Dystrophin-deficient mice (known as mdx mice) have been used in experiments as a model of human Duchenne muscular dystrophy (DMD) for decades. However, scientists have long noted that mdx mice, even though they develop a disease that mimics some aspects of human DMD, fare much better than human DMD patients. Mdx mouse muscles don't deteriorate as severely, and their ability to move and maintain heart function is far better than that of humans with the disease.
DMD experts have long suspected that figuring out why mdx mice respond differently than humans do to the loss of dystrophin from their muscles could provide valuable clues to understanding and ultimately treating human DMD.
Now, researchers in California, funded in part by MDA, have found that a key mechanism of muscle regeneration and repair is far more effective in mice than it is in humans. The finding has allowed scientists to develop a new research mouse that may be a better model for studying the human form of the disease and its treatment, and may provide new ideas for repair-based therapies.
About the new findings
Long-time MDA grantee Helen Blau, and her colleagues, corresponding author Jason Pomerantz and co-lead authors Alessandra Sacco and Foteini Mourkioti, led the Stanford University School of Medicine research team, which published its findings online Dec. 9, 2010, in the journal Cell.
The findings confirm the investigators' hypothesis that mice lacking dystrophin are better able to repair damaged muscle fibers than are humans with the same problem and that this difference is related to the longer chromosome tips, known as telomeres, present in the stem cells of the mice, as compared to humans.
As cells divide and replicate, telomeres normally shorten and have to be restored to a functional length by an enzyme called telomerase. With aging, at least in tissues in which a lot of cell turnover occurs, telomeres continue to shorten despite the actions of telomerase, and ultimately repair of damage becomes impossible. Normally, muscle tissue doesn't turn over very much, because it doesn't sustain much damage, but when dystrophin is missing, the need for repair and replacement of muscle is markedly increased.
Since mice start out with longer telomeres, the researchers speculated that muscle stem cells called satellite cells might enable muscle-fiber repair longer in dystrophin-lacking mice than they can in dystrophin-lacking people.
To test their hypothesis, Blau’s team bred mice that lacked dystrophin and also lacked telomerase, the enzyme that maintains telomere length. These mice mimicked human DMD to a much greater degree than the usual mdx mice, which have telomerase.
As in the human form of DMD, the telomerase-deficient, dystrophin-deficient mice exhibited profound loss of muscle force, poor exercise performance, increased leakage of the creatine kinase enzyme from their muscle fibers (indicating damage to the fibers), scarring in their muscles, curved spines and a shortened life span. And, as in human DMD, their condition worsened with age.
The researchers noted that the satellite repair cells in the telomerase-deficient mdx mice showed a severe "proliferation deficit" and an inability to respond adequately to muscle fiber damage.
|Chromosomes (blue) have tips called telomeres (red), which need constant repair.|
"Our results indicate that DMD, a muscle degenerative disease, is due to a multifactorial process," the investigators note, "due to both a structural defect of the tissue and progressive exhaustion of its regenerative potential."
Meaning for people with DMD
The researchers say their findings have implications for understanding human DMD and for therapeutic development in this disease.
First, the new dystrophin-deficient, telomerase-deficient mouse appears to provide a better model in which to study the human disease. This mouse not only has the clinical signs of human DMD but has telomeres that more closely approximate those found in humans and therefore has reduced regenerative potential in its muscles.
Second, they note, researchers developing cell-based therapies for DMD, such as stem cell transplantation, need to consider not only the potential for the cells to become muscle tissue but also their telomere length, which appears to sustain their capacity to proliferate. Both aspects of the behavior of stem cells — maturation into muscle and the ability to replicate themselves — are necessary for adequate muscle-fiber repair when dystrophin is missing, they say.
The new findings also imply that strategies to increase the proliferative capacity of satellite cells and perhaps other types of muscle progenitor cells could benefit those with DMD, even in the face of dystrophin deficiency.
"DMD patients would be predicted to fare better if stem cells as well as muscle fibers are targeted and if treatment is initiated earlier in life, when telomere reserve in the muscle stem cells is still adequate," Blau said.
Editor's note: This article was modified Dec. 16, 2010, to correct inaccuracies in the listing of researchers who worked on the project. It was modified Dec. 23, 2010, to include a photo of chromosomes showing their tips.