title: Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats.
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.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan. obayashi.hisakuni.ma@daiichisankyo.co.jp
authors.forename: Hisakuni
authors.initials: H
authors.lastname: Obayashi
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nezu
authors.forename: Hatsue
authors.initials: H
authors.lastname: Yokota
authors.forename: Naoki
authors.initials: N
authors.lastname: Kiyosawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Mori
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Maeda
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Tani
authors.forename: Sunao
authors.initials: S
authors.lastname: Manabe
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbuissho
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008933:Mitochondrial Swelling / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000648:ultrastructure; D009135:Muscular Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; C086276:cerivastatin; D003402:Creatine Kinase