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Large and reversible myosin-dependent forces in rigidity sensing

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A new study by researchers from Columbia University, National University Singapore and Institut Curie suggests that cells are capable of generating unexpectedly large forces when sensing the mechanical properties of their environment.

In order to modulate processes such as growth, differentiation, and cell migration, cells constantly collect and transduce information about the molecular and mechanical properties of their environment. To probe the rigidity of their surroundings, for instance, myosin molecular motors temporarily generate small contractions within actin filaments anchoring the cell to neighboring tissues. Until now, it was largely unknown how much force single myosin molecules are able to generate during these contractions in living cells.

To measure those forces, the researchers study mouse embryonic fibroblasts on microfabricated dual-stiffness pillars. Using high-resolution microscopy to measure cell-induced pillar deflection, they show that during rigidity sensing, myosin motors generate forces that are about an order of magnitude larger than previously measured in single molecule in-vitro experiments. Furthermore, the authors observe that contractions and relaxations occur at the same rate, and in both cases, displacements occur in relatively slow discrete steps.

To better understand how large forces and slow stepwise displacements might be linked, Lohner et al. adapted a mathematical model of collective acto-myosin contractility developed at the Curie Institute in 1995. In the cell, acto-myosin contractions are powered by ATP hydrolysis. In order to explain the large force measurements in the model, the researchers had to assume that ATP hydrolysis rate greatly exceeds the step rate of myosin contractions and that the energy gained by a single ATP hydrolysis event is not sufficient for a single step. In this regime, what appears as a step is better described as an avalanche process, by which motors collectively move by half the periodicity of actin filaments. The large energy released during these events explains the resultant large forces found experimentally. The low probability of the events explains the relatively low frequency of discrete displacement steps.

These results provide new insights into the mechanisms of in-vivo cellular force generation and how cells achieve efficient and accurate mechano-sensitivity over a wide range of extracellular environments.

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