title: Myotoxicity of statins: Mechanism of action.
abstract: Statins are effective drugs to reduce cardiovascular events secondary to dyslipidemia; however, they cause frequent undesirable side effects. The incidence of statin-induced myotoxicity (SIM) is presented by 7 to 29% of patients, depending upon the report. SIM may develop in presence of abnormally high concentrations of statins in the myocyte and/or in presence of muscular conditions that may predispose to SIM. High concentrations of statins in the myocyte may occur whenever the activity of liver influx membrane transporters, namely OATP1B1, of drug metabolizing enzymes, and of liver and muscular efflux transporters, MDR1 and BCRP, is reduced. In the muscle, conditions that may predispose to SIM include mitochondrial damage with disruption of the mitochondrial respiratory chain and decreased production of ATP, increase of ROS, and leak of cytochrome c and Ca2+. In the sarcoplasma, statins activate MAPK and diminish the RhoA/AKT/mTOR/PGC-1α pathway. All these effects contribute to activate apoptosis, proteolysis, and muscle remodeling. Moreover, in the sarcoplasma, statins can reduce the resting chloride channel conductance, as well as lactate efflux. These changes will be responsible of fatigue, cramps, myalgia and elevation of serum CK. To date, besides avoiding drug-drug interactions and alcohol consumption, and correcting hypothyroidism, two strategies could be useful to prevent/diminish SIM, e.g. gradual dose titration with statins less prone to produce SIM, and high supplements of vitamin D in subjects with low plasma concentrations of 25(OH) D3.
authors.affiliation: Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada; Clinique de Nutrition, Métabolisme et Athérosclérose, Institut de Recherche Clinique de Montréal, 120, Avenue des Pins Ouest, Montréal, Québec, Canada. Electronic address: Patrick.du.souich@umontreal.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: du Souich
authors.affiliation: Clinique de Nutrition, Métabolisme et Athérosclérose, Institut de Recherche Clinique de Montréal, 120, Avenue des Pins Ouest, Montréal, Québec, Canada.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Roederer
authors.affiliation: Clinique de Prévention Cardiovasculaire, Institut de Recherche Clinique de Montréal, Canada; Département de nutrition, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Dufour
mesh_terms: D000818:Animals; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D032342:Muscle Cells / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
keywords: Chloride channels; Lactate; Mechanism of action; Mitochondria; Muscle remodeling; Statins myopathy