Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes

Summary 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. 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 • DMD hiPSC-CMs exhibit aberrant calcium handling and defective force generation • DMD hiPSC-CMs undergo proliferation-independent telomere shortening • Telomere shortening activates the p53 DNA damage pathway • Telomere shortening in DMD hiPSC-CMs is contraction dependent
In this article, Chang, Blau, and colleagues show that Duchenne muscular dystrophy (DMD) iPSC-derived cardiomyocytes exhibit proliferation-independent telomere shortening, p53 activation and mitochondrial dysfunction.