Chronic Neuromyopathy Triggered by Statin Use - part 2 of 2

Part 2 - Mechanisms of Action
What is the possible mechanism of action whereby a mevalonate pathway reductase inhibitor — a statin — can affect muscles and nerves in such a manner that even after stopping the statin, the neuromuscular condition slowly worsens?
The vital components of the mevalonate metabolic pathway have been identified:

a) Inhibition of cholesterol synthesis.
b) Inhibition of CoQ10 synthesis.
c) Inhibition of dolichol synthesis.
d) Inhibition of normal geranyl-geranyl phosphorylation with its reported secondary enhancement of tau protein synthesis and
e) Inhibition of selenoprotein synthesis.

Draeger's findings support the hypothesis that statin induced cholesterol lowering per se contributes to myocyte damage and suggests further that it is the specific lipid/protein organs of the skeletal muscle itself that renders it particularly vulnerable.

He did skeletal muscle biopsies from statin treated and non-statin treated patients and examined them using electron microscopy and biochemical approaches. They reported clear evidence of skeletal muscle damage in statin treated patients despite them being asymptomatic.

Caso reports that myopathy may be related in part to statin inhibition of the endogenous synthesis of coenzyme Q10, an essential co-factor for mitochondrial energy production.

He found that after a 30-day intervention study, pain severity decreased by 40% (p <0.001) and pain interference with daily activities decreased by 38% (p <0.02) in the group treated with coenzyme Q10.

CoQ10 has long been known to have a role both in cellular structural integrity and in mitochondrial energy production.


William Campbell in the October 2006 issue of Muscle and Nerve presents a number of statin associated neuromuscular problems recently encountered by clinicians and an excellent review of the vital role of cholesterol with its extraordinary sensitivity to statin manipulation in some people.

He goes on to discuss polymyositis-like cases requiring steroids that point to a pro-inflammatory effect of statins. Campbell proposes a previously unsuspected effect of statins on muscle cell lipid / protein "rafts" that results in a tendency to apoptosis (cell death and disintegration).

It is these remnants of apoptosis that incite the autoimmune reaction and cause the inflammatory response. Campbell also discusses the dolichols, another vital product synthesized through the mevalonate pathway and hence inhibited by statins.

Researchers now know that cholesterol and other lipids are not evenly distributed throughout a cell but exist with proteins as cholesterol "rafts" having key roles in cell signaling.

All this under the direction of dolichols, giving us still another way in which statin drugs can complicate the lives of some people.

Georgirene Vladutiu PhD of the Robert Guthrie Genetics Laboratory in Buffalo thinks that some patients may have a genetic susceptibility to statin use. Special genetic susceptibility may explain not only much of the statin associated rhabdomyolysis but also the curious pattern of persistent myopathy, often following only a short course of statins.

Since susceptibility testing of this type is not yet available, there is no way to identify these susceptibles until the damage is done.

One of these genetic determined enzymatic conditions is carnitine palmitoyl transferase (CPT) deficiency. The enzymes involved are found on different membranes of our mitochondria, those busy factories within each of our cells responsible for the production of adenosine triphosphate (ATP) energy.

Produced in each of the body's millions of cells, mitochondrial ATP is the body's sole source of energy. CPT enzymes work together with Coenzyme Q10 in the process of transport of fatty acids into the mitochondria and their ultimate conversion into fuel. Deficiency of this class of enzymes is characterized by unusual muscle pain and stiffness after exercise or work.

Mooseman and Behl postulate that this type of myopathy is due to direct interference of the isopentyl step of the mevalonate pathway as a consequence of the almost inevitable statin induced fall in available selenoproteins. The substrate for this reaction, isopentanyl pyrophosphate IPP, is a direct metabolite of mevalonate. All statins inhibit this function.

The resulting clinical picture of statin associated myopathy includes a non-uniform pattern of muscle aches and pains, weakness and tenderness with easy fatigability. It can vary from mild to very severe, or even be disabling.

This pattern of signs and symptoms is very similar clinically and pathologically to those induced by severe selenium (selenoprotein) deficiency, supporting their hypothesis
Of the various possibilities, I am betting on Campbell's dolichols.

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

Updated January 2016

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