title: Evaluation of microRNAs-208 and 133a/b as differential biomarkers of acute cardiac and skeletal muscle toxicity in rats.
abstract: Conventional circulating biomarkers of cardiac and skeletal muscle (SKM) toxicity lack specificity and/or have a short half-life. MicroRNAs (miRNAs) are currently being assessed as biomarkers of tissue injury based on their long half-life in blood and selective expression in certain tissues. To assess the utility of miRNAs as biomarkers of cardiac and SKM injury, male Sprague-Dawley rats received a single dose of isoproterenol (ISO); metaproterenol (MET); allylamine (AAM); mitoxantrone (MIT); acetaminophen (APAP) or vehicle. Blood and tissues were collected from rats in each group at 4, 24 and 48h. ISO, MET, and AAM induced cardiac and SKM lesions and APAP induced liver specific lesions. There was no evidence of tissue injury with MIT by histopathology. Serum levels of candidate miRNAs were compared to conventional serum biomarkers of SKM/cardiac toxicity. Increases in heart specific miR-208 only occurred in rats with cardiac lesions alone and were increased for a longer duration than cardiac troponin and FABP3 (cardiac biomarkers). ISO, MET and AAM induced increases in MyL3 and skeletal muscle troponin (sTnl) (SKM biomarkers). MIT induced large increases in sTnl indicative of SKM toxicity, but sTnl levels were also increased in APAP-treated rats that lacked SKM toxicity. Serum levels of miR-133a/b (enriched in cardiac and SKM) increased following ISO, MET, AAM and MIT treatments but were absent in APAP-treated rats. Our results suggest that miR-133a/b are sensitive and specific markers of SKM and cardiac toxicity and that miR-208 used in combination with miR-133a/b can be used to differentiate cardiac from SKM toxicity.
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States. Electronic address: Jacqueline.Calvano@bms.com.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Calvano
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States.
authors.forename: William
authors.initials: W
authors.lastname: Achanzar
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States.
authors.forename: Bethanne
authors.initials: B
authors.lastname: Murphy
authors.affiliation: Discovery Toxicology, Bristol-Myers Squibb, Route 206 and Province Line Road, Lawrenceville, NJ 08540, United States.
authors.forename: Janet
authors.initials: J
authors.lastname: DiPiero
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States.
authors.forename: Clifford
authors.initials: C
authors.lastname: Hixson
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Parrula
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States.
authors.forename: Holly
authors.initials: H
authors.lastname: Burr
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States.
authors.forename: Raja
authors.initials: R
authors.lastname: Mangipudy
authors.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Tirmenstein
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000499:Allylamine / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000097:blood*; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000633:toxicity; D008297:Male; D009921:Metaproterenol / Q000633:toxicity; D035683:MicroRNAs / Q000097:blood*; D008942:Mitoxantrone / Q000633:toxicity; D018482:Muscle, Skeletal / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; C548234:MIRN133 microRNA, human; C550906:MIRN208 microRNA, human; D035683:MicroRNAs; D000082:Acetaminophen; D000499:Allylamine; D009921:Metaproterenol; D008942:Mitoxantrone; D007545:Isoproterenol
keywords: Biomarker; Cardiotoxicity; Skeletal myotoxicity; miR-133a/b; miR-208; miRNA