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PREreview of "Tension-Induced Stiffening of Cytoskeletal Components Regulates Cardiomyocyte Contractility"

In the Paper Tension-Induced Stiffening of Cytoskeletal Components Regulates Cardiomyocyte Contractility, by Jafari et al., the authors investigate how mechanical tension and cytoskeletal mechanics influence the contractile behavior of cardiomyocytes, combining a theoretical model with experimental validation.

Cardiomyocytes possess cytoskeletal elements that experience either tension (actin, intermediate filaments) or compression (microtubules) during contraction. Using a spring model, the authors represent the cytoskeleton as springs arranged either in parallel or in series with an active myosin element. The entire system is anchored between elastic pillars to mimic the experimental conditions. They begin by considering the role of environmental stiffness and external stretch in modulating contractility. According to the simulation results, increased extracellular stiffness amplifies both baseline and peak contractility, consistent with prior work that intracellular tension is essential for proper force generation.

A key feature of the model is the incorporation of strain stiffening in cytoskeletal elements under tension, reflecting the nonlinear stiffening behavior of cardiomyocytes. Simulations show that this property enhances both the baseline and amplitude of contractile stress in response to external stretching, in agreement with engineered heart tissue (EHT) experiments. Without strain stiffening, stretch raises baseline stress but not its amplitude, indicating that strain induced stiffening is essential for length dependent activation.

The authors then extend their analysis to tissue-level tension modulated by fibroblast activity. Fibroblast activation via TGF-β increases tissue tension, which in turn elevates cardiomyocyte baseline and amplitude stresses, an effect dependent on strain stiffening. Conversely, after reducing fibroblast contractility with a therapeutic agent, myocyte contractility was also reduced. This demonstrates that fibroblast-generated tension can indirectly tune cardiomyocyte function.

The paper is generally well written and easy to follow. The abstract has a good balance between motivating the study, summarizing the methods and giving a clear statement of the broader relevance of the work, making it accessible to readers from different backgrounds. The figures are well integrated into the text and the logical flow from theoretical framework to experimental validation helps the reader keep track of the argument. The authors also make great use of both the main text and supplementary material to provide detailed model equations. One aspect of the modeling that stood out is that it focuses entirely on elastic responses, which keeps the framework straightforward but may leave out certain time-dependent behaviors observed in the experiments.

While the paper’s results are important for cardiac science, several shortcomings should be addressed before it can be considered for publication.

Major Issues

• The free energy formulation lacks a dissipative term. Cardiomyocytes naturally lose energy during contraction and their internal structures and active processes cause their force to slowly adjust when the external strain changes. This behavior is evident in Fig. 2E, where the experimental data shows relaxation in the mean contractile force in response to an increased external stretch. By modeling the system as purely elastic, the framework cannot capture these time-dependent responses, which may or may not be physiologically relevant for the experiments. The authors should at least provide a clear justification, or cite supporting evidence from other work, to explain why dissipation can be neglected in their model.

• The model used in the paper is one-dimensional, assuming that the cells are only stretched along their length. However, in the experiments, the tissue is stretched by pressing down at the center, which would naturally cause it to bend and curve. This could mean that some parts of the cells experience different strains than others, which a purely 1D model cannot capture. If the tissue span is much longer than a single cell, such bending could be negligible, but the authors do not provide key information such as tissue length or geometry to support this. Including these parameters would allow readers to judge whether bending effects are indeed insignificant and the 1D assumption is valid.

• The theoretical model includes many parameters whose values are not explained, making it unclear whether they were taken from literature, measured independently, or fitted to match the experimental data. If any were fitted, this would weaken the argument that the close agreement between model and experiment independently corroborates the importance of strain stiffening. To avoid such doubt, the authors should state the origin of each parameter and justify their choices.

Minor Issues

• In Fig. 2E, the authors plot the measured vertical force from the indentation experiment, whereas in all other figures they present stress σ. It is unclear what model quantity this force corresponds to, since σ in the model represents tensile stress and would require knowledge of tissue cross-sectional area to convert to a force.

• Key model details are presented only in the supplementary information without being explicitly referenced at the relevant points in the main text. For example, in the description of the indentation experiments (Fig. 2E), the authors could direct the reader to the supplementary section where the boundary condition modification for external strain is explained (Eq. S13). Adding such references would improve clarity.

• While the indentation experiments are linked to the model via modified boundary conditions described in the supplementary material, the paper does not explain how increased or decreased fibroblast activity (via TGF-β treatment or IVS201 inhibition) was implemented in the simulations. Without knowing which parameters or elements were adjusted, it is difficult to understand how these experimental conditions were represented in the model.

Competing interests

The authors declare that they have no competing interests.