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

摘要: Summary Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening cardiomyocytes of DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived (hiPSC-CMs). Using traction force microscopy, show hiPSC-CMs exhibit deficits generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, post-mitotic coincident downregulation shelterin complex, capping proteins, activation the p53 DNA damage response. This blocked by blebbistatin, which inhibits contraction cardiomyocytes. Our studies underscore role fibrotic stiffening etiology cardiomyopathy. In addition, our data indicate progressive, dependent, mechanosensitive, suggest points therapeutic intervention.