Statins inhibit synthesis of mevalonate by HMG-CoA reductase, the rate-limiting step in hepatic cholesterol synthesis, and are used clinically for cholesterol reduction. However statin therapy is also associated with myopathic changes (Thompson et al., 2003). The ubiquitin-dependent proteolytic system is central to muscle atrophy, and is mainly regulated by two muscle specific ubiquitin (E3) ligases, i.e., MAFbx and MuRF-1 (Glass, 2003). Furthermore, the transcription factor, FOXO, which activates MAFbx and MuRF-1, also activates pyruvate dehydrogenase kinase (PDK) transcription, thereby potentially inhibiting muscle carbohydrate oxidation (Furuyama et al., 2003). Therefore, we investigated the effect of chronic treatment with Simvastatin on muscle glycogen concentration, the protein:DNA ratio and on the transcription of MAFbx, MuRF-1 and PDK4 to determine its impact, if any, on muscle fuel metabolism and atrophy-related signalling. Twenty nine, female Wistar Hannover rats were given Simvastatin (80mg/kg/day) for 4 (n=6), 8 (n=6), 10 (n=6) and 12 days (n=5), or vehicle (0.5% w/v hydroxypropyl methylcellulose and 0.1% w/v polysorbate 80) (Control, n=6) for 12 days by oral gavage, after which muscle was harvested under terminal anaesthesia. Animal procedures were performed in accordance with the Animals (Scientific Procedures) Act 1986. Muscle glycogen concentration, the protein:DNA ratio and the expression of MAFbx, MuRF-1 and PDK4 mRNA were measured in Biceps Femoris (Table 1). One-way ANOVA was used to identify the effects of Simvastatin administration (treatment effects). The increase in glycogen concentration 12 days after Simvastatin administration suggests a shift in muscle fuel utilisation towards increased fat oxidation occurred, possibly through increased PDK4 mRNA expression (observed at day 4 and 12) inhibiting PDC activation, thereby reducing glycogen utilisation. Simvastatin administration also caused marked upregulation in the expression of MAFbx and MuRF-1 at Day 12, but without any change in the alkaline soluble protein:DNA ratio. It is possible, therefore, that the changes in MAFbx and MuRF-1 were secondary to FOXO-linked changes in fuel metabolism, rather than reflecting the induction of a muscle atrophy programme.