREATMENT_SUMMARY             	genotype), or both were generated using Cre lox recombination. Controls were IR
TR:TREATMENT_SUMMARY             	lox/lox, IGF-1 lox/lox, or both. Additional, 10 mice were included that were fed
TR:TREATMENT_SUMMARY             	different diets for 8 weeks, chow or high fat diet.
#SAMPLEPREP
SP:SAMPLEPREP_SUMMARY            	TCA concentrations in muscle tissue
#CHROMATOGRAPHY
CH:CHROMATOGRAPHY_TYPE           	GC
CH:INSTRUMENT_NAME               	Agilent 7890A
CH:COLUMN_NAME                   	Agilent HP5-MS (30m × 0.25mm, 0.25 um)
#ANALYSIS
AN:ANALYSIS_TYPE                 	MS
#MS
MS:MS_COMMENTS                   	-
MS:INSTRUMENT_NAME               	Agilent 5975
MS:INSTRUMENT_TYPE               	Single quadrupole
MS:MS_TYPE                       	EI
MS:ION_MODE                      	POSITIVE
#MS_METABOLITE_DATA
MS_METABOLITE_DATA:UNITS         	nmol/mg tissue
MS_METABOLITE_DATA_START
Samples	Sample # 1	Sample # 2	Sample # 3	Sample # 4	Sample # 5	Sample # 6	Sample # 7	Sample # 8	Sample # 9	Sample # 10	Sample # 11	Sample # 12	Sample # 13	Sample # 14	Sample # 15	Sample # 16	Sample # 17	Sample # 18	Sample # 19	Sample # 20	Sample # 21	Sample # 22	Sample # 23	Sample # 24	Sample # 25	Sample # 26	Sample # 27	Sample # 28	Sample # 29	Sample # 30	Sample # 31	Sample # 32	Sample # 33	Sample # 34	Sample # 35	Sample # 36	Sample # 37
Factors	Group:Control | Genotype:IRlox IGFR lox | Diet:Chow	Group:Control | Genotype:IRlox IGFR lox | Diet:Chow	Group:Control | Genotype:IRlox IGFR lox | Diet:Chow	Group:Control | Genotype:IRlox IGFR lox | Diet:Chow	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Group:MIGIRKO | Genotype:IR -/- IGFR -/- | Diet:Chow	Group:Control | Genotype:Irlox | Diet:Chow	Group:Control | Genotype:Irlox | Diet:Chow	Group:Control | Genotype:Irlox | Diet:Chow	Group:Control | Genotype:Irlox | Diet:Chow	Group:IRKO | Genotype:IR -/- | Diet:Chow	Group:IRKO | Genotype:IR -/- | Diet:Chow	Group:IRKO | Genotype:IR -/- | Diet:Chow	Group:IRKO | Genotype:IR -/- | Diet:Chow	Group:IRKO | Genotype:IR -/- | Diet:Chow	Group:IRKO | Genotype:IR -/- | Diet:Chow	Group:Control | Genotype:IGFR lox | Diet:Chow	Group:Control | Genotype:IGFR lox | Diet:Chow	Group:Control | Genotype:IGFR lox | Diet:Chow	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Group:IGFRKO | Genotype:IGFR -/- | Diet:Chow	Group:CD | Genotype:Irlox | Diet:Chow	Group:CD | Genotype:Irlox | Diet:Chow	Group:CD | Genotype:Irlox | Diet:Chow	Group:CD | Genotype:Irlox | Diet:Chow	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Group:HFD | Genotype:Irlox | Diet:High Fat Diet	Group:HFD | Genotype:Irlox | Diet:High Fat Diet
Lactate	23.519	22.290	36.820	19.519	9.341	9.423	10.272	9.722	8.567	6.950	44.998	19.105	27.794	24.944	15.320	21.210	19.337	16.772	21.213	31.419	31.316	35.378	20.154	30.973	16.434	25.010	24.812	15.690	20.087	27.900	26.999	29.373	29.202	24.857	31.446	25.666	34.705
Succinate	0.048	0.090	0.166	0.067	0.130	0.088	0.096	0.056	0.020	0.015	0.139	0.035	0.072	0.077	0.055	0.058	0.031	0.030	0.096	0.066	0.033	0.040	0.059	0.093	0.058	0.104	0.079	0.059	0.107	0.116	0.049	0.110	0.095	0.062	0.104	0.094	0.065
Fumarate	0.229	0.293	0.442	0.222	0.398	0.384	0.477	0.442	0.305	0.211	0.390	0.145	0.239	0.265	0.132	0.228	0.158	0.168	0.306	0.319	0.175	0.218	0.181	0.336	0.262	0.326	0.286	0.229	0.230	0.303	0.176	0.319	0.205	0.162	0.262	0.221	0.277
Oxaloacetate	0.004	0.011	0.007	0.017	0.011	0.002	0.006	0.015	0.017	0.003	0.013	0.009	0.010	0.006	0.005	0.006	0.008	0.005	0.004	0.005	0.008	0.014	0.004	0.007	0.003	0.006	0.006	0.003	0.004	0.006	0.005	0.004	0.005	0.006	0.004	0.005	0.004
Ketoglutarate	0.007	0.002	0.002	0.004	0.004	0.003	0.011	0.024	0.022	0.004	0.001	0.001	0.002	0.003	0.000	0.001	0.001	0.000	0.000	0.004	0.006	0.004	0.002	0.003	0.000	0.001	0.002	0.000	0.001	0.001	0.001	0.004	0.005	0.001	0.002	0.002	0.004
Malate	0.196	0.254	0.380	0.188	0.343	0.341	0.417	0.385	0.269	0.186	0.337	0.124	0.203	0.233	0.114	0.198	0.136	0.147	0.264	0.278	0.154	0.191	0.160	0.295	0.231	0.282	0.243	0.201	0.203	0.265	0.154	0.280	0.180	0.139	0.229	0.195	0.238
Glutamate	0.610	0.497	0.431	0.562	0.825	0.949	0.863	0.966	0.991	0.577	0.656	0.373	0.421	0.538	0.308	0.379	0.408	0.372	0.492	0.350	0.263	0.412	0.416	0.397	0.658	0.362	0.324	0.570	0.340	0.298	0.405	0.355	0.230	0.479	0.403	0.552	0.353
cis-Aconitic Acid	0.001	0.001	0.001	0.001	0.002	0.002	0.002	0.003	0.002	0.001	0.002	0.001	0.001	0.001	0.001	0.001	0.001	0.002	0.001	0.006	0.003	0.011	0.001	0.002	0.002	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.001	0.008
Citrate	0.093	0.101	0.125	0.094	0.169	0.144	0.179	0.183	0.153	0.070	0.184	0.088	0.115	0.080	0.094	0.085	0.069	0.079	0.091	0.085	0.128	0.110	0.084	0.145	0.153	0.129	0.112	0.086	0.100	0.093	0.088	0.100	0.127	0.104	0.117	0.110	0.119
Isocitrate	0.057	0.048	0.072	0.093	0.035	0.022	0.016	0.020	0.022	0.019	0.135	0.048	0.074	0.058	0.054	0.049	0.056	0.084	0.073	0.024	0.006	0.006	0.036	0.043	0.033	0.036	0.052	0.052	0.033	0.040	0.045	0.043	0.019	0.042	0.046	0.033	0.006
MS_METABOLITE_DATA_END
#METABOLITES
METABOLITES_START
metabolite_name
Lactate
Succinate
Fumarate
Oxaloacetate
Ketoglutarate
Malate
Glutamate
cis-Aconitic Acid
Citrate
Isocitrate
METABOLITES_END
#END