Scientists identify mechanism behind statin-induced muscle weakness

New research suggests that muscle weakness and related side effects that can arise from statin

use is likely due to the drug’s effect on the energy production centers, or mitochondria, of muscle

cells.

The researchers found lactone forms of statins can disrupt

the function of mitochondria in muscle cells by interfering with a protein structure called complex

III.
Image credit: Schirris et al.

The researchers, from Radboud University Nijmegen Medical Center in the Netherlands, report their

findings in the journal Cell Metabolism.

Statins are a commonly prescribed medication for lowering cholesterol; they work by blocking

cholesterol production in the liver. Cholesterol is a major risk factor for heart disease and stroke,

which cause nearly 1 in 3 deaths among Americans.

According to the Centers for Disease Control and Prevention (CDC), more than a quarter of American adults

aged 40 and over use a prescription cholesterol-lowering medication, the vast majority of these being

statins.

However, for around 25% of patients, statins can give rise to unpleasant side effects in the

form of muscle weakness, pain and cramps, without any sign of damage to the tissue. These side effects

can impair quality of life and often cause patients to stop taking the drugs.

Frans Russel, co-senior author of the new study and professor in molecular pharmacology and

toxicology, says previous studies have linked side effects of statins and other drugs to mitochondria,

but the underlying mechanisms are often unknown.

Lactone form of statin interferes with mitochondrial function

In the human body, statins exist in two forms: acid and lactone. Most statin drugs are of the acid

form and target cholesterol production in the liver. The lactone form has no therapeutic effect –

however, the acid form can convert to this type.

This would not normally be a problem except that the study shows the lactone form can interfere with

the function of mitochondria – the powerhouses inside cells that produce ATP, the cellular “currency”

of energy.

Using muscle cells from mice, the team showed that statins of the lactone form are around

three times more powerful at disrupting mitochondria than those of the acid form.

They confirmed this finding in cells taken from muscle biopsies of patients experiencing statin-induced side effects.

They showed that the cells of the patients had reduced ATP production compared with

cells from healthy controls. The lactone form of statins appears to reduce activity in a protein structure known as “complex III.”

Prof. Russel says further independent studies are needed to look at the effects of different statins

on mitochondrial function, and to confirm whether the mechanism they have identified could be a useful

marker to predict which patients are likely to experience side effects from statin use. He also notes

that:

“Interindividual differences in the enzymatic conversion of the acid into the lactone

form could be an explanation for the differences between patients in susceptibility for statin-induced

muscle pain.”

He and his colleagues believe their findings will lead to new classes of cholesterol-lowering drugs

without the unwanted muscle effects.

In their study, the team also found they could reduce lactone’s ability to interfere with

mitochondrial function, suggesting there are ways to prevent or reverse the side effects of

statins.

The team is currently pursuing both opportunities.

Meanwhile, Medical News Today recently learned about new research that suggests statins are being used by very elderly Americans “without any evidence

from testing.”

Writing in JAMA Internal Medicine, the researchers note that despite a lack of clear

recommendation for statin use in the very elderly, over the last decade or so there has been a large

increase in the use of the cholesterol-lowering drugs among the over-80s.

Written by Catharine Paddock PhD

Copyright: Medical News Today