Validation of a clinically-relevant rodent model of statin-associated muscle symptoms for use in pharmacological studies

Highlights: • Different SAMS models produce different changes in skeletal muscle integrity. • The SIM80 model produces myotoxicity characteristic of SAMS. • The effects of the SIM80 model are fibre-selective. • The SIM80 model should be used for pharmacological studies of SAMS. Various rodent models of statin-associated muscle symptoms (SAMS) have been used to investigate the aetiology of statin myotoxicity. Variability between these models, however, may be contributing to the ambiguity currently surrounding the pathogenesis of SAMS. Furthermore, few studies have assessed the reproducibility of these models. The aim of this study was to compare two established rodent models of statin myotoxicity, differing in treatment duration and dose, to determine which reproducibly caused changes characteristic of SAMS. Isolated skeletal muscle organ bath experiments, biochemical analyses, real-time quantitative-PCR and biometric assessments were used to compare changes in skeletal muscle and renal integrity in statin-treated animals and time-matched control groups. The SIM80 model (80 mg kg⁻¹ day⁻¹ simvastatin for 14 days) produced fibre-selective skeletal muscle damage characteristic of SAMS. Indeed, fast-twitch gastrocnemius muscles showed increased Atrogin-1 expression, reduced peak force of contraction and decreased Myh2 expression while slow-twitch soleus muscles were unaffected. Contrastingly, the SIM50 model (50 mg kg⁻¹ day⁻¹ simvastatin for 30 days) produced little evidence of significant skeletal muscle damage. Neither statin treatment protocol caused significant pathological changes to the kidney. The results of this study indicate that the SIM80 model induces a type of SAMS in rodents that resembles the presentation of statin-induced myalgia in humans. The findings support that the SIM80 model is reproducible and can thus be reliably used as a platform to assess the aetiology and treatment of this condition.