PONE-D-19-23641

In vivo elongation of thin filaments results in heart failure

PLOS ONE

Dear Dr. Gregorio,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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ACADEMIC EDITOR: The authors should better highlight limitations of the study. Moreover, it is important to measure capillary density, cardiomyocyte size and collagen content.

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PLOS ONE

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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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Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: The Authors have developed a novel transgenic mouse model stably overexpressing Lmod2 in cardiac tissues in a reversible manner, in order to study the consequences of longer thin filaments. This sudy confirms that the maintenance of thin filament lengths is critical for heart muscle function and shows that mammalian intact hearts with longer thin filaments in vivo result in a complex cardiomyopathy. The paper is well written, the methods appear appropriate and the results are clearly stated and quite interesting.

Reviewer #2: Review of PONE-D-19-23641 submitted by Mi-Mi et al.

Title of MS: In vivo elongation o thin filaments results in heart failure.

This is a beautifully written, well documented and carefully deduced conclusions on the effects of increasing the amount of a thin filament pointed end associated protein leiomodin-2 in mouse models. Increasing the level of this protein resulted in a 10 to sometimes 26% longer thin filaments. Examination of the effects of raising the intracellular levels of lmod2 also lead to effects on the Z-Bands and intercalated discs in the mouse hearts.. The sarcomeres from muscle expressing this higher level of Lmod2 resulted in a loss of upto 50% loss of contractile forces resulting in cardiac failure. It is very impressive that their experiments in which they lower the high levels on Lmod2 lead to a reversal of the effects of the high levels of Lmod2. The authors have previously demonstrated that lowering the amount of Lmod in the cardiomyocytes lead to shorter filaments, and also cardiac defects. The combination of these two reports demonstrates the importance of Lmod in the health of the heart. This manuscript is a first-rate contribution to our understanding of the role of Lmod2 in myofibril assembly, and how changing the normal levels of Lmod2 can lead to cardiac failure. This manuscript should be published without changes.

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Reviewer #1: No

Reviewer #2: No

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Attachments

Attachment

Submitted filename: PONE-D-19-23641 Mi-Mi et al.docx

In vivo elongation of thin filaments results in heart failure

PONE-D-19-23641R1

Dear Dr. Gregorio,

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

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With kind regards,

Vincenzo Lionetti, M.D., PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

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

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper is well written and the study has been properly conducted. The data as to the role of Lmod2 in cardiac failure are novel and of interest.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No