Molecular clues into the pathogenesis of statin-mediated muscle toxicity.
The pathophysiology of statin-mediated muscle dysfunction is poorly defined. Reductions in skeletal muscle membrane cholesterol were initially thought to account for the range of myopathic reactions, e.g., myalgia, elevated serum creatine kinase, or rhabdomyolysis. This assumption however, does not consider a potential role of the isoprenoids in the pathophysiology of statin myopathy. The observation that derangements in mevalonate kinase (MK), but not more distal enzymes of cholesterologenesis, are associated with a skeletal myopathy suggests a critical role for the isoprenoids in the maintenance of muscle. Statins also deplete the isoprenoid pool by inhibiting the enzyme, beta-hydroxy-beta-methylglutaryl coenzyme A reductase, which is upstream of MK. Identifying candidate proteins that are both dependent on isoprenoid-mediated modification and associated with muscle disease, when genetically mutated, offers further insight into potential mechanisms of statin myopathy. For example, lamin A/C, selenoprotein N, alpha- and beta-dystroglycan, and cytoskeletal G-proteins all require isoprenylation for optimal function. Understanding the pleiotropic effects of protein prenylation, and the potential consequences of a generalized insufficiency of this form of protein modification, may help clarify the molecular pathogenesis of statin myopathy.
Baker
Steven K
SK
Division of Physical Medicine and Rehabilitation, Department of Medicine, McMaster University, McMaster University Medical Center, Room 4U4, Hamilton, Ontario, L8N 3Z5, Canada. bakersjj@hotmail.com
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D003067:Coenzymes; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology; D013729:Terpenes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000378:metabolism
D003067:Coenzymes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009124:Muscle Proteins; D013729:Terpenes; D014451:Ubiquinone; C024989:coenzyme Q10; D008798:Mevalonic Acid