I don't know about you, but I think telomeres are one of the most interesting parts of our DNA. These stretches of repetitive sequence at the ends of our chromosomes protect our genomes like the plastic tips on the end of shoelaces. (They are called aglets, if you want to impress someone.) But every time our DNA is replicated, a tiny portion at the very end of the telomere is left off. It's just the mechanics of the thing. This means that telomeres shorten with each cell division, serving as a kind of molecular clock marking off the age of a cell.
Now Stanford microbiologist and immunologist Helen Blau, PhD, and postdoctoral scholar Alex Chang, PhD, have discovered that telomeres also shorten drastically in heart muscle cells from laboratory mice carrying the same genetic mutation that causes Duchenne muscular dystrophy in humans. This is interesting because these cells stop dividing shortly after birth, says Blau, who is also the Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Foundation Laboratory for Stem Cell Biology.
That shortening causes the cell to activate a DNA damage pathway that hurts the cell's mitochondria, or energy factories, and hampers the ability of the cells to efficiently pump blood throughout the body. This is important because most people with the muscle-wasting disease eventually die of respiratory or cardiac failure.
As Blau described in our release:
This is the first time that telomere shortening has been directly linked to mitochondrial function via a DNA damage response in non-dividing cells. We’ve outlined the molecular steps in this process that lead to death, giving novel insights into the condition and identifying alternative strategies for heading off heart failure in human patients with Duchenne.
The researchers used a mouse model of the disease they developed in 2013 that is the first to accurately recapitulate Duchenne muscular dystrophy in humans. These mice were bred to have human-length telomeres (normally mice have much longer telomeres than humans) and a mutation in the gene that makes the dystrophin protein. Blau and Chang anticipate that the new mouse model will led to a much greater understanding of the human disease.
More from our release:
Chang and Blau are interested in learning exactly how the absence of functional dystrophin contributes to telomere shortening in cardiomyocytes. They are also planning to investigate whether artificially lengthening the telomeres could head off heart damage in the mice.
'More research is clearly needed before we attempt to devise any new therapies for humans,' said Blau. 'But these findings highlight the important role telomeres play in this and possibly many other human diseases in nondividing tissues like neurons and heart muscle.'
The researchers published their results yesterday in the Proceedings of the National Academies of Science.
Previously: Mouse model of muscular dystrophy points finger at stem cells, Visible symptoms: Muscular-dystrophy mouse model's muscles glow like fireflies as they break down, and New mouse model of muscular dystrophy provides clues to cardiac failure
Photo of cardiomyocytes by arboreus
