Prolonged treatment of compactin, atorvastatin, lovastatin or simvastatin decreased glucose consumption and expressions of proteins for glucose metabolism and insulin signaling in L6 skeletal muscle cells

Abstract Statins inhibit mevalonate synthesis and successfully lower plasma cholesterol levels and decrease the risk of cardiovascular diseases in humans, but also lead to myalgia in some patients. We hypothesize that statins may modulate glucose metabolism and insulin signaling in the skeletal muscle cells during and after differentiation, and in turn lead to side effects. Here, differentiating and differentiated L6 muscle cells were treated with 1 μM of different class of statins (compactin, pravastatin, atorvastatin, lovastatin and simvastatin) with or without insulin or mevalonate for extended periods of time. The glucose consumption and expression levels of proteins for glucose metabolism and insulin receptor (IR)/Akt signaling were determined. The prolonged statin treatments (except pravastatin) decreased glucose consumption in L6 skeletal muscle cells. In differentiating L6 cells, compactin, lovastatin or simvastatin decreased the expression levels of proteins involved in glucose metabolism and insulin signaling, including glucose transporter 4 (GLUT4), pyruvate dehydrogenase (PDH), glycogen synthase (GS), glycogen synthase kinase 3β (GSK3β) and insulin receptor β subunit (IRβ). In differentiated L6 cells, long-term treatment of compactin or simvastatin also decreased levels of proteins in glucose metabolism and IR/Akt signaling, including GLUT4, GSK3β, IRβ and PI3K p110α. Insulin treatment restored statin-mediated impairments in L6 cells. The insulin-mediated phosphorylation of Akt Ser473 was attenuated in differentiating and differentiated L6 cells in the presence of atorvastatin (differentiated only), compactin, lovastatin or simvastatin. In addition, mevalonate supplementation reversed the statin-mediated impairments in differentiated and differentiating L6 cells. Statin affected glucose usage and insulin signaling by inhibiting mevalonate synthesis in L6 cells. Our results provides a possible mechanism of adverse effects of statins in skeletal muscle and calls for cautious use of the medication in patients with impaired insulin sensitivity and glucose metabolism.