Researchers link statins to disruption of muscle mitochondria.


Statins are a popular and easy-to-swallow option for people looking to lower their cholesterol. However, for a quarter of patients, statins come with muscle pain, stiffness, cramps, or weakness without any clear signs of muscle damage. These symptoms may affect daily activities so much that people stop using the drugs.  Yet the mechanical reason for these side-effects is still unclear.

Now, a study from researchers at Radboud University has shown in mice and humans that statins yield an off-target reaction that disrupts muscle mitochondria function, possibly causing the side effects.  The opensource study is published in the journal Cell Metabolism.

Previous studies show that adverse drug effects, like those of statins and many other drugs, have been linked to mitochondria, the cell’s powerhouses, though the exact mechanisms are often unknown.  Statins have been shown to exist in the body in two chemical forms, acid and lactone. Most statins are administered as a tablet in their acid form, which slows down the production of cholesterol in the liver. The acid form can turn into the lactone form within the body, however it has long been known that the lactone form has no therapeutic effect.

The current study found that lactones can unintentionally interfere with a mitochondrial pathway that produces the cell’s energy currency, ATP. Results show that in mouse muscle cells, lactones are about three times more potent at disturbing mitochondrial function than their acid forms. These findings could be confirmed in muscle biopsies of patients suffering from statin-induced side effects, in which ATP production via lactone inhibition of the mitochondrial phosphorylation system was reduced, as compared to healthy control subjects.  Specifically, the data findings show that the lactone inhibits the Qo site of complex III of the mitochondrial oxidative phosphorylation system.

The lab state that further independent studies are needed on the effects of the different statins on mitochondrial function and to indicate the usefulness of complex III activity as a predictive marker for statin-induced myopathies.  The team conclude that they were able to reduce lactone’s ability to interfere with mitochondrial function, which is early evidence that side effects could be prevented or reversed.

The researchers surmise that their findings could lead to several opportunities to synthesize new classes of cholesterol-lowering drugs without the unwanted muscle effects, as well as the development of new avenues to counteract these effects, both of which they are currently investigating.

Source: Radboud University Medical Center

 

Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. In C2C12 myoblasts, several statin lactones reduced respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III (CIII) activity, up to 84% inhibition. The lactones were in general three times more potent inducers of cytotoxicity than their corresponding acid forms. The Qo binding site of CIII was identified as off-target of the statin lactones. These findings could be confirmed in muscle tissue of patients suffering from statin-induced myopathies, in which CIII enzyme activity was reduced by 18%. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into CIII, restoring respiration up to 89% of control. In conclusion, CIII inhibition was identified as a potential off-target mechanism associated with statin-induced myopathies.  Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition.  Russel et al 2015.

Cholesterol-lowering statins effectively reduce the risk of major cardiovascular events. Myopathy is the most important adverse effect, but its underlying mechanism remains enigmatic. In C2C12 myoblasts, several statin lactones reduced respiratory capacity and appeared to be strong inhibitors of mitochondrial complex III (CIII) activity, up to 84% inhibition. The lactones were in general three times more potent inducers of cytotoxicity than their corresponding acid forms. The Qo binding site of CIII was identified as off-target of the statin lactones. These findings could be confirmed in muscle tissue of patients suffering from statin-induced myopathies, in which CIII enzyme activity was reduced by 18%. Respiratory inhibition in C2C12 myoblasts could be attenuated by convergent electron flow into CIII, restoring respiration up to 89% of control. In conclusion, CIII inhibition was identified as a potential off-target mechanism associated with statin-induced myopathies. Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition. Russel et al 2015.

 

 

 

 

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