August 3, 2011

Study Explains Why Muscles Weaken with Age and Points to Possible Therapy

 

EMBARGOED UNTIL: 12 NOON (ET), TUESDAY, AUGUST 2, 2011

Newswise — (NEW YORK, NY, (August 2, 2011) – Researchers at Columbia University Medical Center have discovered the biological mechanism behind age-related loss of muscle strength and identified a drug that may help reverse this process. Their findings were published in the August 2 online edition of Cell Metabolism.

As we grow older, our skeletal muscles tend to wither and weaken, a phenomenon known as sarcopenia. Sarcopenia, which begins to appear at around age 40 and accelerates after 75, is a major cause of disability in the elderly. Exercise can help counter the effects of age-related muscle loss. Otherwise, there are no established treatments.

According to the new study, conducted in mice, sarcopenia occurs when calcium leaks from a group of proteins in muscle cells called the ryanodine receptor channel complex. These leaks then trigger a chain of events that ultimately limits the ability of muscle fibers to contract, reports study leader Andrew R. Marks, M.D., chairman and professor of physiology and cellular biophysics, the Clyde and Helen Wu Professor of Medicine, and director of the Wu Center for Molecular Cardiology at Columbia University Medical Center (CUMC).

Ryanodine receptors, which are calcium channels found in most body tissues, have been the focus of Dr. Marks’ research since 1989. After cloning the ryanodine receptor gene, he later discovered, in studies of mice, that leaky ryanodine receptors are involved in the development of heart failure and arrhythmias. In 2009, he showed that leaks in these channels also contribute to Duchenne muscular dystrophy, a genetic disorder characterized by rapidly progressing muscle weakness and early death.

Since muscular dystrophy and sarcopenia have some commonalities, Dr. Marks suspected that ryanodine receptor leakage may also be involved in age-related muscle loss, which the present study shows is the case.

“This is a completely new concept — that the damage that occurs in aging is very similar to what happens in muscular dystrophy,” says Dr. Marks, “thus as we age we essentially develop an acquired form of muscular dystrophy.”

Both the aging process and the genetic defect responsible for muscular dystrophy cause an increase in the production of oxygen free radicals, highly reactive and harmful molecules. “Our data suggest that this sets up a vicious cycle, in which the free radicals cause ryanodine receptors to leak calcium into the cell. The calcium poisons mitochondria — organelles that power the cell — leading to the release of even more free radicals. This, in turn, causes more calcium leakage. With less calcium available for contraction, the muscles get weaker,” says first author Daniel C. Andersson, M.D., Ph.D., a postdoctoral fellow in physiology and cellular biophysics at CUMC.

The study also points to a possible therapy for sarcopenia: an experimental drug called S107, developed by Dr. Marks and his colleagues. The drug acts by stabilizing calstabin1, a protein that binds to ryanodine receptors and prevents calcium leakage.

In the study, 24-month-old mice (roughly the equivalent of 70-year-old humans) were given S107 for four weeks. The mice showed significant improvements in both muscle force and exercise capacity, compared with untreated controls. “The mice ran farther and faster during voluntary exercise,” says Dr. Andersson. “When we tested their muscles, they were about 50 percent stronger.” The drug had no effect on younger mice with normal ryanodine receptors.

A similar drug is now in phase II clinical trials for the treatment of heart failure.

“Most investigators in the field of aging have been saying that the way to improve muscle strength is to build muscle mass, using such therapies as testosterone, growth hormone, and insulin-like growth factor-1,” says Dr. Marks. “But an increase in muscle mass is not necessarily accompanied by an increase in muscle function. Our results suggest that you can improve muscle function by fixing leaky calcium channels. And in fact, treating aged mice with S107 enhanced muscle strength without increasing muscle size, at least during the four-week treatment period.”

Dr. Marks’ paper is titled, “Ryanodine Receptor Oxidation Causes Intracellular Calcium Leak and Muscle Weakness in Aging.” In addition to Dr. Andersson, his coauthors include Mathew J. Betzenhauser, Steven Reiken, Albano C. Meli, Alisa Umanskaya, Wenjun Xie, Takayuki Shiomi, and Ran Zalk at CUMC, and Alain Lacampagne at Universités Montpellier, Montpellier, France.

A.R. Marks is a consultant for a start-up company, ARMGO Pharma, Inc., which is targeting ryanodine receptors to improve exercise capacity in muscle diseases.

This research was supported by grants from the National Heart, Lung, and Blood Institute and the Swedish Research Council.
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Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest in the United States.

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April 21, 2011

GSK Receives FDA Approval to Move Forward with Exon Skipping Trial in the US

The US Food and Drug Administration has lifted the partial clinical hold on the Investigational New Drug Application for GSK2402968.  This means they can now proceed with longer term clinical studies of GSK2402968 in DMD patients in the US.  As a result, plans for a randomised placebo controlled study in the US are advancing.  Details regarding the study, including inclusion/exclusion criteria and investigator sites, will be posted to www.clinicaltrials.gov as soon as they are finalized. 

 

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 Apr 05, 2011 08:25 ET

SOURCE: Phrixus Pharmaceuticals, Inc.

Phrixus Pharmaceuticals, Inc. Announces $890,000 in NIH Funding for Its Programs in Duchenne Muscular Dystrophy and Heart Failure

Awards to Fund Respiratory Studies for Carmeseal^TM in Duchenne Muscular Dystrophy and Mechanism of Action Studies in Heart Failure

ANN ARBOR, MI--(Marketwire - April 5, 2011) - Phrixus Pharmaceuticals, Inc., a clinical-stage,specialty pharmaceutical company focused on innovative therapies for Duchenne muscular dystrophy (DMD) and heart failure, today announced that it has received a total of $890,000 in awards from the National Institutes of Health (NIH). Funding is in the form of one SBIR Phase 1 award titled "Effects of P-188 on Respiratory Function and Diaphragm Degeneration in the mdx Mouse" and one STTR Phase 1 award titled "Poloxamer 188 Mechanism of Action in Ischemic Heart Failure." The latter award is in collaboration with Dr. Joseph M. Metzger, Chair of Integrative Biology and Physiology at the University of Minnesota.

"This funding constitutes validation for the potential utility of Carmeseal not just in cardiomyopathy but also in respiratory disease in patients with DMD, for whom it is the leading killer," said Thomas A. Collet, president and CEO. "Completion of the work funded by these grants will significantly advance our knowledge of how Carmeseal achieves its dramatic effects," adds Dr. Bruce Markham, Vice President of Research and Chief Scientific Officer.

DMD is the most devastating of the muscular dystrophies. No drug is approved for its treatment. It is a genetic disease that affects about one out of every 3,500 boys. Approximately 20,000 boys and young men live with this disease in the United States. The hallmarks of DMD are skeletal muscle weakness, respiratory distress, and cardiomyopathy. It is a degenerative disease that leads to premature death.

Heart failure occurs when the heart is unable to pump enough blood around the body. It affects five million Americans and costs the health care system $37 billion annually according to the American Heart Association. Acute Decompensated Heart Failure (ADHF) is the most severe form of heart failure. It causes one million hospitalizations each year.

About Carmeseal™
Carmeseal, generically known as poloxamer 188 (P-188), has been shown to boost the blood pumping capacity of damaged hearts. When Carmeseal, which appears to act as a molecular bandaid, is infused into the bloodstream, it encounters and binds to microscopic tears in the heart muscle. This may prevent the pathological leak of calcium into the heart cells, which could cause calcium overload and keep the heart from delivering sufficient oxygenation to the vital organs. Carmeseal, which has been shown to be effective in four animal models of DMD and heart failure, is expected to have its effect in patients with DMD irrespective of the genetic defect that causes the disease.

About Phrixus Pharmaceuticals, Inc.
Phrixus Pharmaceuticals is developing Carmeseal for DMD and for acute decompensated heart failure. For more information about Phrixus Pharmaceuticals, please visitwww.phrixuspharmaceuticals.com.

Phrixus Pharmaceuticals, Inc. Forward-Looking Statement Disclaimer
This announcement may contain, in addition to historical information, certain forward-looking statements that involve risks and uncertainties. Such statements reflect management's current views and are based on certain assumptions. Actual results could differ materially from those currently anticipated as a result of a number of factors. The company is developing several products for potential future marketing. There can be no assurance that such development efforts will succeed, that such products will receive required regulatory clearance or that, even if such regulatory clearance were received, such products would ultimately achieve commercial success.

http://www.marketwire.com/press-release/Phrixus-Pharmaceuticals-Inc-Announces-890000-NIH-Funding-Its-Programs-Duchenne-Muscular-1422585.htm

Thomas A. Collet
President and CEO
Phrixus Pharmaceuticals, Inc.
+1 (734) 926-0966 ext. 12

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STUDY BLURB

March 22, 2011

The first few young men with DMD have enrolled in the clinical trial REVERSE-DMD at The Kennedy Krieger Institute and Johns Hopkins School of Medicine.  This trial, being conducted by neurologist Kathryn Wagner and cardiologist Daniel Judge  will examine whether Revatio (Sildenafil) improves cardiac function in DMD.  Sildenafil has been shown to improve cardiac function in multiple different animal models including the mouse model of DMD.   Thirty males, aged 15 and older who have been diagnosed with DMD and cardiac dysfunction are being recruited to participate in this randomized, double-blind, placebo-controlled study for six months.  An open-label period during which all participants will receive Revatio (Sildenafil) will follow for an additional six months.   For more information regarding the trial, visit: http://clinicaltrials.gov/ct2/show/NCT01168908?term=Duchenne.

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Phase III Study of Idebenone in Duchenne Muscular Dystrophy (DMD) (DELOS)

Duchenne Muscular Dystrophy Is Ultimately a Stem Cell Disease, Researchers Find

 

ScienceDaily (Dec. 10, 2010) — For years, scientists have tried to understand why children with Duchenne muscular dystrophy experience severe muscle wasting and eventual death. After all, laboratory mice with the same mutation that causes the disease in humans display only a slight weakness. Now research by scientists at the Stanford University School of Medicine, and a new animal model of the disease they developed, points a finger squarely at the inability of human muscle stem cells to keep up with the ongoing damage caused by the disorder.

"Patients with muscular dystrophy experience chronic muscle damage, which initiates a never-ending cycle of repair and wasting," said Helen Blau, PhD, the Donald E. and Delia B. Baxter Professor and a member of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "We found that in mice the muscle stem cells can keep up with the demands on them to cycle."

The difference is caused, the researchers found, by the fact that mice have significantly longer protective caps on the ends of their chromosomes. The caps, called telomeres, allow the cells to continue to divide and replenish the damaged muscle long after the human cells have reached their capacity for division.

The research marks the first time that muscular dystrophy has been shown definitively to be a stem-cell-based disorder, according to the scientists, who also generated the first-ever mouse model of Duchenne muscular dystrophy that closely mimics the human disease. Similar to human patients, the animals exhibit severe muscle weakness and shortened life span. The mouse model will allow clinicians and researchers to better study the disease and test new therapies.

"The results suggest that treatments directed solely at the muscle fiber will not suffice and could even exacerbate the disease. The muscle stem cells must be taken into consideration," said Blau. Former postdoctoral fellow Jason Pomerantz, MD, co-corresponding author and now an assistant professor at the University of California-San Francisco, said, "if a treatment does not replenish the stem cell compartment, it will likely fail; it would be like pushing the gas pedal to the floor when there is no reserve."

Blau is the senior author of the research, which will be published online Dec. 9 in Cell. Postdoctoral scholars Alessandra Sacco, PhD, and Foteini Mourkioti, PhD, are co-first authors of the work. Sacco is now an assistant professor at the Sanford-Burnham Medical Research Institute.

Duchenne muscular dystrophy is the most prevalent form of the muscular dystrophies. It is caused by a mutation in the dystrophin gene, which connects the interior cytoskeleton of the muscle fiber to the extracellular matrix. Its absence leads to death of the muscle tissue and progressive weakness, which eventually affects a patient's ability to breathe; 10-year-olds are often wheelchair-bound. Death usually occurs by the second or third decade as a result of respiratory and heart problems. The disorder affects about one of every 3,500 boys in the United States, whereas girls are generally spared because the gene lies on the X-chromosome.

Unfortunately, for decades the trusty laboratory mouse failed scientists trying to study the disease in animals. Mice with the same mutation showed only minimal muscle weakness. This left researchers without an easy way to test drugs and therapies. It also gave them a puzzle: Why were the mice so resistant to the muscle damaged caused by the dystrophin mutation?

Blau, Pomerantz, Sacco and Mourkioti, thought the answer might lie in the muscle stem cells. Like other types of stem cells, the muscle stem cells can divide to both replenish themselves and to make new muscle cell precursors. These precursor cells can replace damaged or dead muscle cells that make up the muscle fiber. But even muscle stem cells have their limits, and in this case, the mouse cells outperform their human counterparts.

The reason, the Stanford researchers found, is in the length of the telomeres on the DNA of the two species. The average length of telomeres in laboratory mice is greater than 40 kilobases; in humans it's about 5 to 15 kilobases. Telomeres serve as protective caps on the ends of chromosomes, buffering them from the gradual shortening that occurs during each round of replication. When the telomeres become too short, the cells are no longer able to divide.

To test their theory, the researchers blocked the expression of a component of the telomerase enzyme, which maintains telomeric DNA. Mice with both the dystrophin mutation and the faulty telomerase expression experienced progressive, debilitating muscle degeneration with age -- as exhibited by treadmill stamina tests and muscle damage assays -- and had shorter-than-normal life spans. Muscle stem cells from the mice also had a reduced ability to proliferate, both in the animals and in culture, and were less able to engraft and begin growing when transplanted into wild-type animals.

"What we're seeing is that muscular dystrophy is a multi-factorial disease," said Blau. "The lack of dystrophin causes muscle damage. These damaged muscles are replaced by dividing muscle stem cells, but the repeated rounds of division cause the telomeres to shorten until the stem cells can't fix the damage anymore. This is what happens in humans, and in our new mouse model."

The idea that the symptoms of muscular dystrophy reflect an inability of stem cells to repair ongoing damage has some interesting implications. It implies that any successful treatment should begin early, before the stem cell pool is depleted. It also indicates that researchers and clinicians should investigate stem-cell-based therapies as well as those aimed at protecting the muscle fibers themselves. Finally, it suggests that a highly targeted approach to increase telomerase activity in the muscle stem cells could be useful.

"Finding out that this is a stem cell defect is really exciting," said Blau. "In the early 1980s we reported that muscle cells from DMD patients had less capacity to divide but we did not have the tools to figure out why, since muscle stem cells, the dystrophin gene and telomere function had yet to be identified. Finally, now we can get a handle on what is going on, and learn how best to target future therapies. Having a mouse model that mimics the human disease will benefit all in the field and is very exciting for patients."

Other Stanford researchers involved in the work include Rose Tran, now a graduate student; Peggy Kraft, research assistant and Blau lab manager; postdoctoral scholars Jinkuk Choi, PhD, and Marina Shkreli, PhD; research fellow Michael Llewellyn, PhD; Steve Artandi, MD, PhD, associate professor of medicine; and Scott Delp PhD, the James H. Clark Professor of Bioengineering, Mechanical Engineering and Orthopaedic Surgery.

The research was funded by the American Heart Association, the National Institutes of Health, the Muscular Dystrophy Association and the Baxter Foundation.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

 

New compound brings hope of muscular dystrophy remedy