Elucidating mechanisms leading to Duchenne Muscular Dystrophy and testing novel therapies


3. Telomeres and Duchenne Muscular Dystrophy:

  A conundrum in the muscle field has been that the mouse model (mdx) of Duchenne Muscular Dystrophy (DMD), which has the same genetic absence of the contractile protein, dystrophin, is only mildly affected, whereas in boys this defect is lethal.

This absence of a mouse model limits tests of potential therapies including cells, pharmacologic agents, or gene therapy. Early on, we noted that muscle cells from DMD patients had reduced proliferative capacity in culture, but the tools to pursue this finding did not exist at the time.

Recently, we reasoned that a major difference between humans and mice is telomere length and that humans have significantly shorter telomeres than mice. Stem cells constitute a reservoir of cells poised to repair muscle damage.

Our lab postulated that upon continuous demand for skeletal muscle repair in the absence of the structural protein, dystrophin, the muscle stem cell pool could be exhausted, leading to the dystrophic phenotype. To test this hypothesis, mice lacking dystrophin were mated with mice lacking a key component of telomerase, TERC – yielding mdx/TRKO mice.

The resulting mouse model has shortened telomeres in its stem cells that result in reduced regenerative capacity. This mouse model most closely approximates DMD, with essentially all of its features, shedding light on the etiology of the disease and suggesting new therapies and a means to test them.

The cardiac phenotype that leads to lethal dilated cardiomyopathy as seen in DMD patients is also manifested in our mouse model.

* Blau et al., PNAS, 1983 (PDF)

* Sacco et al., Cell, 2010 (PDF)