Navigation Links
Scientists identify gene responsible for statin-induced muscle pain
Date:11/27/2007

BOSTON 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 studys co-senior author Stewart 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. And, 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.


'/>"/>

Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

Related medicine news :

1. New prion protein discovered by Canadian scientists may offer insight into mad cow disease
2. Scientists Probe Sepsis Deadly Secrets
3. Scientists puzzled by severe allergic reaction to cancer drug in the middle Southern US
4. Scientists Develop Natural Protection for Stored Foods
5. Scientists detect presence of marburg virus in african fruit bats
6. Scientists Spot Brains Free Will Center
7. Scientists ID Likely Culprit in Popcorn Lung
8. Scientists explain how insulin secreting cells maintain their glucose sensitivity
9. Scripps Research scientists shed new light on how antibodies fight HIV
10. Scientists, physicians present latest findings in personalized cancer treatment and prevention
11. Scientists demonstate link between genetic variant and effectiveness of smoking cessation meds
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/5/2016)... ... February 05, 2016 , ... Today, the Whole-Food Warrior TV show, ... much-anticipated feature with author Jahnavi Foster, specialist in healthy vegetarian cuisine, will stream on ... week, on his weekly Whole-Food Warrior TV show, Frank Davis highlights Whole-Food Warriors - ...
(Date:2/5/2016)... New York, New York (PRWEB) , ... February 05, 2016 , ... ... your life? The answer may be at the tips of your toes. Foot massage, ... benefits as well as pure comfort and relaxation. The American Board of Multiple ...
(Date:2/5/2016)... ... February 05, 2016 , ... In the fourth quarter of ... at the La Valencia Hotel in San Diego, California to discuss changes in ... year’s most outstanding franchise, walking away with the coveted David Wright Award of ...
(Date:2/5/2016)... ... 2016 , ... Pivot Point Consulting, a leading national Healthcare ... Services for HIT Implementation Support & Staffing report with an outstanding score of ... healthcare executives, managers and clinicians representing over 4,500 hospitals and 2,500 clinics. , ...
(Date:2/5/2016)... ... , ... Colorize is a web theme package created exclusively for ... Colorize's dynamic moving camera. Colorize is perfect for personal and web related videos and ... 1 to 5 focus points per scene, stage floor scene presets that are great ...
Breaking Medicine News(10 mins):
(Date:2/4/2016)... Feb. 4, 2016  SciClone Pharmaceuticals, Inc. (NASDAQ: ... has entered into a settlement agreement with the ... resolving the SEC,s investigation into possible violations of ... terms of the settlement agreement, SciClone has agreed ... disgorgement, pre-judgment interest and a penalty.  This payment ...
(Date:2/4/2016)... -- Frontier Pharma: Chronic Obstructive Pulmonary Disease (COPD) ... Chronic Obstructive Pulmonary Disease (COPD) is a ... airways and lungs. Persistent breathing difficulties and repeated ... of the leading causes of morbidity and the ... is linked to cumulative exposure to risk factors, ...
(Date:2/4/2016)... ALBANY, N.Y. , Feb. 4, 2016  AMRI (NASDAQ: ... Vice President of Pfizer Inc. and President of Pfizer Global ... effective as of February 4, 2016. In addition, the Company ... member of the audit committee since 2010, has retired from ... time and attention to his other business ventures.  ...
Breaking Medicine Technology: