ToxSci Advance Access originally published online on July 23, 2009
Toxicological Sciences 2009 111(2):402-412; doi:10.1093/toxsci/kfp166
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Biomarkers of Drug-Induced Skeletal Muscle Injury in the Rat: Troponin I and Myoglobin
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* Bristol-Myers Squibb, Princeton, New Jersey 08540
Lehigh University, Iacocca Hall, Bethlehem, Pennsylvania 18015
Life Diagnostics, Inc., West Chester, Pennsylvania 19380
1 To whom all correspondence should be addressed at Bristol-Myers Squibb, Route 206 and Provinceline Road, Princeton, NJ 08540. Fax: (609) 252-7046. E-mail: jeff.vassallo{at}bms.com.
Received June 4, 2009; accepted July 21, 2009
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Abstract |
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The purpose of this investigation was to determine the utility of fast-twitch skeletal muscle troponin I (fsTnI) and urinary myoglobin (uMB) as biomarkers of skeletal muscle injury in 8-week-old Sprague-Dawley rats. fsTnI and uMB were quantified by enzyme-linked immunosorbent assay and compared with standard clinical assays including creatine kinase, aldolase, aspartate aminotransferase, and histopathological assessments. Detectable levels of uMB were normalized to urinary creatinine to control for differences in renal function. Seven compounds, including those with toxic effects on skeletal muscle, cardiac muscle, or liver, were evaluated. fsTnI was typically nondetectable (< 5.9 ng/ml serum) in vehicle-treated female and male rats but increased in a dose-dependent manner to at least 300 ng/ml in cerivastatin-induced severe fast-twitch specific myotoxicity. Minimal myopathy induced by investigational compounds BMS-600149 and BMS-687453 increased serum fsTnI to about 30–50 ng/ml, suggesting a reasonable dynamic range for detecting mild to severe skeletal muscle toxicity. In direct contrast, fsTnI was only marginally increased relative to population control values in rats treated with triamcinolone acetonide, which produces muscle atrophy or the cardiotoxins isoproterenol and CoCl2. uMB was typically nondetectable (< 1.6 ng/ml urine) in vehicle-treated female and male rats but increased to approximately 140, 300, and 30 ng/mg creatinine in rats treated with cerivastatin, BMS-687453, and triamcinolone acetonide, respectively. Cardiotoxicity also increased uMB in rats treated with isoproterenol and CoCl2 with urine concentrations ranging from 20 to 30 ng/mg creatinine. Severe hepatotoxicity (coumarin) did not significantly affect serum fsTnI or uMB levels. Collectively, these data suggest that fsTnI is specific for skeletal muscle toxicity, whereas uMB is nonspecific, increasing with skeletal muscle and cardiac toxicity. Accordingly, the complement of fsTnI and uMB, in conjunction with standard clinical assays may comprise a useful diagnostic panel for assessing drug-induced myopathy in rats.
Key Words: biomarkers; myopathy; skeletal muscle; troponin I; myoglobin; rat; cerivastatin; triamcinolone; isoproterenol; cobalt; coumarin.