Roles of Exercise and Pharmacokinetics in Cerivastatin-Induced Skeletal Muscle Toxicity

Abstract

Three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are associated with adverse skeletal muscle effects, but the underlying mechanisms remain unclear. To determine whether toxicity involves the level of drug exposure in muscle tissue and to test the effect of exercise on cerivastatin (CVA)-induced skeletal muscle damage, female rats were administered vehicle or CVA at 0.1, 0.5, and 1.0 mg/kg/day by gavage for two weeks and exercised or not on treadmills for 20 min/day. Clinical chemistry and plasma and tissue pharmacokinetics were evaluated; light and transmission electron microscopy (TEM) of Type I and Type II fiber-predominant skeletal muscles were performed. Serum levels of AST, ALT, CK, and plasma lactic acid were significantly elevated dose-dependently. CVA treatment decreased psoas and quadriceps weights. At 1 mg/kg all muscles except soleus demonstrated degeneration. Exercise-exacerbated severity of CVA-induced degeneration was evident in all muscles sampled except soleus and quadriceps. Early mitochondrial involvement in toxicity is suggested by the numerous membranous whorls and degenerate mitochondria observed in muscles at 0.5 mg/kg. No significant differences in CVA concentrations between either EDL and soleus or plasma and muscle were found. We found that CVA had no effect on cleaved caspase 3. In summary, we found that treadmill exercise exacerbated the incidence and severity of CVA-induced damage in Type II fiber-predominant muscles. Tissue exposure is likely not the key factor mediating CVA-induced skeletal muscle toxicity.

Efeito do exercício físico e estatinas na função muscular em animais com dislipidemia

“…However, there is reference that the hydroxy acid from fluvastatin may offer tissue selectivity, especially hepatic, with possibility to present lower muscular severity 21 . These results corroborate the research by Seachrist et al 22 , who investigated the muscular effects of the administration of cerivastatin associated to physical exercise on treadmill during two weeks. They observed muscle injuries, such as injuries in the sarcoplasma, internal nuclei, fibers degeneration, inflammatory infiltrate, being dose-dependent and more severe in the trained group.…”

Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats

“…Anatomically, the mitochondria were more abundant in the soleus compared with EDL (Gauthier, 1986), supporting a hypothesis that more abundant mitochondria in the soleus muscle, rather than in the EDL or tibialis anterior, may have been exaggerated the CER-induced myotoxicity. Such mitochondrial abnormalities in the statin-induced myotoxic lesions were consistently observed for other statins, including simvastatin, rosuvastatin, and pravastatin, in multiple species including humans (Bergman et al, 2003;Gambelli et al, 2004;Sirvent et al, 2005;Westwood et al, 2005;Seachrist et al, 2005;Westwood et al, 2008). Mitochondria are the organelles that show the first morphological changes following statin treatment, although there is controversy regarding whether mitochondria is the primary target of statin-induced myotoxicity in rats (Waclawik et al, 1993;Schaefer et al, 2004;Westwood et al, 2008).…”

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

“…Light microscopic findings in patients with statin myopathy are variable and not pathognomonic (52), but muscle from statin-treated rats often demonstrates mitochondrial damage and multilamellar structures suggestive of autophagic vacuole formation (53,54). Indeed, recent data suggest that atrophying muscle generally activates autophagic proteolytic pathways (J. Zhao, A. Goldberg, and M. Sandri, unpublished observations).…”