title: Elucidation of the mechanism of atorvastatin-induced myopathy in a rat model.
abstract: Myopathy is among the well documented and the most disturbing adverse effects of statins. The underlying mechanism is still unknown. Mitochondrial dysfunction related to coenzyme Q10 decline is one of the proposed theories. The present study aimed to investigate the mechanism of atorvastatin-induced myopathy in rats. In addition, the mechanism of the coenzyme Q10 protection was investigated with special focus of mitochondrial alterations. Sprague-Dawely rats were treated orally either with atorvastatin (100mg/kg) or atorvastatin and coenzyme Q10 (100mg/kg). Myopathy was assessed by measuring serum creatine kinase (CK) and myoglobin levels together with examination of necrosis in type IIB fiber muscles. Mitochondrial dysfunction was evaluated by measuring muscle lactate/pyruvate ratio, ATP level, pAkt as well as mitochondrial ultrastructure examination. Atorvastatin treatment resulted in a rise in both CK (2X) and myoglobin (6X) level with graded degrees of muscle necrosis. Biochemical determinations showed prominent increase in lactate/pyruvate ratio and a decline in both ATP (>80%) and pAkt (>50%) levels. Ultrastructure examination showed mitochondrial swelling with disrupted organelle membrane. Co-treatment with coenzyme Q10 induced reduction in muscle necrosis as well as in CK and myoglobin levels. In addition, coenzyme Q10 improved all mitochondrial dysfunction parameters including mitochondrial swelling and disruption. These results presented a model for atorvastatin-induced myopathy in rats and proved that mitochondrial dysfunction is the main contributor in statin-myopathy pathophysiology.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharos University, Alexandria, Egypt. Electronic address: samarossama@hotmail.com.
authors.forename: Samar O
authors.initials: SO
authors.lastname: El-Ganainy
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharos University, Alexandria, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Mallah
authors.affiliation: Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
authors.forename: Dina
authors.initials: D
authors.lastname: Abdallah
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Khattab
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharos University, Alexandria, Egypt.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Mohy El-Din
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Aiman S
authors.initials: AS
authors.lastname: El-Khatib
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000069059:Atorvastatin / Q000633:toxicity*; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009211:Myoglobin / Q000097:blood; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009211:Myoglobin; D014451:Ubiquinone; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D000069059:Atorvastatin; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; C024989:coenzyme Q10
keywords: Atorvastatin; Coenzyme Q10; Mitochondrial dysfunction; Myopathy