Statin Therapy Alters Lipid Storage in Diabetic Skeletal Muscle

Irena A. Rebalka, Matthew J. Raleigh, Laelie A. Snook, Alexandra N. Rebalka, Rebecca E. K. MacPherson, David C. Wright, Jonathan D. Schertzer, Thomas J. Hawke

While statins significantly reduce cholesterol levels and thereby reduce the risk of cardiovascular disease, the development of myopathy with statin use is a significant clinical side effect. Recent guidelines recommend increasing inclusion criteria for statin treatment in diabetic individuals; however, the impact of statins on skeletal muscle health in those with diabetes (who already suffer from impairments in muscle health) is ill defined. Here, we investigate the effects of fluvastatin treatment on muscle health in wild type (WT) and streptozotocin (STZ)-induced diabetic mice. WT and STZ-diabetic mice received diet enriched with 600 mg/kg fluvastatin or control chow for 24 days. Muscle morphology, intra and extracellular lipid levels, and lipid transporter content were investigated. Our findings indicate that short-term fluvastatin administration induced a myopathy that was not exacerbated by the presence of STZ-induced diabetes. Fluvastatin significantly increased ectopic lipid deposition within the muscle of STZ-diabetic animals, findings that were not seen with diabetes or statin treatment alone. Consistent with this observation, only fluvastatin-treated diabetic mice downregulated protein expression of lipid transporters FAT/CD36 and FABPpm in their skeletal muscle. No differences in FAT/CD36 or FABPpm mRNA content were observed. Altered lipid compartmentalization resultant of a downregulation in lipid transporter content in STZ-induced diabetic skeletal muscle was apparent in the current investigation. Given the association between ectopic lipid deposition in skeletal muscle and the development of insulin-resistance, our findings highlight the necessity for more thorough investigations into the impact of statins in humans with diabetes.