Scientists Identify Gene Responsible for Statin-Induced Muscle Pain

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Scientists Identify Gene Responsible for Statin-Induced Muscle Pain

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Statins, the popular class of drugs used to lower cholesterol, are

among the most commonly prescribed medications in developed

countries. But for some patients, accompanying side effects of

muscle weakness and pain become chronic problems and, in rare cases,

can escalate to debilitating and even life-threatening damage. Now a

study led by investigators at Beth Israel Deaconess Medical Center

helps explain the source of these problems.

Statins, the popular class of drugs used to lower cholesterol, are

among the most commonly prescribed medications in developed

countries. But for some patients, accompanying side effects of

muscle weakness and pain become chronic problems and, in rare cases,

can escalate to debilitating and even life-threatening damage.

Now a study led by investigators at Beth Israel Deaconess Medical

Center (BIDMC), helps explain the source of these problems.

Published in the December 2007 issue of The Journal of Clinical

Investigation, the findings offer the first evidence that a gene

known as atrogin-1 plays a key role in statin-related muscle

toxicity.

" Although it is not known exactly how many of the 500 million

individuals who take statins experience muscle pain and weakness,

muscle symptoms are generally considered the most common side

effects of these medications, " explains co-senior author Vikas P.

Sukhatme, MD, PhD, Vice Chair of Medicine for Interdepartmental and

Translational Programs, Chief of the Division of Nephrology, and

Chief of the Division of Interdisciplinary Medicine and

Biotechnology at BIDMC.

" Statin users describe a wide spectrum of symptoms – at the most

extreme end is a severe breakdown of skeletal muscle known as

rhabdomyolysis, " says Sukhatme, who is also the Victor J. Aresty

Professor of Medicine at Harvard Medical School (HMS). " At the other

end is `grumbling muscles,' milder, more diffuse muscle soreness and

cramps. This kind of symptomatic muscle weakness and pain is quite

frequent, but often difficult to quantitate. "

Known by such trade names as Lipitor, Zocor, Pavacol and Mevacor,

statins lower cholesterol by inhibiting HMG-CoA reductase, a key

enzyme in cholesterol synthesis.

Approximately five years ago, the study's co-senior author

Lecker, MD, PhD, and colleagues in the HMS laboratory of Alfred

Goldberg, MD, first discovered the atrogin-1 gene, so named for its

role in muscle atrophy.

" We learned that atrogin-1 is rapidly turned on in wasting muscle, "

explains Lecker, who is an investigator in the Division of

Nephrology at BIDMC and Assistant Professor of Medicine at HMS.

Muscle wasting occurs in a large number of disease states, including

cancer, AIDS, and kidney disease and can also occur when muscles are

underused due to injury or lack of exercise. " In the absence of

atrogin-1 activation, " he adds, " muscle atrophy is diminished. "

Since this initial discovery, atrogin-1 has been found in every

existing model of muscle wasting, prompting Lecker and Sukhatme to

investigate whether cholesterol-lowering statins might also

be " turning on " this gene.

" We reasoned that since atrogin-1 plays a key role in the

development of wasting in skeletal muscle, it might also mediate

part of [patients'] sensitivity to statins, " the authors write.

They proceeded to conduct three separate experiments to test this

hypothesis. They first examined the expression of the atrogin-1 gene

in biopsies of 19 human quadricep muscles from five control

patients, six patients with muscle pain who were not being treated

with statins and eight patients with muscle pain/damage who were

using statins. Their results showed that atrogin-1 expression was

significantly higher among the statin users.

Next, the scientists studied statins' effects on cultured muscle

cells treated with various concentrations of lovastatin. Compared

with control samples, the lovastatin-treated cells became

progressively thinner and more damaged. But remarkably, say the

authors, the cells lacking the atrogin-1 gene were resistant to

statins' deleterious effects.

Finally, the authors tested the drug in zebrafish. They showed that

just as in mammalian muscle cell culture, lovastatin led to muscle

damage, even at low concentrations; as the concentration was

increased, so too was the damage. And, once again, they observed

that fish lacking the atrogin-1 gene were resistant to statin-

induced damage.

" These three complementary experiments demonstrate that atrogin-1

has a fundamental role in statin-induced toxicity, " notes

Lecker. " Future experiments will be aimed at understanding how

statins turn on the atrogin-1 response in muscle, and in

ascertaining what transpires in muscle following atrogin-1

activation that leads to muscle damage and atrophy. The hope is that

eventually patients will be able to glean statins' positive benefits

to cholesterol metabolism and reduction of cardiovascular events

while being spared accompanying muscle toxicities. "

This study was funded, in part, by grants from the National

Institutes of Health.

Study coauthors include BIDMC investigators Jun-Ichi Hanai and

Peirang Cao (lead authors) and Preeti Tanksale; Shintaro Imamura,

o Koshimizu and Shuji Kishi of Schepens Eye Research Institute;

Michiaki Yamashita, of the National Research Institute of Fisheries

Science, Yokohama, Japan; and of Scripps Mercy

Hospital, San Diego, California.

Beth Israel Deaconess Medical Center is a patient care, teaching and

research affiliate of Harvard Medical School, and consistently ranks

in the top four in National Institutes of Health funding among

independent hospitals nationwide. BIDMC is clinically affiliated

with the Joslin Diabetes Center and is a research partner of the

Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of

the Boston Red Sox. For more information, visit

http://www.bidmc.harvard.edu.