IGF-I Protects Against Statin Myotoxicity

Abstract

HMG reductase inhibitors (statins) are widely prescribed in the treatment of hypercholesterolemia. Previous research has demonstrated a toxic effect of statins on myoblasts and myofibers in vitro accounting for observed myopathy in some patients. Different statins produce different degrees of toxicity, the most potent including simvastatin (SS) and mevastatin (MS), with pravastatin (PS) having little to no effect. PURPOSE: The purpose was to establish if the stimulatory growth factor, IGF-I, can effectively block statin-induced myotoxicity. METHODS: C2C12 myoblasts were cultured and plated in 96-well plates (2,500 cells/well). After 48 hours, media was changed, exposing the cells to the following experimental conditions: control; SS, MS or PS alone (1, 5, 10, 50, 100μM); IGF-I alone (25, 50, 100ng/mL); SS (10μM) + IGF-I (25, 50, 100ng/mL). After 72 hours of incubation, MTS cell proliferation assays were performed. Multiple independent experiments were run for all conditions and data was analyzed via one-way ANOVA with significance set at p<0.05. RESULTS: Consistent with previous results, both SS and MS produced a dose-dependent inhibition of proliferation. At the highest doses absorbance was only slightly above background suggesting the absence of viable cells when exposed to either SS or MS alone (0.006 ± 0.017, 0.113 ± 0.057 respectively). In contrast, no significant changes were noted with PS even at the highest doses. As expected, IGF-I produced a significant mitogenic effect, increasing cell proliferation by 48% with 100ng/mL IGF-I. To establish a protective effect, IGF-I was added in combination with the dose of SS that inhibited proliferation by about 50%. At 25 and 50ng/mL IGF-I, cell proliferation was equivalent to control conditions. Interestingly, when added to SS, 100ng/mL IGF-I produced significantly greater proliferation than control values, indicating a complete block of statin toxicity. CONCLUSION: There is a statin specific effect on myotoxicity with the response being effectively blocked by addition of IGF-I. This suggests the potential for blockade of a major side effect of statins via a concurrent application of growth factors known to activate myoblast proliferation. Therefore, if administered clinically, mitogens such as IGF may protect against the negative effects of statins.