Many patients with Duchenne muscular dystrophy, the most common of the heritable muscular dystrophies, die from heart failure. Stanford researchers are beginning to understand why their hearts become weakened and enlarged in the first place.
Telomeres, the protective caps on the ends of chromosomes, shorten with each cell division, measuring out a cell’s life span. But telomere length is usually stable in healthy tissues that don’t divide, like heart muscle cells.
Telomeres do shorten, however, in the heart muscle cells of lab mice bred to model Duchenne, which is caused by mutations in the gene that produces dystrophin, a protein that stabilizes muscle. The shortening triggers a DNA damage response that compromises the cells’ energy generators, or mitochondria, resulting in the inability of the heart muscle cells to efficiently pump blood throughout the body.
“This is the first time that telomere shortening has been directly linked to mitochondrial function via a DNA damage response in nondividing cells,” says Helen Blau, PhD, professor of microbiology and immunology and the senior author of the recent study. “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 study was published online Oct. 31, 2016, in Proceedings of the National Academies of Science.