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ToxSci Advance Access published online on February 27, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn042
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Fabp3 as a biomarker of skeletal muscle toxicity in the rat: comparison with conventional biomarkers

Michael L. Pritt1, D. Greg Hall, Justin Recknor, Kelly M. Credille, Donna D. Brown, Nathan P. Yumibe, A. Eric Schultze and David E. Watson1

Investigative Toxicology, Lilly Research Laboratories, Greenfield, IN 46140

1 Correspondence may be addressed to either of these individuals at Eli Lilly and Company 2001 W. Main St. Greenfield, IN 46140. Fax: (317) 277-5002. E-mail: pritt_michael_l{at}lilly.com, Watson_David_E{at}Lilly.com

Received December 14, 2007; revision received February 20, 2008; accepted February 20, 2008


  Abstract

Fatty acid binding protein 3 (Fabp3) has been used as a serological biomarker of cardiac injury, but its utility as a preclinical biomarker of injury to skeletal muscle is not well described. Fabp3 concentrations were determined for tissues from Sprague-Dawley rats and found to occur at highest concentrations in cardiac muscle and in skeletal muscles containing an abundance of type I fibers, such as the soleus muscle. Soleus is also a primary site of skeletal muscle (SKM) injury caused by lipid-lowering peroxisome proliferator-activated receptor alpha (PPAR{alpha}) agonists. In rats administered repeat doses of a PPAR{alpha} agonist, the kinetics and amplitude of plasma concentrations of Fabp3 were consistent with plasma compound concentrations and histopathology findings of swollen, hyalinized, and fragmented muscle fibers with macrophage infiltration. Immunohistochemical detection of Fabp3 revealed focal depletion of Fabp3 protein from injured SKM fibers which is consistent with increased serum Fabp3 concentrations in treated rats. We then assessed the predictivity of serological Fabp3 for SKM necrosis in short duration toxicology studies. Rats were treated with various doses of 27 different compounds, and the predictivity of serological biomarkers was assessed relative to histology in individual rats and in treatment groups. Under these study conditions, Fabp3 was the most useful individual biomarker based on concordance, sensitivity, positive and negative predictive value, and false negative rate. In addition, the combination of Fabp3 and AST had greater diagnostic value than the combination of CK and AST.

Key Words: biomarker; skeletal muscle; necrosis; predictivity; rat; tissue distribution.


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