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Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats.
J Toxicol Sci 2011; 36(4):445-52JT

Abstract

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are associated with adverse skeletal muscle toxicity, but the underlying mechanism remains unclear. To investigate the pathological mechanism of statin-induced myotoxicity, cerivastatin (20 ppm; corresponding to 2 mg/kg/day) was dietarily administered to young male F344 rats for 10 days, and time-course clinical observations, measurement of plasma creatine kinase activity, and light and electron microscopy of type I fiber-predominant skeletal muscle (soleus) or type II fiber-predominant skeletal muscles (extensor digitorum longus and tibialis anterior), were performed. Clinical symptoms including weakness of hind limbs, staggering gait and body weight loss, accompanied by marked plasma creatinine kinase elevation in rats fed cerivastatin at around Day 6 to 8. Interestingly, microscopic examination revealed that cerivastatin-induced muscle damages characterized by hypercontraction (opaque) and necrosis of the fibers were of particular abundance in the soleus muscle at Day 8, whereas these histological lesions in the extensor digitorum longus and tibialis anterior were negligible, even at Day 9. Prior to manifestation of muscle damage, swollen mitochondria and autophagic vacuoles in the soleus were observed as the earliest ultra structural changes at Day 6; then activated lysosomes, disarray of myofibril and dilated sarcoplasmic reticulum vesicles became ubiquitous at Day 8. These results demonstrate that cerivastatin induces type I fiber-predominant muscles injury, which is associated with mitochondrial damage, in young male F344 rats. Since the rat exhibiting type I fiber-targeted injury is a unique animal model for statin-induced myotoxicity, it will be useful for gaining insight into mechanisms of statin-induced myotoxicity.

Authors+Show Affiliations

Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. obayashi.hisakuni.ma@daiichisankyo.co.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21804308

Citation

Obayashi, Hisakuni, et al. "Cerivastatin Induces type-I Fiber-, Not type-II Fiber-, Predominant Muscular Toxicity in the Young Male F344 Rats." The Journal of Toxicological Sciences, vol. 36, no. 4, 2011, pp. 445-52.
Obayashi H, Nezu Y, Yokota H, et al. Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats. J Toxicol Sci. 2011;36(4):445-52.
Obayashi, H., Nezu, Y., Yokota, H., Kiyosawa, N., Mori, K., Maeda, N., ... Sanbuissho, A. (2011). Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats. The Journal of Toxicological Sciences, 36(4), pp. 445-52.
Obayashi H, et al. Cerivastatin Induces type-I Fiber-, Not type-II Fiber-, Predominant Muscular Toxicity in the Young Male F344 Rats. J Toxicol Sci. 2011;36(4):445-52. PubMed PMID: 21804308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats. AU - Obayashi,Hisakuni, AU - Nezu,Yoshikazu, AU - Yokota,Hatsue, AU - Kiyosawa,Naoki, AU - Mori,Kazuhiko, AU - Maeda,Naoyuki, AU - Tani,Yoshiro, AU - Manabe,Sunao, AU - Sanbuissho,Atsushi, PY - 2011/8/2/entrez PY - 2011/8/2/pubmed PY - 2011/12/14/medline SP - 445 EP - 52 JF - The Journal of toxicological sciences JO - J Toxicol Sci VL - 36 IS - 4 N2 - 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are associated with adverse skeletal muscle toxicity, but the underlying mechanism remains unclear. To investigate the pathological mechanism of statin-induced myotoxicity, cerivastatin (20 ppm; corresponding to 2 mg/kg/day) was dietarily administered to young male F344 rats for 10 days, and time-course clinical observations, measurement of plasma creatine kinase activity, and light and electron microscopy of type I fiber-predominant skeletal muscle (soleus) or type II fiber-predominant skeletal muscles (extensor digitorum longus and tibialis anterior), were performed. Clinical symptoms including weakness of hind limbs, staggering gait and body weight loss, accompanied by marked plasma creatinine kinase elevation in rats fed cerivastatin at around Day 6 to 8. Interestingly, microscopic examination revealed that cerivastatin-induced muscle damages characterized by hypercontraction (opaque) and necrosis of the fibers were of particular abundance in the soleus muscle at Day 8, whereas these histological lesions in the extensor digitorum longus and tibialis anterior were negligible, even at Day 9. Prior to manifestation of muscle damage, swollen mitochondria and autophagic vacuoles in the soleus were observed as the earliest ultra structural changes at Day 6; then activated lysosomes, disarray of myofibril and dilated sarcoplasmic reticulum vesicles became ubiquitous at Day 8. These results demonstrate that cerivastatin induces type I fiber-predominant muscles injury, which is associated with mitochondrial damage, in young male F344 rats. Since the rat exhibiting type I fiber-targeted injury is a unique animal model for statin-induced myotoxicity, it will be useful for gaining insight into mechanisms of statin-induced myotoxicity. SN - 1880-3989 UR - https://www.unboundmedicine.com/medline/citation/21804308/Cerivastatin_induces_type_I_fiber__not_type_II_fiber__predominant_muscular_toxicity_in_the_young_male_F344_rats_ L2 - http://joi.jlc.jst.go.jp/JST.JSTAGE/jts/36.445?lang=en&from=PubMed DB - PRIME DP - Unbound Medicine ER -