A team from Harvard Medical School says it has cracked the mystery behind statins’ tendency to cause muscle damage in some patients.
The cholesterol-lowering drugs are used successfully in millions of people. However, the rare, but serious, and poorly understood side effect of skeletal muscle breakdown (a process known as atrophy) prevents many people from taking them. The most severe problems are rare – affecting only one in 10,000 patients – however fatalities have been reported and the researchers say that fear of muscle toxicity “remains a major impediment preventing patients and their physicians from complying with statin therapy guidelines”.
They estimate that, largely as a result of this, fewer than half of patients who meet the criteria for statin therapy are currently receiving the drugs. New insight into the mechanism of statin-induced skeletal muscle atrophy is revealed, however, by the Harvard team led by Dr Stewart Lecker, in the latest issue of the Journal of Clinical Investigation.
The team focused on the activity of atrogin-1, a gene highly associated with skeletal muscle atrophy. Following treatment with lovastatin, a commonly prescribed statin, atrogin-1 was seen to be switched on in cultured mouse muscle cells and in zebrafish embryos. Furthermore, statin-induced muscle injury in the zebrafish was prevented by reducing the gene’s activity.
In addition, when the protein PGC-1-alpha (which protects against skeletal muscle damage and atrophy) was expressed in zebrafish, both atrogin-1 expression and lovastatin-induced muscle damage were prevented. The team also say that the findings suggest atrogin-1 is a critical mediator of statin-induced muscle damage and that inhibiting the atrogin-1 function offers the possibility of preventing this statin-induced side effect.
“This report provides the first evidence that statins induce muscle damage by induction of the muscle-specific atrogen-1 gene,” said Dr Lecker. The researchers add that follow-up studies may enable patients with a genetic susceptibility to statin-induced muscle damage to be identified and excluded from treatment – thereby paving the way for greater use of the drugs by the general population. By Michael Day
