Correlation analysis of gene expression and clinical chemistry to identify biomarkers of skeletal myopathy in mice treated with PPAR agonist GW610742X.
Data from individual animals were used to identify genes in mouse skeletal muscle whose expression correlated with a known serum marker of skeletal myopathy, creatine kinase activity (CK), after treatment with a peroxisome proliferator-activated receptors (PPAR) agonist, GW610742X. Six genes had correlation coefficients of >or=0.90: Mt1a (metallothionein 1a), Rrad (Ras-related associated with diabetes), Ankrd1 (ankyrin repeat domain 1), Stat3 (signal transducer and activator of transcription 3), Socs3 (suppressor of cytokine signalling 3) and Mid1ip1 (Mid1 interacting protein 1). The physiological function of these genes provides potentially useful information relating to the mechanism of PPAR-induced skeletal myopathy, with oxidative stress and disruption of glycolysis most closely associated with myopathic damage. Some of the muscle genes most highly correlated with serum CK in mice also appear to be good indicators of PPAR-induced myopathy in rat skeletal muscle, demonstrating the translational potential of this approach. This study clearly shows the utility of using correlation analysis as a simple tool for identifying novel biomarkers and investigating mechanisms of toxicity.
Casey
W M
WM
GlaxoSmithKline, US Research & Development, Safety Assessment, NC 27709, USA.
Brodie
T
T
Yoon
L
L
Ni
H
H
Jordan
H L
HL
Cariello
N F
NF
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D003402:Creatine Kinase / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008297:Male; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000097:blood / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology*; D018631:ras Proteins / Q000235:genetics
C104844:Ankrd1 protein, mouse; C491303:Ankrd1 protein, rat; D015415:Biomarkers; C503394:GW 610742; D009124:Muscle Proteins; D009687:Nuclear Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D012097:Repressor Proteins; C490030:Rrad protein, mouse; C490031:Rrad protein, rat; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013844:Thiazoles; D008668:Metallothionein; D003402:Creatine Kinase; D018631:ras Proteins