Statin side effects linked to off-target reaction in muscle mitochondria

Statins are a favorite and easy-to-swallow option for folks seeking to lower their cholesterol. But also for 25 % of patients, statins include muscle pain, stiffness, cramps, or weakness without the clear signs of muscle damage. These symptoms may affect daily activities so much that folks stop using the drugs. On September 1 in Cell Metabolism, Dutch researchers show, in humans and mice, that statins yield an off-target reaction that disrupts muscle mitochondria function, possibly creating the side effects.

“Adverse drug effects, like those of statins and a great many other drugs, have been associated with mitochondria�the cell’s powerhouses�though the precise mechanisms tend to be unknown,” says co-senior study author Frans Russel of the Nijmegen Center for Mitochondrial Disorders at the Radboud University INFIRMARY in holland. “This research causes several opportunities to synthesize new classes of cholesterol-lowering drugs with no unwanted muscle effects, as well as the introduction of new avenues to counteract these effects, both which we are investigating.”
Statins exist in the torso in two chemical forms, lactone and acid. Most statins are administered (as a tablet) in their acid form, which decreases the production of cholesterol in the liver. The acid form can change in to the lactone form in the body, however the lactone form does not have any therapeutic effect.
Russel, along with co-senior author Jan Smeitink, postdoctoral researcher Tom Schirris, and colleagues, discovered that lactones can, however, unintentionally hinder a mitochondrial pathway that produces the cell’s energy currency, ATP. In mouse muscle cells, lactones were around three times stronger at disturbing mitochondrial function than their acid forms. These findings could be confirmed in muscle biopsies of patients experiencing statin-induced side effects, where ATP production (via lactone inhibition of the Qo site of complex III of the mitochondrial oxidative phosphorylation system) was reduced, when compared with healthy control subjects.
“Further independent studies are needed on the consequences of the several statins on mitochondrial function also to indicate the usefulness of complex III activity as a predictive marker for statin-induced myopathies,” Russel says. “Interindividual distinctions in the enzymatic conversion of the acid in to the lactone form could be a conclusion for the distinctions between patients in susceptibility for statin-induced muscle pain.”
The researchers are also excited to explore whether current statins can be improved or supplemented without impacting muscles in the foreseeable future. Within their study, these were in a position to reduce lactone’s ability to hinder mitochondrial function, which is early evidence that side effects could be reversed or prevented.

Explore further:
Study cautions against statins as general preventive medicine

More info:
Cell Metabolism, Schirris et al.: “Statin-Induced Myopathy Is Connected with Mitochondrial Complex III Inhibition” dx.doi.org/10.1016/j.cmet.2015.08.003

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