title: Murine intramyocellular lipids quantified by NMR act as metabolic biomarkers in burn trauma.
abstract: It has been suggested that intramyocellular lipids (IMCLs) may serve as biomarkers of insulin resistance and mitochondrial dysfunction. Using a hind-limb mouse model of burn trauma, we tested the hypothesis that severe localized burn trauma involving 5% of the total body surface area causes a local increase in IMCLs in the leg skeletal muscle. We quantified IMCLs from ex vivo intact tissue specimens using High-Resolution Magic Angle Spinning (HRMAS) 1H NMR and characterized the accompanying gene expression patterns in burned versus control skeletal muscle specimens. We also quantified plasma-free fatty acids (FFAs) in burn versus control mice. Our results from HRMAS 1H NMR measurements indicated that IMCL levels were significantly increased in mice exposed to burn trauma. Furthermore, plasma FFA levels were also significantly increased, and gene expression of Glut4, insulin receptor substrate 1 (IRS1), glycolytic genes, and PGC-1beta was downregulated in these mice. Backward stepwise multiple linear regression analysis demonstrated that IMCL levels correlated significantly with FFA levels, which were a significant predictor of IRS1 and PGC-1beta gene expression. We conclude from these findings that IMCLs can serve as metabolic biomarkers in burn trauma and that FFAs and IMCLs may signal altered metabolic gene expression. This signaling may result in the observed burn-induced insulin resistance and skeletal muscle mitochondrial dysfunction. We believe that IMCLs may therefore be useful biomarkers in predicting the therapeutic effectiveness of hypolipidemic agents for patients with severe burns.
authors.affiliation: NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. atzika@partners.org
authors.forename: A Aria
authors.initials: AA
authors.lastname: Tzika
authors.forename: Loukas G
authors.initials: LG
authors.lastname: Astrakas
authors.forename: Haihui
authors.initials: H
authors.lastname: Cao
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Mintzopoulos
authors.forename: Qunhao
authors.initials: Q
authors.lastname: Zhang
authors.forename: Katie
authors.initials: K
authors.lastname: Padfield
authors.forename: Hongue
authors.initials: H
authors.lastname: Yu
authors.forename: Michael N
authors.initials: MN
authors.lastname: Mindrinos
authors.forename: Laurence G
authors.initials: LG
authors.lastname: Rahme
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tompkins
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000032:analysis* / Q000097:blood; D001830:Body Surface Area; D002056:Burns / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005230:Fatty Acids, Nonesterified / Q000032:analysis / Q000097:blood / Q000378:metabolism; D020869:Gene Expression Profiling; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006614:Hindlimb / Q000378:metabolism / Q000473:pathology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008055:Lipids / Q000032:analysis*; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012044:Regression Analysis; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D008055:Lipids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors