Gene Linked to Statin-induced Muscle Damage

Researchers have traced a molecular pathway that explains how statins, popular drugs that reduce cholesterol by inhibiting HMG-CoA reductase, cause muscular pain and damage in some patients.

Investigators at Beth Israel Deaconess Medical Center (Boston, MA, USA) studied the interaction between statins and the gene atrogin-1, previously found to be overexpressed in wasting muscles.

Their recent study was published in the November 8, 2007, issue of the Journal of Clinical Investigation and detailed findings from three different groups of experiments. The investigators examined the expression of atrogin-1 in biopsy specimens taken from quadricep muscles from five control patients, six patients with muscle pain who were not being treated with statins, and eight patients with muscle pain and damage who were using statins. Their results showed that atrogin-1 expression was significantly higher among the statin users.

In a second set of experiments, cultured muscle cells were treated with various concentrations of lovastatin. Results showed that compared with control samples, the lovastatin-treated cells became progressively thinner and more damaged. In contrast, cells lacking the atrogin-1 gene were resistant to damage.

The third set of experiments employed the zebrafish model system. In this system as well, lovastatin caused muscle damage, even at low concentrations. As the concentration was increased, so too was the damage. Fish genetically engineered to lack the atrogin-1 gene were resistant to statin-induced damage.

"These three complementary experiments demonstrate that atrogin-1 has a fundamental role in statin-induced toxicity,” said senior author Dr. Stewart Lecker, assistant professor of medicine at Beth Israel Deaconess Medical Center. "Future experiments will be aimed at understanding how statins turn on the atrogin-1 response in muscle, and in ascertaining what transpires in muscle following atrogin-1 activation that leads to muscle damage and atrophy. The hope is that eventually patients will be able to glean statins' positive benefits to cholesterol metabolism and reduction of cardiovascular events while being spared accompanying muscle toxicities.”


Related Links:
Beth Israel Deaconess Medical Center