Abstract 337: Cell-Substrate Adhesion Regulates Early Steps of Myofibrillogenesis in Human Cardiomyocytes

Abstract

Forces generated by myofibrils within cardiomyocytes must be balanced by adhesion to the extracellular matrix proteins and to other cardiomyocytes for proper heart function. Loss of this force balance results in cardiomyopathies and heart failure. Using a sarcomere assembly assay we previously developed utilizing human induced pluripotent stem cell-derived cardiomyocytes, we show coupling of focal adhesions to myofibrils during early steps of de novo myofibrillogenesis is essential for myofibril maturation. Increasing the extent of adhesion by inhibition of Focal adhesion kinase (FAK), a known regulator of adhesion dynamics, or by increasing the concentration of fibronectin on which the cardiomyocytes are cultured, led to precocious myofibril formation. Decreasing the extent of adhesion by siRNA-mediated FAK knockdown or by decreasing the concentration of fibronectin attenuated myofibrillogenesis. In each case, increased or decreased adhesion extent inversely correlated with rate of retrograde flow of myofibril precursors known as muscle stress fibers (AKA, non-muscle stress fiber-like structures or pre-myofibrils). This suggests a relationship between cell-substrate adhesion and substrate coupling to muscle stress fibers, facilitating their maturation into myofibrils. Taken together, our findings implicate a role for classical mechano-transduction in the assembly of sarcomere containing myofibrils.