Abstract The mechanical properties of the extracellular matrix (ECM) determine cell differentiation, proliferation and migration through mechanoresponsive proteins including YAP. However, how different mechanical signals cooperate, synergize or compete to steer cell behavior remains poorly understood. Here, we have examined competition between the two major ECM mechanical cues, i.e. rigidity, which activates cell mechanosensing, and viscous energy dissipation, which reduces stiffness blunting cell mechanotransduction. To trigger competition, we have engineered protein hydrogels allowing concomitant modulation of stiffness and viscosity by mechanisms characteristic of native ECM. Culturing cells on these hydrogels, we have found that substrate energy dissipation attenuates YAP mechanosensing prevailing over stiffness cues. Hampered YAP activation on more dissipative substrates correlates with faster actin flow and smaller focal adhesions. Mechanistically, inhibition of actomyosin contractility reverses the outcome of the competition between rigidity and energy dissipation. Our results highlight the dominating contribution of substrate viscosity to the biology of the cell.

Cell response to extracellular matrix energy dissipation outweighs rigidity sensing