#METABOLOMICS WORKBENCH edmundcui_1988_20180922_042655 DATATRACK_ID:1513 STUDY_ID:ST001064 ANALYSIS_ID:AN001829 PROJECT_ID:PR000714 VERSION 1 CREATED_ON January 10, 2019, 1:34 pm #PROJECT PR:PROJECT_TITLE Cachexia symptoms induced by Gliomas - NMR metabolomics PR:PROJECT_SUMMARY Malignant gliomas are considered to be one of the deadliest human cancers, PR:PROJECT_SUMMARY accounting for about 60% of all primary brain tumors. Cachexia is a complex PR:PROJECT_SUMMARY metabolic derangement and muscle atrophy syndrome, which causes high mortalities PR:PROJECT_SUMMARY in patients with advanced cancers including brain tumors. However, cachexia PR:PROJECT_SUMMARY symptoms induced by gliomas and mechanisms underlying muscle atrophy are PR:PROJECT_SUMMARY unclear. Herein, we developed a glioma cachexia model using nude mice PR:PROJECT_SUMMARY orthotopicly implanted with two glioma cell lines (WHO II CHG5 and WHO IV U87). PR:PROJECT_SUMMARY U87 mice developed more severe cachexia symptoms than CHG5 mice, including more PR:PROJECT_SUMMARY evident anorexia, greater body weight loss and mortality. Unlike non-central PR:PROJECT_SUMMARY nervous system cancer cachexia, glioma cachexia did not induce remarkable PR:PROJECT_SUMMARY systemic inflammation but massive multi-organ atrophy. It also caused PR:PROJECT_SUMMARY significantly decreased skeletal muscle mass and strength, which were associated PR:PROJECT_SUMMARY with down-regulated myosin and AKT, and up-regulated AMPK, FOXO and Atrogin1. PR:PROJECT_SUMMARY Interestingly, expressions of MuRF1, MyoD1, eIF3f, desmin and vimentin were not PR:PROJECT_SUMMARY significantly changed. Consistently, NMR-based metabolomic analyses revealed PR:PROJECT_SUMMARY pronounced metabolic derangements in cachectic gastrocnemius relative to PR:PROJECT_SUMMARY controls. Glucose, glycerol, 3-hydroxybutyrate and glycine were remarkably PR:PROJECT_SUMMARY down-regulated, whereas largely released amino acids due to proteolysis PR:PROJECT_SUMMARY including glutamate, arginine, leucine and isoleucine were up-regulated in PR:PROJECT_SUMMARY cachectic gastrocnemius. Moreover, glucose and lipid metabolism, protein PR:PROJECT_SUMMARY biosynthesis and amino acid metabolism were disturbed dramatically in both PR:PROJECT_SUMMARY glioma-bearing mice. U87 mice showed more changed metabolite levels and altered PR:PROJECT_SUMMARY metabolic pathways. This work uncovers malignant grade-dependent glioma cachexia PR:PROJECT_SUMMARY symptoms and metabolic derangements of skeletal muscle for the first time, and PR:PROJECT_SUMMARY provides hints for new therapeutic approaches. PR:INSTITUTE Xiamen University PR:DEPARTMENT Chemistry PR:LAST_NAME Cui PR:FIRST_NAME Pengfei PR:ADDRESS 422 siming south road PR:EMAIL edmundcui@126.com PR:PHONE 86-15060796092 #STUDY ST:STUDY_TITLE Nude mice orthotopicly implanted with human glioma cell lines ST:STUDY_SUMMARY Malignant gliomas are considered to be one of the deadliest human cancers, ST:STUDY_SUMMARY accounting for about 60% of all primary brain tumors. Cachexia is a complex ST:STUDY_SUMMARY metabolic derangement and muscle atrophy syndrome, which causes high mortalities ST:STUDY_SUMMARY in patients with advanced cancers including brain tumors. However, cachexia ST:STUDY_SUMMARY symptoms induced by gliomas and mechanisms underlying muscle atrophy are ST:STUDY_SUMMARY unclear. Herein, we developed a glioma cachexia model using nude mice ST:STUDY_SUMMARY orthotopicly implanted with two glioma cell lines (WHO II CHG5 and WHO IV U87). ST:STUDY_SUMMARY U87 mice developed more severe cachexia symptoms than CHG5 mice, including more ST:STUDY_SUMMARY evident anorexia, greater body weight loss and mortality. Unlike non-central ST:STUDY_SUMMARY nervous system cancer cachexia, glioma cachexia did not induce remarkable ST:STUDY_SUMMARY systemic inflammation but massive multi-organ atrophy. It also caused ST:STUDY_SUMMARY significantly decreased skeletal muscle mass and strength, which were associated ST:STUDY_SUMMARY with down-regulated myosin and AKT, and up-regulated AMPK, FOXO and Atrogin1. ST:STUDY_SUMMARY Interestingly, expressions of MuRF1, MyoD1, eIF3f, desmin and vimentin were not ST:STUDY_SUMMARY significantly changed. Consistently, NMR-based metabolomic analyses revealed ST:STUDY_SUMMARY pronounced metabolic derangements in cachectic gastrocnemius relative to ST:STUDY_SUMMARY controls. Glucose, glycerol, 3-hydroxybutyrate and glycine were remarkably ST:STUDY_SUMMARY down-regulated, whereas largely released amino acids due to proteolysis ST:STUDY_SUMMARY including glutamate, arginine, leucine and isoleucine were up-regulated in ST:STUDY_SUMMARY cachectic gastrocnemius. Moreover, glucose and lipid metabolism, protein ST:STUDY_SUMMARY biosynthesis and amino acid metabolism were disturbed dramatically in both ST:STUDY_SUMMARY glioma-bearing mice. U87 mice showed more changed metabolite levels and altered ST:STUDY_SUMMARY metabolic pathways. This work uncovers malignant grade-dependent glioma cachexia ST:STUDY_SUMMARY symptoms and metabolic derangements of skeletal muscle for the first time, and ST:STUDY_SUMMARY provides hints for new therapeutic approaches. ST:INSTITUTE Xiamen University ST:LAST_NAME Cui ST:FIRST_NAME Pengfei ST:ADDRESS 422 siming south road ST:EMAIL edmundcui@126.com ST:PHONE 15060796092 #SUBJECT SU:SUBJECT_TYPE Mammal 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 - H1 Celltype:HEB | Treatment:control SUBJECT_SAMPLE_FACTORS - H2 Celltype:HEB | Treatment:control SUBJECT_SAMPLE_FACTORS - H3 Celltype:HEB | Treatment:control SUBJECT_SAMPLE_FACTORS - H4 Celltype:HEB | Treatment:control SUBJECT_SAMPLE_FACTORS - H5 Celltype:HEB | Treatment:control SUBJECT_SAMPLE_FACTORS - H6 Celltype:HEB | Treatment:control SUBJECT_SAMPLE_FACTORS - H7 Celltype:HEB | Treatment:control SUBJECT_SAMPLE_FACTORS - C1 Celltype:CHG5 | Treatment:lowgrade SUBJECT_SAMPLE_FACTORS - C2 Celltype:CHG5 | Treatment:lowgrade SUBJECT_SAMPLE_FACTORS - C3 Celltype:CHG5 | Treatment:lowgrade SUBJECT_SAMPLE_FACTORS - C4 Celltype:CHG5 | Treatment:lowgrade SUBJECT_SAMPLE_FACTORS - C5 Celltype:CHG5 | Treatment:lowgrade SUBJECT_SAMPLE_FACTORS - C6 Celltype:CHG5 | Treatment:lowgrade SUBJECT_SAMPLE_FACTORS - U1 Celltype:U87 | Treatment:highgrade SUBJECT_SAMPLE_FACTORS - U2 Celltype:U87 | Treatment:highgrade SUBJECT_SAMPLE_FACTORS - U3 Celltype:U87 | Treatment:highgrade SUBJECT_SAMPLE_FACTORS - U4 Celltype:U87 | Treatment:highgrade SUBJECT_SAMPLE_FACTORS - U5 Celltype:U87 | Treatment:highgrade SUBJECT_SAMPLE_FACTORS - U6 Celltype:U87 | Treatment:highgrade #COLLECTION CO:COLLECTION_SUMMARY Muscles were rapidly dissected, weighted and frozen in liquid nitrogen and CO:COLLECTION_SUMMARY stored at -80 °C until analyses. CO:SAMPLE_TYPE Muscle #TREATMENT TR:TREATMENT_SUMMARY Right caudate nuclei of mice were separately injected with 2.0 ?L of the TR:TREATMENT_SUMMARY suspension of 2.0 × 105 of HEB, CHG5 and U87 cells. muscles were rapidly TR:TREATMENT_SUMMARY dissected, weighted and frozen. #SAMPLEPREP SP:SAMPLEPREP_SUMMARY Generally, gastrocnemius muscle samples were homogenized after adding ice-cold SP:SAMPLEPREP_SUMMARY methanol, chloroform and water at a volume ratio of 4:4:2.85 to obtain a SP:SAMPLEPREP_SUMMARY two-phase extract. #CHROMATOGRAPHY CH:CHROMATOGRAPHY_TYPE - CH:INSTRUMENT_NAME - CH:COLUMN_NAME - #ANALYSIS AN:ANALYSIS_TYPE NMR #NMR NM:INSTRUMENT_NAME Bruker AVANCE III NM:INSTRUMENT_TYPE FT-NMR NM:NMR_EXPERIMENT_TYPE 1D-1H NM:SPECTROMETER_FREQUENCY 850MHz NM:NMR_RESULTS_FILE ST001064_AN001829_Results.txt UNITS:ppm #END