PONE-D-23-33513Strain rate of stretch affects crossbridge detachment during relaxation of intact cardiac trabeculaePLOS ONE

Dear Dr. Chung,

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Additional Editor Comments:

Both reviewers and myself found this work to be an interesting follow up from previous work from the lab. However, there were a number of issues that need to be resolved, including some mention of the additional limitation brought up by Reviewer 1, and also a number of typographical and presentation errors.

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: The study aims to explore cross bridge mechanisms responsible for the lusitropic effect of small, fast, stretches in the twitching cardiac muscle. The subject may be of interest for both basic and translational research.

I had reviewed a previous version of this manuscript that had been rejected several months ago by a different journal. I must recognize that the changes the Authors have made to the present version of their work recognize most of the limits of the previous version. The changes are in line with the criticisms the Authors had received. The new version is improved even though the Authors should recognize, as a limitation of their work, that the stress vs time data calculated as the difference between the reference and ramp-stretch twitch traces (see Fig 1 central panel) are meaningful only if they assume that the Calcium transient and the myofilament activation level are unaffected by the applied stretches, i.e. the Authors are assuming that the activation and its decay are the same in the reference twitch and in the ramp-stretch twitch. The study provides some advancement in the description of the Mechanical Control of Relaxation reported in a previous paper.

Minor points:

- the Authors should carefully check the text for typos and mistakes (e.g. Fig1 panels: the Authors should pay attention, there is no A B C panels in the Figure as indicated in the legend).

- ‘trabeculae’ is plural in Latin and ‘trabecula’ should be used for the singular case.

Reviewer #2: This is a manuscript which presents an elegant series of measurements on the effect of strain and strain rate on the relaxation of rat cardiac muscle fibers. The work is novel, technically challenging and well presented. It is a follow up to work published by the corresponding author in the J Mol Cell Cardiol in 2017 which established relaxation is dependent upon the rate of stretch just before the start of relaxation. In this study a potential confounding variable was tested (time to stretch and speed of stretch). - The conclusion is that all effects on the time of stretch were compatible with the view that cross bridge detachment and relaxation rate are accelerated by strain rate.

The work is sound and will be of interest to a specialist group of experimentalists.

The conclusions ae sound but not very remarkable.

Minor issues

Introduction Line 13: “relaxaiton”

Methods: subscripts are missing for all chemical formulae e.g. KHCO3 - KHCO3.

Just before Fig 1 legend: “was acquired by repeating the load-clamp was repeated”

Fig 1 is missing A, B, C labels.

Fig 1C It is not clear what t12 refers to. It would be useful to include t0, t1 & t2

There are two Fig 6’s, one is Fig 5

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Reviewer #1: No

Reviewer #2: No

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Strain rate of stretch affects crossbridge detachment during relaxation of intact cardiac trabeculae

PONE-D-23-33513R1

Dear Dr. Chung,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Daniel M. Johnson, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Please check the proofs of the paper carefully, as there are still spelling errors which need to be eliminated. For example, ''Ryanode' should be 'Ryanodine' in the last part of the new section added.

Reviewers' comments: