Investigation into the role of creatine in muscle toxicity associated with statin-use

Jason Bowie, The College of Wooster


Statins are a class of drugs that are used extensively in the treatment of high blood cholesterol, one of the primary risk factors for cardiovascular disease. While statins are well tolerated by most individuals, some develop myotoxicity, a potentially severe side effect. The only diagnostic tests currently used to monitor muscle toxicity in statin-users measure the breakdown of muscle cells. Due to the fact that these tests measure plasma levels of enzymes, such as creatine kinase (CK) and aldolase, which are normally found in muscle cells, they fail to detect the more subtle changes in muscle toxicity that can cause myopathy. A more sensitive diagnostic test for measuring myotoxicity may lead to earlier identification and prevention of myopathy in statin-users. A mechanism for describing the cause of statin myopathy has not yet been described. In this study, we hypothesized that serum creatine/creatinine ratios are elevated in statin-users that experience the muscle symptoms associated with myotoxicity when compared to nonsymptomatic statin-users. This hypothesis was based on a previous study, which showed that statin-intolerant individuals had elevated creatine/creatinine ratios when compared to statin-tolerant patients. This previous study, however, looked at a very small and specific population. As such, our study looked at a larger population of statin-users. Serum samples were collected at the Cleveland Clinic Wooster laboratory and analyzed at The College of Wooster to calculate creatine and creatinine concentrations. Our study indicates that there is a trend toward the elevation of the mean serum creatine/creatinine ratio in statin-users that experience muscle toxicity symptoms when compared to asymptomatic statin-users, but that this trend is not significant (p = 0.0605). We also hypothesized that the cause of statin-myopathy and, in turn, the elevation of creatine/creatinine ratios is caused by inefficient creatine transport into myoblasts. To test this hypothesis, we treated mouse myoblasts with varying concentrations of lovastatin and pravastatin to determine if there was a dose dependent decrease in creatine uptake into statin-treated cells compared to untreated cells. We also determined the Vmax and KM for the creatine transporter when treated with the two statins. The KM for the statin-treated cells was ~60% lower than the KM for the untreated cells. The Vmax was only affected by lovastatin, which decreased the rate of creatine transport by ~67%. Total creatine uptake was also affected by statin treatment. In cells treated with 5 µM lovastatin, there was significant decrease in creatine uptake by mouse myoblasts (p < 0.0002). Our results indicate that statin treatment has a significant impact on the efficiency of creatine transport into muscle cells.


© Copyright 2008 Jason Bowie