Geranylgeraniol prevents statin-induced skeletal muscle fatigue without causing adverse effects in cardiac or vascular smooth muscle performance

Abstract

The administration of geranylgeranyl pyrophosphate (GGPP) (or its precursor, geranylgeraniol [GGOH]) has been shown by several in vitro studies to be capable of abrogating statin-induced myotoxicity. Nonetheless, the potential of GGPP repletion to prevent statin-associated muscle symptoms (SAMS) in vivo is yet to be investigated. Therefore, this study aimed to evaluate the ability of GGOH to prevent SAMS in rodents. Female Wistar rats (12 weeks of age) were randomised to 1 of 4 treatment groups: control, control with GGOH, simvastatin or simvastatin with GGOH. Ex vivo assessment of force production was conducted in skeletal muscles of varying fiber composition. Ex vivo left ventricular performance and blood vessel function was also assessed to determine if the administration of GGOH caused adverse changes in these parameters. Statin administration was associated with reduced force production in fast-twitch glycolytic muscle, but coadministration with GGOH completely abrogated this effect. Additionally, GGOH improved the performance of muscles not adversely affected by simvastatin (ie, those with a greater proportion of slow-twitch oxidative fibers), and increased force production in the control animals. Neither control nor statin-treated rodents given GGOH exhibited adverse changes in cardiac function. Vascular relaxation was also maintained following treatment with GGOH. The findings of this study demonstrate that GGOH can prevent statin-induced skeletal muscle fatigue in rodents without causing adverse changes in cardiovascular function. Further studies to elucidate the exact mechanisms underlying the effects observed in this investigation are warranted.