Determining a Rodent Model to Investigate Glutamate as a Mechanism Underlying Statin Myalgia

Abstract

HMG-CoA reductase inhibitors, known commonly as statins are one of the most widely prescribed medications worldwide. Statins reduce circulating cholesterol levels and are very effective at reducing one’s risk for all-cause and cardiovascular mortality. Though generally well tolerated, statin-associated muscle symptoms (SAMS) present in more than a quarter of statin users. The most common SAMS is myalgia or muscle pain. Statin myalgia often presents in the absence of myofibre damage, making its origin and treatment ambiguous. There are numerous rodent models for statin myopathy in the literature, but surprisingly there is no representation of statin myalgia that we are aware of. This is shocking given the high prevalence of statin myalgia compared to statin myopathy. Recently, our lab published an in vitro model of statin myalgia that focused on elevated xCT transporter activity and interstitial glutamate. This model explains that pain perceived in statin myalgia is the result of statins’ downstream ability to elevate skeletal muscle interstitial glutamate concentrations, thereby activating peripheral nociceptors. The studies herein aimed to create an in vivo rodent model of statin myalgia based on the aforementioned in vitro model. We hypothesized that glutamate, sampled by way of skeletal muscle microdialysis, would be elevated in the skeletal muscle interstitium of rats following statin treatment. Drawing conclusions on the role of glutamate in statin myalgia was not a straightforward process and required multiple model adjustments due to confounding variables. Additionally, many of the recognized effects of statins that were assumed from human and in vitro studies did not translate well to our rodent model. This was the first attempt at creating an in vivo model of statin myalgia and evidence suggests that a rodent model may not be an appropriate representation of what occurs in humans. While these studies also raised doubt on the efficacy of rodent models for SAMS investigations in general and highlighted the importance of having standardized models, certain limitations and assumptions of our model must be addressed before concrete conclusions can be drawn.