Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice « too New to yoU

by Symptom Advice on December 27, 2010

Scientists have long recognized Duchenne muscular dystrophy (DMD) is due to dystrophin gene mutations caused by a single a devastating disease. Dystrophin protein in the maintenance of muscle integrity play a crucial role; when the body’s lack of Dystrophin, the muscles are extremely vulnerable. recently, however, researchers from Stanford University published in the journal Cell, said no longer play when the skeletal muscle stem cells repair function, disease symptoms will appear. So that in essence Duchenne muscular dystrophy may be a stem cell disease.

"This shows that the Duchenne muscular dystrophy and dystrophin deficiency is not just a single-gene genetic diseases, it is a stem cell disease," study leader, Helen Blau of Stanford University School of Medicine, said: "This means that to be successful treatment of the disease can not just target muscle fiber, may also need to target muscle stem cells. "

"The new discovery researchers find treatment for the disease and the most appropriate treatment time is of great significance," the paper’s corresponding author, University of California at San Francisco’s Jason Pomerantz, said: "it indicates that only the use of muscles or enhance muscle function treatment, while ignoring the role of stem cells will likely lead to failure, and may even accelerate the disease progression. This is like gasoline in the tank is no longer the case, no matter how hard to step on the gas pedal is useless. "

"in addition to this discovery has opened a mystery over the past 25 years, the genetic defect in mice show only mild or asymptomatic performance reasons. The existence of the phenomenon has never been the researchers used a mouse modelDuchenne muscular dystrophy to carry out the pathophysiology of or related therapy. "Blau said:" in addition it may also be that the mice are smaller and life expectancy is not long enough, therefore not suitable for resolution of the disease. This concept has been continued to the present. "

In the new study, researchers showed that mice and humans because the chromosomes characteristic of the two species led to the differences between the symptoms of the disease. The top of mouse chromosome telomere repeat DNA region is also known as longer relative to humans. Blau and her team found that mutation of dystrophin gene with shortened telomeres in mice, and often show a more severe disease symptoms and with age deteriorating condition, just as the performance of human patients.

Telomeres in the cell is mainly to protect the role of chromosomes, telomere length gradually shortened with cell division. When it reduced to a certain length, you can start the intracellular events leading to cell death. Study found that longer telomeres in mice muscle stem cells have a more lasting effect and greater ability to repair defects caused by the dystrophin muscle damage.

"Mice with short telomeres were shown all the features of this disease," Blau said: "these animals can not treadmill running, their power was weakened, and their thin diaphragm. And in the muscle weakness also accompanied by a decline in muscle stem cell regeneration. "

"Dystrophin leads to muscle loss sustained damage. And when stem cell depletion, the symptoms will appear. these mice caught in a vicious cycle that damage, repair, and then damage, then repair until the repair capacity is exhausted. And those who side short grain sooner run out of mice’s ability to repair them, "Pomerantz said.

When the researchers isolated muscle stem cells transplanted into healthy mice sick, the disease symptoms appeared to reduce the signs.

"This is the first time in mice as a model system to study the disease. a new type of mouse model of physiological changes in the study of disease pathology in our way," the first authors Foteini Mourkioti said: "Now we know that muscle stem cells are the Duchenne muscular dystrophy important factor. and we have begun to consider using some of the more accurate method to treat this disease. just treatment of muscle repair may only play a role in the short term, do not even play a role. in fact , it will quickly run out of muscle stem cells to cause disease worse. Timing is a critical factor. " "The strategy for treatment of DMD patients should be in the first years of life on them for early intervention treatment, and this organization has emerged compared to late treatment failure, no doubt there will come a better therapeutic effect," first author of the article, Sanford-Burnham Medical Research Institute of Alessandra Sacco said.


Cell  DOI: 10.1016/j.cell.2010.11.039

Short Telomeres and Stem Cell Exhaustion Model Duchenne Muscular Dystrophy in mdx/mTR Mice

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Alessandra Sacco1, 4, 5, Foteini Mourkioti1, 4, Rose Tran1, Jinkuk Choi2, Michael Llewellyn3, Peggy Kraft1, Marina Shkreli2, Scott Delp3, Jason H. Pomerantz1, 6, , , Steven E. Artandi2 and Helen M. Blau1, ,

1 Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA

2 Department of Medicine, Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA

3 BioX Program, James H. Clark Center for Biomedical Engineering and Science, Stanford University, CA 94305, USA

Received 18 may 2010;  revised 18 September 2010;  accepted 2 November 2010.  Published online: December 9, 2010.  available online 9 December 2010.

In Duchenne muscular dystrophy (DMD), dystrophin mutation leads to progressive lethal skeletal muscle degeneration. For unknown reasons, dystrophin deficiency does not recapitulate DMD in mice (mdx), which have mild skeletal muscle defects and potent regenerative capacity. we postulated that human DMD progression is a consequence of loss of functional muscle stem cells (MuSC), and the mild mouse mdxphenotype results from greater MuSC reserve fueled by longer telomeres. we report that mdx mice lacking the RNA component of telomerase (mdx/mTR) have shortened telomeres in muscle cells and severe muscular dystrophy that progressively worsens with age. Muscle wasting severity parallels a decline in MuSC regenerative capacity and is ameliorated histologically by transplantation of wild-type MuSC. these data show that DMD progression results, in part, from a cell-autonomous failure of MuSC to maintain the damage-repair cycle initiated by dystrophin deficiency. The essential role of MuSC function has therapeutic implications for DMD.

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Tags: DMD, dystrophin, mTR, Stem Cells

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