Duchenne muscular dystrophy is ultimately a stem cell disease

December 09, 2010

Researchers have long known that the devastating disease called Duchenne muscular dystrophy (DMD) is caused by a single mutation in a gene called dystrophin. The protein encoded by that gene is critical for the integrity of muscle; without it, they are easily damaged. But new findings in mice reported online in the journal Cell on December 9th by researchers at Stanford suggest that disease symptoms, including progressive muscle weakening leading to respiratory failure, only set in when skeletal muscle stem cells can no longer keep up with the needed repairs.

"This is not just a disease of dystrophin deficiency" said Helen Blau of Stanford University School of Medicine, who led the study. "It's also a disease of stem cells." That means that successful treatments would likely need to target muscle stem cells, not just muscle fibers, she says.

"These findings are critical for thinking about how to treat the disease and when," added Jason Pomerantz, the study's co-corresponding author who is now at the University of California, San Francisco. "It predicts any treatment designed solely to build muscle or enhance muscle function without replenishing the stem cell compartment is likely to fail and may even accelerate the decline. It's like pushing the gas pedal to the floor when there is no reserve."

The new study also answers a long-standing puzzle in the field that has stymied basic studies in search of potential treatments or treatment strategies: Mice carrying the same dystrophin mutation found in human patients show only mild symptoms of the disease.

"It has been a mystery for the past 25 years that mice with the genetic defect show minimal or no symptoms," Blau said, "and consequently there has been no mouse model in which to study the pathophysiology of the disease or potential treatments." People thought maybe it was because mice are smaller or don't live as long, but there was no real explanation. That is, until now.

The new findings attribute the discrepancy between the mouse and human symptoms to a characteristic of chromosomes. Regions of repetitive DNA found at the tips of chromosomes, known as telomeres, are longer in mice than they are in humans. Blau and her team have found that mice with the dystrophin mutation and another that leads them to have shortened telomeres have severe symptoms of the disease that worsen with age just as they do in human patients.

Telomeres protect chromosomes from deterioration and they tend to get shorter each time a cell divides. When telomeres become critically shortened, it triggers events that lead cells to die. The longer telomeres normally found in mice apparently give their muscle stem cells greater staying power and a greater capacity to repair the damage caused by the deficiency of dystrophin.

"Mice with shorter telomeres show all the parameters of the disease," Blau said. The animals won't run on a treadmill, their strength is really diminished, and their diaphragms (the muscle needed to breathe) are reduced to the point that they are "thin remnants, or strips of tissue." This muscle weakening paralleled a decline in the regenerative capacity of their muscle stem cells.

"There is continuous damage due to the loss of dystrophin," Pomerantz explained. "When the stem cell reserve is depleted, the symptoms emerge. The mice are spinning their wheels in a cycle of damage, repair, damage, repair, until the ability to repair gives out. In these mice [with shortened telomeres], it gives out earlier."

When the researchers isolated and transplanted healthy muscle stem cells into the sick mice, it alleviated symptoms of the disease.

The mice are now the first tractable model system for studying the disease, and that should come as good news to families affected by this form of muscular dystrophy, the researchers say.

"Our new mouse model changed the way we were thinking about the pathophysiology of the disease," said Foteini Mourkioti of Stanford who is the co-first author on the paper. "We now understand that muscle stem cells are an essential component of this dystrophin-deficient disease and we can now start thinking of more precise ways to treat Duchenne muscular dystrophy."

Treatments intended to restore muscle will likely work only temporarily or not at all. In fact, they are likely to exacerbate the problem by exhausting muscle stem cells more rapidly. Timing will also be key.

"Therapeutic strategies aimed at intervening early in DMD patients, in the first years of their life, are more likely to have a better outcome as they would act before this end-stage tissue failure is reached," said Alessandra Sacco, the study's first author who is now at the Sanford-Burnham Medical Research Institute.
For more news from Cell please go to http://www.eurekalert.org/jrnls/cell/pages/cell.php.

Cell Press

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.