Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats
Open accessAbstract
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.
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Myopathy has been difficult to induce with statin treatment in preclinical models.
“However, progress has been hampered by the fact that myopathy has been difficult to induce with statin treatment in preclinical models.100–103”
From Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management (2015) · cites this paper as [100]
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- Authors
- Obayashi, H., Nezu, Y., Yokota, H., Kiyosawa, N., Mori, K., Maeda, N., Tani, Y., Manabe, S., & Sanbuissho, A.
- Affiliations
- Daiichi-Sankyo (Japan) (JP)
- Venue
- The Journal of Toxicological Sciences
- Publisher
- Japanese Society of Toxicology
- Published
- 2011
- Volume
- 36
- Issue
- 4
- Pages
- 445-452
- ISSN
- 0388-1350 (ISSN-L)
- 1880-3989
- OpenAlex
- W2090241730
- Cited by
- 26
- References
- 23
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Toxicological Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- cerivastatin, statin-induced myopathy, skeletal muscle injury, type I muscle fibers, soleus muscle, creatine kinase elevation, mitochondrial damage, muscle fiber necrosis, autophagosomes, F344 rats
- MeSH terms
- Aging, Animals, Body Weight, Creatine Kinase, Dose-Response Relationship, Drug, Eating, Male, Mitochondrial Swelling, Muscular Diseases, Pyridines, Rats, Inbred F344, Time Factors, Muscle Fibers, Skeletal, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Microscopy, Electron, Transmission, Rats
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