Clinical and Therapeutic Implications of BCAAs Metabolism during Chronic Liver Disease in Humans: Crosstalk between Skeletal Muscle and Liver

Round 1

Reviewer 1 Report

In this manuscript, Trillos-Almanza et al., reviewed the clinical and therapeutic implications of branched-chain amino acids (BCAAs) metabolism during chronic liver disease in humans. They focused their review on the crosstalk between skeletal muscle and liver. The objective of this review was to discuss the relationship between muscle and liver in BCAAs metabolism, with special emphasis on end-stage chronic liver (ESLD). This review is relevant to the field, is pretty pleasant and interesting to read. The authors reported that BCAAs might have beneficial effects on muscle mass improvement. This could be linked to their precursor role for protein synthesis and their preferential energy source in skeletal muscle. In context of ESLD, nutritional challenges appear resulting decreased BCAAs levels in patients. Supplementation in BCAAs could help the imbalance in protein synthesis to help maintain the muscle mass but also be beneficial for the liver.

This review is pretty well written and organized. However, there are some definitions missing and maybe too much descriptive results without enough discussion/conclusion in some parts. You need to be more consistent and more precise, especially when you describe results with numbers from other studies. Units are missing sometimes.

Some minor linguistic issues have been found in this manuscript. Indeed, you should not talk about gender-based but sex-based. Sex and gender do not have the same definition and from what it is written it is sex and not gender in this review. Moreover, you should talk always about male and female (table 1), that are sex and not men and women that are gender. Finally, today we have to say adults with cirrhosis and not cirrhotic patients (Line 236). Individuals should not be defined by their pathology.

Major comments :

-       Title: as it seems you focusing a lot on ESLD, could it be maybe better to write it in the title instead of “Chronic liver disease” ?

-          Introduction:

o   Line 65-67: This sentence may need to be re-written.

o   Line 68-69: This sentence may need to be linked with the next one or maybe a little bit more information (one sentence max) could be added.

o   In the introduction, a suggestion could be to talk about BCAAs, then liver metabolism linked with BCAAs, liver disease then finishing with the muscle part. It would make more sense for the reader.

-          In the part 2: Metabolism of BCAAs: interplay between muscle and liver. Maybe specified skeletal muscle in the title could be interesting. Moreover, in this part, you could add a summary figure with the BCAAs metabolism, that could be really relevant for your review.

-          Part 2.2: BCAA oxidation:

o   Line 142-143: It is written “BCAT activity is physiologically regulated by exercise and starvation. What about food intake ? Does BCAT regulated by BCAT ? Moreover, when regulated in written, we should be able to determine if it is up or down regulated.

o   You should write a conclusion for this part that could help the reader to summarize all the information.

-          Part 3.1: It seems that you only focussing on ESLD in this review. But what is ESLD ? There is no definition. Moreover, this is full of descriptive sentences with no discussion/conclusions coming from it. Adding more of discussion/conclusion could improve the meaning of this part that is a central point of your review.

-          Part 3.2: Correlation of muscle health and BCAAs in patients with ESDL

o   Line 102 : it is written “by a decline in muscle mass, strength and functional capacity”. What are the number, the units, … from this study ? Maybe you should replace “decline” by “decrease”.

o   Line 205 : Compared to other pathologies or aging, is the 45.4% prevalence of sarcopenia is really high ? What is the SARC-F questionnaire complete name ?

o   Line 207 : You talk about quantity and quality. What does it mean really ? You need to be more precise ?

o   Line 217-220 : You talk about the study conducted by Xiang Q et al. the decreased of performance of 25.47 ± 5.84 kg correspond to what exactly ? You need to be more precise in all the manuscript when describing results from other studies.

-          Part 3.3: Interplay of BCAAs, mTOR signaling, ammonia and mitochondrial dysfunction in cirrhotic muscle.

o   What is a cirrhotic muscle ? It is the only time you talk about it into the manuscript.

o   Line 232. This sentence is not needed.

o   How low levels of BCAAs are defined in the literature ?

-          Part 4: Intervention with BCAAs supplementation in patients with chronic liver diseases : implication for muscle. It is confusing because sometimes it focuses only on ESLD and sometimes it is chronic liver diseases. You need to clarify this in your review. What are the pathologies you are talking about ?

-          Part 4.1: Effect on BCAAs on skeletal muscle mass and muscle strength.

o   In the same title the description for muscle is not consistent because you have “skeletal muscle” and “muscle”. Being consistent enhances the scientific rigor that can be seen in this review by all the work done, but which is sometimes lacking in the writing.

o   What is the “fat fold triceps” ?

o   Line 311-312: Are the number describing pre/post intervention ? A range between ? and ?

o   What is the meaning to analyse serum albumin levels ?

o   How a muscle mass can be restored with a 12.4 ± 3.0 to 12.5 ± 3.2 327 cm2/m. Is restored the good word ? “Maintained” could be a better word to describe this result.

-          Part 4.3: The title is confusing and maybe not precise enough compared to the other title of subparts. “Role of BCAAs on skeletal muscle protein metabolism” could be a more relevant.

-          Part 4.4: Combining BCAAs and exercise.

o   Lines 372 -375 : Is it really BCAAs that increase the muscle mass and not exercise also ?

o   Line 391 : What is a “ceiling effect».

-          Adding a “Clinical Perspectives” part could be relevant for your review?

-          A lot of units are missing into all review and could help to understand what is measured in term of activity, mass, strength, …

Mino comments :

-          In the abbreviation, ESLD is missing.

-          Sometimes it’s written BCAA and sometimes BCAAs, try to be consistent.

-          Line 312, 327, 328, …: Upper score units “??^-?”

The quality of english is good and no major issues have been detected.

Author Response

Dear Reviewer,

Thank you for your thorough review of our manuscript, "Clinical and therapeutic implications of BCAAs metabolism during chronic liver disease in humans: crosstalk between skeletal muscle and liver". Enclosed are the revised version and responses to your comments. Your insights have greatly improved the quality of our work.

Best regards.

Author Response File: Author Response.pdf

Reviewer 2 Report

Dear Authors,

Thank you for providing your manuscript for review. I appreciate your effort in contributing to the field. To enhance the readability for readers, I suggest addressing the following question in your manuscript.

1)      How does this review explore the dynamics of branched-chain amino acids (BCAAs) metabolism in the context of chronic liver disease?

2)      What is the significance of the emerging concept of muscle-liver crosstalk in understanding the clinical implications of BCAAs metabolism?

3)      In what ways are BCAAs indispensable for protein synthesis and metabolic pathways, and how do they undergo unique tissue-specific processing in skeletal muscle and liver?

4)      What distinctive role does the liver play in sensing BCAAs catabolism, and how does it influence glucose regulation and contribute to the systemic metabolism of BCAAs?

5)      In the context of chronic liver disease, how is compromised liver metabolism manifested through amino acid abnormalities, particularly in the decrease of the Fischer ratio?

6)      How does the reduction in the Fischer ratio become important in assessing the severity of liver dysfunction, and what associations does it have with adverse outcomes, including increased mortality and complications related to liver disease?

7)      What positive effects on skeletal muscle mass, strength, and overall nutritional status are observed with BCAAs supplementation in cirrhosis management, as discussed in the review?

8)      What insights into therapeutic strategies for chronic liver diseases are gained by understanding the interplay between BCAAs metabolism and compromised liver function?

9)      How does the review suggest that BCAAs supplementation could pave the way for precision interventions in clinical practice for chronic liver diseases?

10)  What are the potential clinical implications of the information presented in the review for improving patient outcomes in the management of chronic liver diseases?

Thanks again.

Best Regards

Author Response

Dear Reviewer,

Thank you for your thorough review of our manuscript, "Clinical and therapeutic implications of BCAAs metabolism during chronic liver disease in humans: crosstalk between skeletal muscle and liver". Enclosed are the revised version and responses to your comments. Your insights have greatly improved the quality of our work.

Best regards.

Author Response File: Author Response.pdf

Reviewer 3 Report

1. Please add some figures or schematic overviews to demonstrate the metabolism of BCAAs, specifically focusing on the interplay between muscle and liver, both in BCAAs transamination and BCAA oxidation.

2. Double check the citation make sure fit the MDPI requirement.

Author Response

Dear Reviewer,

Thank you for your thorough review of our manuscript, "Clinical and therapeutic implications of BCAAs metabolism during chronic liver disease in humans: crosstalk between skeletal muscle and liver". Enclosed are the revised version and responses to your comments. Your insights have greatly improved the quality of our work.

Best regards.

Author Response File: Author Response.pdf

Reviewer 4 Report

This concise review is good overall. I would suggest to include more graphics/comparison which make readers to understand easily through the pictures

English seems to be okay

Author Response

Dear Reviewer,

Thank you for your thorough review of our manuscript, "Clinical and therapeutic implications of BCAAs metabolism during chronic liver disease in humans: crosstalk between skeletal muscle and liver". Enclosed are the revised version and responses to your comments. Your insights have greatly improved the quality of our work.

Best regards.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

In this second version of the manuscript, Trillos-Almanza et al, took reviewers’ comments into account, responded clearly to them and reviewed well their manuscript. The manuscript has been really improved. The figure 1 is really appreciated and help to the understanding of all the mechanism underlying BCAAs.

Author Response

Dear Reviewer,

Thank you for your thoughtful and constructive feedback on our manuscript. We greatly appreciate your acknowledgment of our efforts to incorporate your comments effectively into the revised version. We are pleased to hear that you found the improvements to be substantial.

Additionally, we are delighted that Figure 1 was instrumental in enhancing the clarity of the mechanisms underlying BCAAs, as we aimed for it to be an informative visual aid.

Once again, we express our gratitude for your input, which has undoubtedly contributed to the refinement of our work.

Reviewer 2 Report

Dear Authors,

Thank you for providing the original version of the manuscript submitted to Muscles titled "Clinical and therapeutic implications of BCAA Metabolism during chronic liver disease in humans: crosstalk between muscle and liver." I have reviewed the revised version of your manuscript along with the authors' responses, and I am pleased to support the recommendation for publication to the editor.

Best regards

Author Response

Dear Reviewer,

Thank you for your support in recommending our manuscript, "Clinical and therapeutic implications of BCAA Metabolism during chronic liver disease in humans: crosstalk between skeletal muscle and liver," for publication in Muscles. We greatly appreciate your time and feedback during the review process.

Best regards.

Reviewer 3 Report

 Accept in present form

Author Response

Dear Reviewer,

Thank you for recommending our manuscript for publication in Muscles. We value your time and feedback during the review process.

Best regards.

Reviewer 4 Report

The manuscript has been improved significantly.

Author Response

Dear Reviewer,

Thank you for recommending our manuscript for publication in Muscles. We value your time and feedback during the review process.

Best regards.