Abstract 13907: Statin-Induced Myopathy is Mediated by Isoprenoid Depletion and is Independent of Serum Cholesterol Levels

Abstract

Statin use is associated with muscle-related side-effects (ie, MRSE) in ~10-20% patients and is the most common reason for discontinuation of treatment. Moreover, high-risk patients who have inadequately controlled LDL-C as a result of statin intolerance present a significant public health problem. A study to assess the role of cholesterol and/or isoprenoid intermediates of the cholesterol biosynthetic pathway in statin-induced myopathy was conducted in female rats treated with cerivastatin for 14 days. Cerivastatin treatment of rats fed standard diet induced myopathy in type II muscle fibers, but not in type I muscle fibers. Cholesterol supplementation in the diet of cerivastatin treated rats increased circulating cholesterol levels, but failed to prevent myopathy, suggesting that statin-mediated myopathy was independent of the cholesterol lowering effects of statins. Conversely, mevalonate supplementation of the diet abrogated cerivastatin induced myopathy evidenced by either microscopy or sensitive biomarkers of muscle injury including AST, CK, sTnI, FABP3, and urinary myoglobin. These data suggest that statin-induced myopathy involves a cholesterol biosynthetic intermediate upstream of cholesterol and downstream of mevalonate. Most animals with myopathy had increased expression of genes involved in stress (UCP1, NRF2), inflammation (Alox5ap), and autophagy/mitophagy (GABARAP), and decreases in genes involved in energy production (GATM, ATP5b, ATP5f1) or mitochondrial biogenesis (PGC-1α). These data suggest that sensitive muscle fibers may have deficits in mitochondrial biogenesis in the presence of increased autophagy/mitophagy that result in an energy crisis. In addition, many of these genes have also been reported to be changed in human statin myopathy, suggesting a similarity in mechanisms between rats and humans. In conclusion, cerivastatin-induced myopathy in rats involves a step upstream of cholesterol in isoprenoid intermediary metabolism that likely results in an energy crisis. These data suggest that lowering of cholesterol by mechanisms other than HMG CoA inhibition-associated isoprenoid intermediate depletion would not be expected to result in myopathy.