Structured PREreview of Cardiomyocyte prohibitin ablation reprograms cardiac metabolism revealing a pathogenic role for mTORC1 in dilated cardiomyopathy

Does the introduction explain the objective of the research presented in the preprint?

Yes

The authors explain the research gap they intend to address by mentioning the unknown mechanisms that underlie mTOR signaling and its maladaptive effects, specifically in the heart. The authors use a cardiomyocyte-specific model to study metabolic mechanisms linked to cardiomyopathy since this has only been studied in cancer cell models that are intrinsically metabolically distinct to cardiomyocytes.

Are the methods well-suited for this research?

Highly appropriate

The authors report their methods in appropriate detail and account for possible confounding factors, clearly stating their choices. The use of PHB and MCM mice as controls, intended to account for possible cardiotoxic effects of tamoxifen, is an example of the robustness of this study design.

Are the conclusions supported by the data?

Highly supported

In general throughout the results sections, the authors performed several assays that support their conclusions independently. For example, the effect of PHB ablation on the myocardium structure and function is assessed via histology, echocardiography and TEM. The same can be said about the evaluation of mitochondrial respiration and structure through the measurement of mitochondrial respiratory flux, immunoblot of OXPHOS complexes, mitochondrial membrane fluidity measurements and TEM.

Are the data presentations, including visualizations, well-suited to represent the data?

Highly appropriate and clear

For each section, the authors provide a schematic of the experimental design which helps the reader follow the experimental flow and data present in each figure. Besides, the colors and patterns are consistent throughout and clearly labelled in all panels.

How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research?

Very clearly

The authors summarize their findings and place them in context with current and relevant literature. However, they also clearly outline the areas that require future work and why their study did not fully answer these specific questions.

Is the preprint likely to advance academic knowledge?

Highly likely

This manuscript studied the effect of PHB and mTOR signalling in the heart in different time points and female and male mice. The conclusions presented in this study offer relevant knowledge into the metabolic mechanisms underlying cardiomyopathy progression, leading to heart failure, and, more importantly, reporting which mechanisms occur earlier and which are clearly different between female and male mice. Together, these findings can help future studies focused on PHB and mTOR as drug targets providing more clarity into the proper treatment timepoints and female vs. male responses.

Would it benefit from language editing?

No

There were some minor typos in this manuscript but nothing that limited the understanding of the main text.

Would you recommend this preprint to others?

Yes, it’s of high quality

Is it ready for attention from an editor, publisher or broader audience?

Yes, as it is

This study is comprehensive, clear, and valuable from a translational viewpoint. The conclusions are fully supported by the data and the limitations and future work needed are clearly stated.

Competing interests

The author declares that they have no competing interests.

Use of Artificial Intelligence (AI)

The author declares that they did not use generative AI to come up with new ideas for their review.