Adult human cardiomyocyte mechanics in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an extracellular matrix disorder characterized by defects in collagen-1 transport or synthesis, resulting in bone abnormalities. Although reduced collagen in OI hearts has been associated with reduced myocardial stiffness and left ventricular remodeling, its impact on cardiomyocyte (CM) function has not been studied. Here, we explore the tissue-level and CM-level properties of a heart from a deceased organ donor with OI type I. Proteomics and histology confirmed strikingly low expression of collagen 1. Trabecular stretch confirmed low stiffness on the tissue level. However, CMs retained normal viscoelastic properties as revealed by nanoindentation. Interestingly, OI CMs were hypercontractile relative to nonfailing controls after 24 h of culture. In response to 48 h of culture on surfaces with physiological (10 kPa) and pathological (50 kPa) stiffness, OI CMs demonstrated a greater reduction in contractility than nonfailing CMs, suggesting that OI CMs may have an impaired stress response. Levels of detyrosinated α-tubulin, known to be responsive to extracellular stiffness, were reduced in OI CMs. Together these data confirm multiple CM-level adaptations to low stiffness that extend our understanding of OI in the heart and how CMs respond to extracellular stiffness.