Abstract
SummaryDuchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention.
Highlights
Duchenne muscular dystrophy (DMD) is caused by >200 mutations in the gene encoding dystrophin, a protein that connects the cytoskeleton to the extracellular matrix, with a prevalence of 1:5,000 boys, DMD patients exhibit early and progressive skeletal muscle degeneration and weakness
Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure
Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels
Summary
Duchenne muscular dystrophy (DMD) is caused by >200 mutations in the gene encoding dystrophin, a protein that connects the cytoskeleton to the extracellular matrix, with a prevalence of 1:5,000 boys, DMD patients exhibit early and progressive skeletal muscle degeneration and weakness. We previously uncovered an unexpected association of dystrophin deficiency with short telomeres, the hexanucleotide TTAGGG repeats that cap and protect the ends of chromosomes. This stemmed from experiments directed at resolving the conundrum that the mdx4cv mouse model, which lacks dystrophin as in DMD patients but has a normal lifespan, does not manifest the cardiac disease from which patients succumb. Human telomeres (~10 kb) are significantly shorter than mouse telomeres (>40 kb) This led us to test our hypothesis that ‘‘humanizing’’ telomere lengths in the mdx4cv mouse might reveal a disease phenotype with greater fidelity to human DMD. Cardiomyocytes in murine mdx4cv/mTRG2 and in DMD patient cardiac tissues exhibited ~50% reduction in telomere
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