IGF-1 prevents simvastatin-induced myotoxicity in C2C12 myotubes

Abstract

Statins are generally well tolerated, but treatment with these drugs may be associated with myopathy. The mechanisms of statin-associated myopathy are not completely understood. Statins inhibit AKT phosphorylation by an unclear mechanism, whereas insulin-like growth factor (IGF-1) activates the IGF-1/AKT signaling pathway and promotes muscle growth. The aims of the study were to investigate mechanisms of impaired AKT phosphorylation by simvastatin and to assess effects of IGF-1 on simvastatin-induced myotoxicity in C2C12 myotubes. C2C12 mouse myotubes were exposed to 10 μM simvastatin and/or 10 ng/mL IGF-1 for 18 h. Simvastatin inhibited the IGF-1/AKT signaling pathway, resulting in increased breakdown of myofibrillar proteins, impaired protein synthesis and increased apoptosis. Simvastatin inhibited AKT S473 phosphorylation, indicating reduced activity of mTORC2. In addition, simvastatin impaired stimulation of AKT T308 phosphorylation by IGF-1, indicating reduced activation of the IGF-1R/PI3K pathway by IGF-1. Nevertheless, simvastatin-induced myotoxicity could be at least partially prevented by IGF-1. The protective effects of IGF-1 were mediated by activation of the IGF-1R/AKT signaling cascade. Treatment with IGF-1 also suppressed muscle atrophy markers, restored protein synthesis and inhibited apoptosis. These results were confirmed by normalization of myotube morphology and protein content of C2C12 cells exposed to simvastatin and treated with IGF-1. In conclusion, impaired activity of AKT can be explained by reduced function of mTORC2 and of the IGF-1R/PI3K pathway. IGF-1 can prevent simvastatin-associated cytotoxicity and metabolic effects on C2C12 cells. The study gives insight into mechanisms of simvastatin-associated myotoxicity and provides potential targets for therapeutic intervention.

Testosterone improves muscle function of the extensor digitorum longus in rats with sepsis

“…2 anabolism and skeletal muscle function 18. In this study, serum testosterone level, IGF-1 protein level, phosphorylated AKT and mTOR levels and rapid myosin expression level all significantly increased in EDL of experimental group.…”

PGC‐1α plays a pivotal role in simvastatin‐induced exercise impairment in mice

“…27 We considered this fibre shift to be one of the reasons for statin-induced myotoxicity, since glycolytic fibres have less antioxidative capacity and are more vulnerable to statins. 4,26 On the other hand, as stated above, musclespecific overexpression of PGC-1α in mice leads to a shift from glycolytic to oxidative fibres. 30,36 Since statins exert their myotoxicity at least partially via increased mitochondrial production of ROS, 15,28,31 this switch from glycolytic to oxidative muscle fibres could possibly explain the protection of PGC-1α OE mice from simvastatin-associated myotoxicity observed in the current study.…”

“…We have shown in a previous study that atorvastatin can induce a shift from an oxidative to a glycolytic fibre type in skeletal muscle of mice . We considered this fibre shift to be one of the reasons for statin‐induced myotoxicity, since glycolytic fibres have less antioxidative capacity and are more vulnerable to statins . On the other hand, as stated above, muscle‐specific overexpression of PGC‐1α in mice leads to a shift from glycolytic to oxidative fibres .…”

“…After one week of acclimatization, mice of each model were randomly divided into 6 groups as follows: (1) WT treated with water (Ctl, n = 10); (2) WT treated with simvastatin 5 mg/kg/d (Simv, n = 10); (3) KO mice treated with water (n = 10); (4) KO mice treated with simvastatin 5 mg/kg/d (n = 10), (5) OE mice treated with water (n = 10) and (6) OE mice treated with simvastatin 5 mg/kg/d (n = 10). These mice were treated by oral gavage for 3 weeks . Body weight, food and water intake were measured daily during the treatment period.…”

“…These mice were treated by oral gavage for 3 weeks. 26 Body weight, food and water intake were measured daily during the treatment period.…”