Skip Navigation



ToxSci Advance Access published online on May 17, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl019
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow Supplementary Data
Right arrow All Versions of this Article:
92/2/578    most recent
kfl019v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by De Souza, A. T.
Right arrow Articles by Ulrich, R. G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Souza, A. T.
Right arrow Articles by Ulrich, R. G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received January 30, 2006
Accepted April 11, 2006

Systems Toxicology

Agonists of the Peroxisome Proliferator Activated Receptor Alpha (PPAR{alpha}) Induce a Fiber-Type Selective Transcriptional Response in Rat Skeletal Muscle

Angus T. De Souza 1 *, Paul D. Cornwell 1, Xudong Dai 1, Michelle J. Caguyong 1, and Roger G. Ulrich 1

1 Rosetta Inpharmatics LLC, a wholly owned subsidiary of Merck & Co., Inc., 401 Terry Ave N, Seattle, WA 98109, USA

* To whom correspondence should be addressed.
Angus T. De Souza, E-mail: angus_desouza{at}w-link.net


  Abstract

In rodents, treatment with peroxisome proliferator-activated receptor alpha (PPAR{alpha}) agonists results in peroxisome proliferation, hepatocellular hypertrophy and hepatomegaly. Drugs in the fibrate class of PPAR{alpha} agonists have also been reported to produce rare skeletal muscle toxicity. Although target-driven hepatic effects of PPAR{alpha} treatment have been extensively studied, a characterization of the transcriptional effects of this nuclear receptor/transcription factor on skeletal muscle responses has not been reported. In this study we investigated the effects of PPAR{alpha} agonists on skeletal muscle gene transcription in rats. Further, since statins have been reported to preferentially effect type II muscle fibers we compared PPAR{alpha} signaling effects between type I and type II muscles. By comparing the transcriptional responses of agonists that signal through different nuclear receptors and, using a selection/deselection analytical strategy based on ANOVA, we identified a PPAR{alpha} activation signature that is evident in type-I (soleus) but not type II (quadriceps femoris) skeletal muscle fibers. The fiber-type selective nature of this response is consistent with increased fatty acid uptake and {beta}-oxidation, which represent the major clinical benefits of the hypolipidemic compounds used in this study, but does not reveal any obvious off-target pathways that may drive adverse effects.

Keywords: Peroxisome proliferator-activated receptor alpha (PPAR{alpha}); microarray; fenofibrate; Wy-14,643; liver.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
J. D. Vassallo, E. B. Janovitz, D. M. Wescott, C. Chadwick, L. J. Lowe-Krentz, and L. D. Lehman-McKeeman
Biomarkers of Drug-Induced Skeletal Muscle Injury in the Rat: Troponin I and Myoglobin
Toxicol. Sci., October 1, 2009; 111(2): 402 - 412.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
A. Liu, A. D. Patterson, Z. Yang, X. Zhang, W. Liu, F. Qiu, H. Sun, K. W. Krausz, J. R. Idle, F. J. Gonzalez, et al.
Fenofibrate Metabolism in the Cynomolgus Monkey using Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry-Based Metabolomics
Drug Metab. Dispos., June 1, 2009; 37(6): 1157 - 1163.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
D. L. Allen, E. R. Bandstra, B. C. Harrison, S. Thorng, L. S. Stodieck, P. J. Kostenuik, S. Morony, D. L. Lacey, T. G. Hammond, L. L. Leinwand, et al.
Effects of spaceflight on murine skeletal muscle gene expression
J Appl Physiol, February 1, 2009; 106(2): 582 - 595.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
B. Faiola, J. G. Falls, R. A. Peterson, N. R. Bordelon, T. A. Brodie, C. A. Cummings, E. H. Romach, and R. T. Miller
PPAR alpha, more than PPAR delta, Mediates the Hepatic and Skeletal Muscle Alterations Induced by the PPAR Agonist GW0742
Toxicol. Sci., October 1, 2008; 105(2): 384 - 394.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
M. L. Pritt, D. G. Hall, J. Recknor, K. M. Credille, D. D. Brown, N. P. Yumibe, A. E. Schultze, and D. E. Watson
Fabp3 as a Biomarker of Skeletal Muscle Toxicity in the Rat: Comparison with Conventional Biomarkers
Toxicol. Sci., June 1, 2008; 103(2): 382 - 396.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.