Nav: Home

Scientists identify gene responsible for statin-induced muscle pain

November 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 study's 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."
-end-
Study coauthors include BIDMC investigators Jun-Ichi Hanai and Peirang Cao (lead authors) and Preeti Tanksale; Shintaro Imamura, Eriko Koshimizu and Shuji Kishi of Schepens Eye Research Institute; Michiaki Yamashita, of the National Research Institute of Fisheries Science, Yokohama, Japan; and Paul Phillips 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 www.bidmc.harvard.edu.

Beth Israel Deaconess Medical Center

Related Cholesterol Articles:

Cholesterol -- a key player at the lung surface
Cholesterol, a naturally occurring compound at the lung surface, has been shown to have a clear effect on the properties of this nanoscale film that covers the inside of our lungs.
Does boosting 'good' cholesterol really improve your health?
A new review addresses the mysteries behind 'good' HDL cholesterol and why boosting its levels does not necessarily provide protection from cardiovascular risk for patients.
Researchers zero-in on cholesterol's role in cells
For the first time, by using a path-breaking optical imaging technique to pinpoint cholesterol's location and movement within the cell membrane, chemists at the University of Illinois at Chicago have made the surprising finding that cholesterol is a signaling molecule that transmits messages across the cell membrane.
Cholesterol important for signal transmission in cells
Cholesterol can bind important molecules into pairs, enabling human cells to react to external signals.
Raising 'good cholesterol' not as effective as lowering 'bad cholesterol'
Low and very high levels of HDL, or 'good cholesterol' are associated with a higher risk of dying from heart disease, cancer and other causes, according to a study today in the Journal of the American College of Cardiology.
New gene for familial high cholesterol
New research from Denmark reveals the gene that explains one quarter of all familial hypercholesterolemia with very high blood cholesterol.
No need to fast before a cholesterol test
New research from Denmark, Canada and the US involving more than 300,000 individuals suggests that patients do not need to check their cholesterol levels on an empty stomach.
Cyclodextrin dissolves away cholesterol crystals
Cyclodextrin has been shown in mice to dissolve cholesterol crystals and prevent plaque formation.
New vaccine could prevent high cholesterol
A new cholesterol-lowering vaccine leads to reductions in 'bad' LDL cholesterol in mice and macaques, according to research published in Vaccine.
Enriched broccoli reduces cholesterol
Including a new broccoli variety in the diet reduces blood LDL-cholesterol levels by around 6 percent, according to the results of human trials led by the Institute of Food Research.

Related Cholesterol Reading:

Cholesterol Down: Ten Simple Steps to Lower Your Cholesterol in Four Weeks--Without Prescription Drugs
by Janet Brill (Author)

Take control of your cholesterol with this 10-point plan from nutrition and fitness expert Dr. Janet Brill—without using drugs.

If you are one of the nearly 100 million Americans struggling with high cholesterol, then Dr. Janet Brill offers you a revolutionary new plan for taking control of your health—without the risks of statin drugs. With Dr. Brill’s breakthrough Cholesterol Down Plan, you simply add nine “miracle foods” to your regular diet and thirty minutes of walking to your daily routine. That’s all. This straightforward and easy-to-follow program can... View Details


The Great Cholesterol Myth Now Includes 100 Recipes for Preventing and Reversing Heart Disease: Why Lowering Your Cholesterol Won't Prevent Heart Disease-and the Statin-Free Plan that Will
by Jonny Bowden (Author), Stephen Sinatra (Author), Deirdre Rawlings (Author)

Get proven, evidence-based strategies from the experts with The Great Cholesterol Myth Now Includes 100 Recipes for Preventing and Reversing Heart Disease.

Heart disease is the #1 killer. However, traditional heart disease protocols--with their emphasis on lowering cholesterol--have it all wrong. Emerging science is showing that cholesterol levels are a poor predictor of heart disease and that standard prescriptions for lowering it, such as ineffective low-fat/high-carb diets and serious, side-effect-causing statin drugs, obscure the real causes of heart disease. Even... View Details


Cholesterol Clarity: What The HDL Is Wrong With My Numbers?
by Jimmy Moore (Author), Eric C. Westman (Author)

Are you confused by what your cholesterol levels really say about your health?

Don't you wish someone could just spell it out in simple, easy-to-understand language and tell you what, if anything, you need to do about your cholesterol? Good news! That's precisely what Cholesterol Clarity is designed to do. Jimmy Moore, a prominent and highly respected health blogger and podcaster, has teamed up with Dr. Eric Westman, a practicing internist and nutrition researcher, to bring you one of the most unique books you'll ever read on this subject, featuring exclusive interviews... View Details


Cholesterol is Not the Culprit: A Guide to Preventing Heart Disease
by Dr Fred Kummerow (Author)

You will find a lot in this book related to diet and heart disease; it is the number one cause of death in the U.S. and throughout much of the world and also the focus of the majority of my career. To me, researching diet and heart disease is like being the detective in a good mystery book who follows clue after clue and finally comes up with an unexpected answer. The detective is always trying to find out who and what killed the person. Some detectives view cholesterol as the killer in heart disease, but I show you why that's not so. I hope in reading this book, you'll not only learn what is... View Details


Fat and Cholesterol Don't Cause Heart Attacks and Statins are Not The Solution
by Paul J. Rosch MD (Author), Zoë Harcombe PhD (Author), Malcolm Kendrick MD (Author), Uffe Ravnskov MD PhD (Author), Fred A. Kummerow PhD (Author), Harumi Okuyama PhD (Author), Peter H. Langsjoen MD (Author), Alena M. Langsjoen MS (Author), Naoki Ohara PhD (Author), David M. Diamond PhD (Author), Tomohito Hamazaki MD PhD (Author), Stephanie Seneff PhD (Author), Carlos Monteiro (Author), Kilmer S. McCully MD (Author), Luca Mascitelli MD (Author), Mark R. Goldstein MD (Author), Michel de Lorgeril MD (Author), Mikael Rabaeus MD (Author), Duane Graveline MD MPH (Author), Sherif Sultan MD Phd (Author), Edel P. Kavanagh PhD (Author)

This book is dedicated to Uffe Ravnskov, MD, Ph.D. for his seminal and propaedeutic achievements in disputing the dogma that fat and cholesterol cause coronary heart disease, and that statins are safe and cardioprotective for everyone. As will be seen, no studies support the notion that restricting fat reduces coronary morbidity or mortality. More importantly, government recommendations mandating low fat diets are likely the cause of the escalating epidemic of obesity and type 2 diabetes. Several chapters detail the panoply of significant adverse health effects of statins that have been... View Details


American Heart Association Healthy Fats, Low-Cholesterol Cookbook: Delicious Recipes to Help Reduce Bad Fats and Lower Your Cholesterol
by American Heart Association (Author)

The classic cookbook for achieving heart health and wellbeing through a diet that is low in cholesterol and saturated fat--updated and revised with 200 recipes (including 50 new to this edition)

Lose the bad fats, but not the flavor.

Now in its fifth edition, American Heart Association Healthy Fats, Low-Cholesterol Cookbook provides the most up-to-date information on heart health and nutrition. Good-for-you food should also be satisfying, and the American Heart Association reveals how easy it is to replace the bad fats in your diet with healthier ones.... View Details


Your Cholesterol Matters: What Your Numbers Mean and How You Can Improve Them
by Richard MD, FACS Furman (Author)

A must-read for those on cholesterol lowering medication and those with stents in their hearts

When it comes to our health, what we don't know can harm us most. Eighty-five percent of people over the age of fifty have significant blockage in the arteries of their hearts without any symptoms. Two-thirds of the time, the initial symptom is a full-blown heart attack. Doctors tell patients to watch their diet, get regular exercise, and lose weight--but they also increasingly prescribe "cholesterol lowering" drugs that patients will take every day for the rest of their lives. The... View Details


The New 8-Week Cholesterol Cure
by Robert E. Kowalski (Author)

Robert Kowalski's personal story is legendary. By the age of forty-one, he had suffered a heart attack and had undergone two coronary bypass surgeries. A traditional dietary approach to lowering his cholesterol failed dismally, and faced with the unpleasant alternative of a lifetime on medication, he created a program that proved astonishingly effective for him -- and legions of others worldwide who use it.

Today Kowalski has beaten heart disease, lives an unlimited and vigorous lifestyle, and uses no prescription drugs. Now, with new information about risk factors, exercise, and... View Details


The Great Cholesterol Myth: Why Lowering Your Cholesterol Won't Prevent Heart Disease-and the Statin-Free Plan That Will
by Jonny Bowden (Author), Stephen Sinatra (Author)

Heart disease is the #1 killer. However, traditional heart disease protocols--with their emphasis on lowering cholesterol--have it all wrong. Emerging science is showing that cholesterol levels are a poor predictor of heart disease and that standard prescriptions for lowering it, such as ineffective low-fat/high-carb diets and serious, side-effect-causing statin drugs, obscure the real causes of heart disease. Even doctors at leading institutions have been misled for years based on creative reporting of research results from pharmaceutical companies intent on supporting the... View Details


The Truth About Statins: Risks and Alternatives to Cholesterol-Lowering Drugs
by Barbara H. Roberts M.D. (Author)

From an award-winning cardiologist comes the most up-to-date, definitive reference book about statins—cholesterol-lowering drugs—providing a thorough examination of the uses and safety claims of this high-profile class of drugs.

COULD STATIN DRUGS ACTUALLY HARM YOU?

Despite the rosy picture painted in the ads of a miracle cure for high cholesterol and its attendant heart disease, the reality of taking statins may be far less pretty. Dr. Barbara H. Roberts, director of the Women’s Cardiac Center at the Miriam Hospital in Rhode Island, discusses both the... View Details

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

The Big Five
What are the five biggest global challenges we face right now — and what can we do about them? This hour, TED speakers explore some radical solutions to these enduring problems. Guests include geoengineer Tim Kruger, president of the International Rescue Committee David Miliband, political scientist Ian Bremmer, global data analyst Sarah Menker, and historian Rutger Bregman.
Now Playing: Science for the People

#457 Trowel Blazing
This week we look at some of the lesser known historical figures and current public perception of anthropology, archaeology, and other fields that end in "ology". Rebecca Wragg Sykes, an archaeologist, writer, and co-founder of the TrowelBlazers, tells us about the Raising Horizons project and how their team is trying to shine the spotlight on the forgotten historical women of archaeological, geological, and palaeontological science. And Kristina Killgrove, assistant professor of anthropology at the University of West Florida and science writer, talks about the public perception of the fields of anthropology and archeology, and how those science are represented -...