Transcriptional Deficits In Oxidative Phosphorylation In Statin-induced Myopathy Patients Following Eccentric Exercise

Abstract

PURPOSE: Statins (HMG-CoA reductase inhibitors) are the most widely used medical treatment for hyperlipidemia. Statins are generally well-tolerated, but can produce skeletal muscle myopathy with symptoms of myalgia, myositis, and even life-threatening rhabdomyolysis. The molecular mechanisms mediating statin myopathy are unknown. The current study compared the effects of statin treatment and eccentric (damaging) exercise on global transcriptional patterns between patients with statin-induced myopathy and those that tolerate statins without complaints. METHODS: Nine subjects with statin-induced myalgia (Sym; 53.6 ± 8.9 yrs) and 6 asymptomatic statin users (Asym; 44.4 ± 11.0 yrs) were recruited. Skeletal muscle biopsies were collected 6h post-exercise at baseline (following statin washout) and after up to 4-months of statin treatment. At each time point, subjects performed concentric (i.e. non-damaging) leg exercise with one leg and concentric + eccentric exercise with the other leg using a cross-over design. Total RNA was hybridized to Affymetrix microarrays and data analyses utilized repeated measures ANOVAs (group * time; P < 0.01) within each exercise condition. RESULTS: Few biological pathways were affected by concentric exercise at baseline or after statin treatment. Eccentric exercise evoked deficits in the expression of multiple oxidative phosphorylation components in Sym vs. Asym subjects. Many differences were independent of statin treatment, meaning they were consistently lower in Sym vs. Asym subjects at baseline and after statin treatment. For example, succinate dehydrogenase complex subunit B (SDHB; Complex II) expression was 1.3 fold lower in myalgic subjects both before and after statin treatment. However, some components of Complex V demonstrated group specific effects of statin treatment. Specifically, statin-induced upregulations of ATP5G3 and ATP6VOA2 expression present in Asym subjects were not seen in myalgic patients. CONCLUSIONS: These findings suggest that eccentric exercise unmasks subclinical defects in oxidative phosphorylation in patients with histories of statin-induced myalgia. ACKNOWLEDGEMENT: Sponsored by the Donaghue Medical Research Foundation.