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Title: Statins and PPAR{alpha} agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment

Abstract

Statins and fibrates (weak PPAR{alpha} agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPAR{alpha} agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPAR{alpha} compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations. In contrast, the PPAR{gamma} agonist Rosiglitazone caused little or no cell death at up to 10 {mu}M and the PPAR{delta} ligand GW-501516 exhibited comparatively less myotoxicity than that seen with Compound A. An experimental statin (Compound B) and Atorvastatin also increased the percentage of TUNEL-positive nuclei and co-treatment with WY-14643, Gemfibrozil or Bezafibrate had less than a full additive effect on statin-induced cell killing. The mechanism of PPAR{alpha} agonist-induced cell death was different from that of statins. Unlike statins, Compound A and WY-14643 did not activate caspase 3/7. In addition, mevalonate and geranylgeraniol reversed the toxicity caused by statins, but did notmore » prevent the cell killing induced by WY-14643. Furthermore, unlike statins, Compound A did not inhibit the isoprenylation of rab4 or rap1a. Interestingly, Compound A and Compound B had differential effects on ATP levels. Taken together, these observations support the hypothesis that in rat myotube cultures, PPAR{alpha} agonism mediates in part the toxicity response to PPAR{alpha} compounds. Furthermore, PPAR{alpha} agonists and statins cause myotoxicity through distinct and independent pathways.« less

Authors:
 [1];  [2];  [3];  [3]
  1. Department of Safety Assessment, Merck Research Laboratories, WP45-319, Merck Research Laboratories, West Point, PA 19486 (United States). E-mail: Timothy_Johnson@merck.com
  2. Department of Biometrics Research, Merck Research Laboratories, West Point, PA 19486 (United States)
  3. Department of Safety Assessment, Merck Research Laboratories, WP45-319, Merck Research Laboratories, West Point, PA 19486 (United States)
Publication Date:
OSTI Identifier:
20722022
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 208; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2005.03.004; PII: S0041-008X(05)00129-8; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADDITIVES; APOPTOSIS; ATP; CELL KILLING; CELL NUCLEI; DRUGS; HEALTH HAZARDS; LIGANDS; LIPIDS; MUSCLES; RATS; RECEPTORS; THERAPY; TOXICITY

Citation Formats

Johnson, Timothy E., Zhang, Xiaohua, Shi, Shu, and Umbenhauer, Diane R. Statins and PPAR{alpha} agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment. United States: N. p., 2005. Web. doi:10.1016/j.taap.2005.03.004.
Johnson, Timothy E., Zhang, Xiaohua, Shi, Shu, & Umbenhauer, Diane R. Statins and PPAR{alpha} agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment. United States. doi:10.1016/j.taap.2005.03.004.
Johnson, Timothy E., Zhang, Xiaohua, Shi, Shu, and Umbenhauer, Diane R. Tue . "Statins and PPAR{alpha} agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment". United States. doi:10.1016/j.taap.2005.03.004.
@article{osti_20722022,
title = {Statins and PPAR{alpha} agonists induce myotoxicity in differentiated rat skeletal muscle cultures but do not exhibit synergy with co-treatment},
author = {Johnson, Timothy E. and Zhang, Xiaohua and Shi, Shu and Umbenhauer, Diane R.},
abstractNote = {Statins and fibrates (weak PPAR{alpha} agonists) are prescribed for the treatment of lipid disorders. Both drugs cause myopathy, but with a low incidence, 0.1-0.5%. However, combined statin and fibrate therapy can enhance myopathy risk. We tested the myotoxic potential of PPAR subtype selective agonists alone and in combination with statins in a differentiated rat myotube model. A pharmacologically potent experimental PPAR{alpha} agonist, Compound A, induced myotoxicity as assessed by TUNEL staining at a minimum concentration of 1 nM, while other weaker PPAR{alpha} compounds, for example, WY-14643, Gemfibrozil and Bezafibrate increased the percentage of TUNEL-positive nuclei at micromolar concentrations. In contrast, the PPAR{gamma} agonist Rosiglitazone caused little or no cell death at up to 10 {mu}M and the PPAR{delta} ligand GW-501516 exhibited comparatively less myotoxicity than that seen with Compound A. An experimental statin (Compound B) and Atorvastatin also increased the percentage of TUNEL-positive nuclei and co-treatment with WY-14643, Gemfibrozil or Bezafibrate had less than a full additive effect on statin-induced cell killing. The mechanism of PPAR{alpha} agonist-induced cell death was different from that of statins. Unlike statins, Compound A and WY-14643 did not activate caspase 3/7. In addition, mevalonate and geranylgeraniol reversed the toxicity caused by statins, but did not prevent the cell killing induced by WY-14643. Furthermore, unlike statins, Compound A did not inhibit the isoprenylation of rab4 or rap1a. Interestingly, Compound A and Compound B had differential effects on ATP levels. Taken together, these observations support the hypothesis that in rat myotube cultures, PPAR{alpha} agonism mediates in part the toxicity response to PPAR{alpha} compounds. Furthermore, PPAR{alpha} agonists and statins cause myotoxicity through distinct and independent pathways.},
doi = {10.1016/j.taap.2005.03.004},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 208,
place = {United States},
year = {Tue Nov 01 00:00:00 EST 2005},
month = {Tue Nov 01 00:00:00 EST 2005}
}
  • The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) beyond cholesterol lowering involve their direct actions on vascular smooth muscle cells (VSMCs). However, the effects of statins on phenotypic modulation of VSMCs are unknown. We herein show that simvastatin (Sm) and atorvastatin (At) inhibited DNA synthesis in human aortic VSMCs dose-dependently, while cell toxicity was not observed below the concentration of 1 {mu}M of Sm or 100 nM of At. Stimulating proliferative VSMCs with Sm or At induced the expression of SM-{alpha}-actin and SM-MHC, highly specific markers of differentiated phenotype. Sm up-regulated the binding activity of GATA-6 to SM-MHCmore » GATA site and activated the transfected SM-MHC promoter in proliferative VSMCs, while mutating the GATA-6 binding site abolished this activation. Geranylgeranylpyrophosphate (10 {mu}M), an inhibitor of Rho family proteins, abolished the statin-mediated induction of the differentiated phenotype in VSMCs. These findings suggest that statins activate GATA-6 and induce differentiated VSMCs.« less
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