A mechanical-biochemical feedback loop regulates remodeling in the actin cytoskeleton.

Cytoskeletal actin assemblies transmit mechanical stresses that molecular sensors transduce into biochemical signals to trigger cytoskeletal remodeling and other downstream events. How mechanical and biochemical signaling cooperate to orchestrate complex remodeling tasks has not been elucidated. Here, we studied remodeling of contractile actomyosin stress fibers. When fibers spontaneously fractured, they recoiled and disassembled actin synchronously. The disassembly rate was accelerated more than twofold above the resting value, but only when contraction increased the actin density to a threshold value following a time delay. A mathematical model explained this as originating in the increased overlap of actin filaments produced by myosin II-driven contraction. Above a threshold overlap, this mechanical signal is transduced into accelerated disassembly by a mechanism that may sense overlap directly or through associated elastic stresses. This biochemical response lowers the actin density, overlap, and stresses. The model showed that this feedback mechanism, together with rapid stress transmission along the actin bundle, spatiotemporally synchronizes actin disassembly and fiber contraction. Similar actin remodeling kinetics occurred in expanding or contracting intact stress fibers but over much longer timescales. The model accurately described these kinetics, with an almost identical value of the threshold overlap that accelerates disassembly. Finally, we measured resting stress fibers, for which the model predicts constant actin overlap that balances disassembly and assembly. The overlap was indeed regulated, with a value close to that predicted. Our results suggest that coordinated mechanical and biochemical signaling enables extended actomyosin assemblies to adapt dynamically to the mechanical stresses they convey and direct their own remodeling.

Lateral communication between stress fiber sarcomeres facilitates a local remodeling response.

Actin stress fibers (SFs) are load-bearing and mechanosensitive structures. To our knowledge, the mechanisms that enable SFs to sense and respond to strain have not been fully defined. Acute local strain events can involve a twofold extension of a single SF sarcomere, but how these dramatic local events affect the overall SF architecture is not believed to be understood. Here we have investigated how SF architecture adjusts to episodes of local strain that occur in the cell center. Using fluorescently tagged zyxin to track the borders of sarcomeres, we characterize the dynamics of resting sarcomeres and strain-site sarcomeres. We find that sarcomeres flanking a strain site undergo rapid shortening that directly compensates for the strain-site extension, illustrating lateral communication of mechanical information along the length of a stress fiber. When a strain-site sarcomere extends asymmetrically, its adjacent sarcomeres exhibit a parallel asymmetric shortening response, illustrating that flanking sarcomeres respond to strain magnitude. After extension, strain-site sarcomeres become locations of new sarcomere addition, highlighting mechanical strain as a trigger of sarcomere addition and revealing a, to our knowledge, novel type of SF remodeling. Our findings provide evidence to suggest SF sarcomeres act as strain sensors and are interconnected to support communication of mechanical information.