A Reassessment of Sarcopenia from a Redox Perspective as a Basis for Preventive and Therapeutic Interventions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,
This review is well-written, with a wealth of information and a clear structure that aligns with the summary presented in the Abstract.
 
I have just a few minor comments.
 
Table 1 Legend (line 93)
- The abbreviations should be corrected: AMS should be changed to ASM, and SBBP to SPPB.
- I recommend adding the full name for the abbreviation EWGSOP2 in the Table 1 legend.
I also suggest consistently using the abbreviation EWGSOP2 (from 2018) in the Introduction (section 1.1, lines 66, 72, and 77).
 
Lines 132-134
“These include the monitoring of oxygen partial pressure in blood for the control of breathing, erythropoietin synthesis, and the regulation of vascular tone. (xi).
The sentence appears disconnected from the preceding text. Please consider clarifying its relevance or removing it. Specifically, how is monitoring partial pressure of oxygen or EPO synthesis related to the harmful or beneficial effects of ROS/RNS, i.e. their high or moderate concentration?

Line 637
The full name of the abbreviation RCS was already provided earlier (line 542), so it may not be necessary to repeat it.
 
The reference list is not fully in line with the journal’s formatting guidelines. Please revise all references carefully to ensure consistency with the required style.

Author Response

Dear Reviewer,

We gratefully acknowledge your review of our manuscript and useful suggestions to improve it. We have responded to your comments as detailed below:

 

Table 1 Legend (line 93):

- The abbreviations should be corrected: AMS should be changed to ASM, and SBBP to SPPB.
- I recommend adding the full name for the abbreviation EWGSOP2 in the Table 1 legend.
I also suggest consistently using the abbreviation EWGSOP2 (from 2018) in the Introduction (section 1.1, lines 66, 72, and 77).

The requested changes have been made (lines 97-98 in Table 1 legend, and lines 71 and 81 in the Introduction).

 
Lines 132-134:

“These include the monitoring of oxygen partial pressure in blood for the control of breathing, erythropoietin synthesis, and the regulation of vascular tone. (xi)”:

The sentence appears disconnected from the preceding text. Please consider clarifying its relevance or removing it. Specifically, how is monitoring partial pressure of oxygen or EPO synthesis related to the harmful or beneficial effects of ROS/RNS, i.e. their high or moderate concentration?

This sentence has been removed. EPO synthesis and the regulation of vascular tone were examples of regulatory actions unrelated to muscle cells enabled in living organisms by oxidative modifications of proteins. In rewriting section 2.2 (formerly section 2.1), to address comments from other reviewers, we have introduced a detailed discussion of specific examples of biological responses of muscle cells to increased ROS/RNS levels associated with muscle contraction, which reflect oxidative modifications of muscle proteins. These include the opening of the Ca²⁺ release channel in the sarcoplasmic reticulum (lines 492-514) and the enhancement of the interaction between the fast isoform of troponin I (TnIf) and troponin C, both mediated by S-glutathionylation (lines 515-522).

 

Line 637:

The full name of the abbreviation RCS was already provided earlier (line 542), so it may not be necessary to repeat it.

The requested change has been made.

 
The reference list is not fully in line with the journal’s formatting guidelines. Please revise all references carefully to ensure consistency with the required style.

Consistency in reference formatting has been ensured, in accordance with the Journal’s formatting criteria.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The research paper titled " A reassessment of sarcopenia from a redox perspective as a basis for preventive and therapeutic interventions" discusses the perturbations of redox balance as a contributing factor to the pathogenesis of sarcopenia. The review distinguishes between oxidative eustress as a physiological response of muscle cells to mild stimulation. The role of oxidative damage to biological macromolecules, both direct and mediated by advanced lipid peroxidation endproducts and advanced glycation/glycoxidation endproducts, is examined in detail. Next, the review discusses antioxidant defense mechanisms. The review then discusses criteria for a rational classification of non-enzymatic antioxidants, according to their biochemical properties and mechanisms of action, considering also their pharmacokinetics and pharmacodynamics. This is followed by a review of some of the main radical-trapping antioxidants, both phenolic and non-phenolic, whose characteristics are compared. This study provides a basis for the selection of appropriate and rational use of antioxidants to prevent, delay and counteract the adverse consequences of sarcopenia.

 

However, I therefore have to point out some comments:

Abstract: It is recommended to articulate the study's significance, necessity, and innovative aspects at the outset of the abstract.

Line 98-100: Explan “the clinical and the pathogenetic standpoint” by providing information.

Line106: The term " frailty spectrum" should be defined for clarity.

Line 111-112: Please support the statement that 'PF has been shown to be predictive of adverse outcomes' with specific evidence or references to relevant studies

Line 125-130: This section makes several claims regarding ROS/RNS without citing appropriate references. Please include supporting literature.

Line 130: Please provide specific examples of the types of cellular or tissue toxicity caused by ROS/RNS at high concentrations.

Line 151–154: "In sarcopenia, the decrease in lean muscle mass is a reflection of the decreased number of total muscle fibers, particularly of type II..." This important point about fiber-type switching deserves a citation to recent literature and would benefit from further elaboration on the metabolic implications of type I fiber predominance.

Line 196–197: "Increased ROS/RNS production is necessary for the adaptation of skeletal muscle to physical exercise of sufficient intensity..." This is a central idea (oxidative eustress), but the statement remains too general. Please specify what level/intensity or duration of exercise is associated with this beneficial response.

Line 237–239: "Furthermore, as ageing progresses, the ability of cells to resist stress may be progressively compromised..." Consider linking this concept with immunosenescence or inflammaging, both of which are redox-relevant and commonly discussed in aging muscle physiology.

Line 267–271: "Sarcopenia in Sod1-/- mice may result from a two-hit mechanism..." This mechanism is compelling. Please consider adding a simple schematic figure to illustrate this two-hit pathway involving motor neurons and NMJ feedback.

Line 284-293: Clarify the term " nor any significant increase" and “significantly reduced” by providing specific data.

Line 330: Clarify the term “the state of energy resources”.

Line 384–387: "It appears that redox imbalance is a main cause of multiple tissue, cell and molecular disorders..." This sentence is too broad and should be supported by specific references to major findings from Sections 2 and 3. Otherwise, it reads like an unsupported claim.

Line414: "The effects of ROS/RNS, ALEs, and AGEs on scavenger receptor pathways should be elaborated upon. Consider discussing specific receptor types (e.g., RAGE, CD36) and downstream consequences."

Line 578–580: "These data show that not all ROS/RNS are harmful for muscle..." Important conceptual statement, but it would benefit from inclusion of a specific example of protective ROS (e.g., H₂O₂-induced PGC-1α signaling) to reinforce the redox balance concept.

Line 608-610, 647-652, 653-658, 695-696, 775-778, 1029-1033, 1033-1037,1564-1567, 1319-1320: add reference.

Line 696–697: "The age-associated decline in antioxidant responses was due in part to dysfunctions in redox signaling mediated by NRF2..." NRF2 is mentioned throughout the paper but inconsistently contextualized. Consider adding a dedicated paragraph summarizing its central role in redox adaptation and therapeutic targeting.

Line 713–716 (start of Section 3.5): "Glycation endproducts may be formed by the non-enzymatic, non-oxidative addition of glucose..." Please clarify the link between AGEs and redox status, as glycation is typically considered a parallel but not directly ROS-mediated process. How does glycoxidation differ in aging muscle?

Line 763, 945, 968, 1300: The font should be consistent

References

Line1651-1654: Several references cited are over 10 years old. Please update key citations with more recent literature (within the last 5 years) to reflect the current state of knowledge.

The DOI is correctly formatted but check if all digital object identifiers (DOIs) are included for other references where available.

The order of references should follow “1,2,3…..”

Authors should be separated by “;” and font size should be standardized.

The use of journal name abbreviations should be consistent. If " J Gerontol A Biol Sci Med Sci" is abbreviated here, ensure all other journal names are treated similarly.

Author Response

Reply to Reviewer no. 2

Dear Reviewer,

We gratefully acknowledge your careful and detailed review of our manuscript. Your expert suggestions prompted us to subject it to a very thorough and comprehensive revision, which included numerous additions and the rewriting of large portions of the body of the text. We believe that this effort, while demanding, has led to a significant improvement in our manuscript, and we express our appreciation for your thoughtful review.

We have responded to all of your comments as detailed below:

 

Abstract: It is recommended to articulate the study's significance, necessity, and innovative aspects at the outset of the abstract.

The initial part of the abstract has been reworded (please see lines 43-49)

 

Line 98-100: Explain “the clinical and the pathogenetic standpoint” by providing information.

We have better elaborated and reworded this paragraph (please see lines 103-115):

 

Line106: The term " frailty spectrum" should be defined for clarity.

A paragraph concerning the spectrum of functional impairments and vulnerabilities included in the definition of frailty, their contributing and risk factors has been added (please see lines 121-130).

 

Line 111-112: Please support the statement that 'PF has been shown to be predictive of adverse outcomes' with specific evidence or references to relevant studies

A paragraph in regard has been added (please see lines 137-148)

 

Line 125-130: This section makes several claims regarding ROS/RNS without citing appropriate references. Please include supporting literature.

We have moved this paragraph to the beginning of renumbered section 2.3 (lines 524-529) and we have added at this point a novel reference to an authoritative review article (Moldogazieva et al., 2020) that covers extensively the topic. We have also added a reference to section 3.2, titled ”ROS/RNS and their sources”, where the topic is discussed in more detail, with supporting bibliographical citations: “as discussed in further detail in Section 3.2 below”.

 

Line 130: Please provide specific examples of the types of cellular or tissue toxicity caused by ROS/RNS at high concentrations.

Line 196–197: "Increased ROS/RNS production is necessary for the adaptation of skeletal muscle to physical exercise of sufficient intensity..." This is a central idea (oxidative eustress), but the statement remains too general. Please specify what level/intensity or duration of exercise is associated with this beneficial response.

These two points are tightly linked and therefore have been addressed jointly.

We have addressed these points robustly by introducing a new section 2.1, titled “The continuum of reactive oxygen/nitrogen species (ROS/RNS)-incited responses in skeletal muscle” (lines 160-307). We describe therein: 1) the sources of ROS/RNS production in muscle cells during muscular contraction; 2) the concept of mitohormesis and the distinctive criteria between oxidative eustress and oxidative distress, with special regard to: a) the H₂O₂ concentrations that were shown to be necessary for physiological quiescent metabolism; b) those that can sustain muscle cell adaptation to exercise; and c) those that can lead to muscle and neuronal cell damage, muscle injury, and inflammation; 3) the limitations of such estimates, the technical difficulties of real-time assays of intracellular H₂O₂ levels in contracting muscles, and an analytical methodology for the H₂O₂ measurement in muscle fibers; 4) the different regimens of physical exercise, and those among them that have been reported to be associated with beneficial effects in sarcopenic older adults. These points are discussed extensively with many updated bibliographic references.

In view of the addition of this new section 2.1, we have been prompted to rewrite and rename large parts of section 2.2 (formerly 2.1), which is now titled “ROS/RNS-mediated adaptation of skeletal muscle to exercise” (lines 309-319, 377-409, 415-440, 456-522). The improved section 2.2 now contains a more comprehensive and detailed description of the redox-regulated responses that mediate muscle cells adaptation to exercise. A new Figure #1 has been added to accompany the new version of this section.

Furthermore, following the changes made to sections 2.1 and 2.2, we have also rewritten parts of section 2.3 (formerly 2.2), titled “Oxidative stress as a pathophysiological response of muscle cells in ageing and disease” (lines 524-529, 605-630, 639-645, 653-663, 667-668, 684-701, 705-709). Major changes and additions to this section pertain to oxidative mtDNA damage, the effects of S-glutathionylation and S-nitrosylation on ATP synthase, and a final paragraph that summarizes the entire section 2 (lines 742-752).

 

Line 151–154: "In sarcopenia, the decrease in lean muscle mass is a reflection of the decreased number of total muscle fibers, particularly of type II..." This important point about fiber-type switching deserves a citation to recent literature and would benefit from further elaboration on the metabolic implications of type I fiber predominance.

We have moved this point from section 2.2 (formerly 2.1) to section 2.3 (formerly 2.2) and further elaborated it, adding an additional reference (please see lines 553-563):

 

Line 237–239: "Furthermore, as ageing progresses, the ability of cells to resist stress may be progressively compromised..." Consider linking this concept with immunosenescence or inflammaging, both of which are redox-relevant and commonly discussed in aging muscle physiology.

We have added a new paragraph at this point (please see lines 532-546)

 

 

Line 267–271: "Sarcopenia in Sod1-/- mice may result from a two-hit mechanism..." This mechanism is compelling. Please consider adding a simple schematic figure to illustrate this two-hit pathway involving motor neurons and NMJ feedback.

A new schematic figure (Fig. 2) has been added, as requested.

 

Line 284-293: Clarify the term " nor any significant increase" and “significantly reduced” by providing specific data.

These terms refer to comparative measurements performed and reported in the article cited, whose significance resides not in their absolute values, but in the absence/presence of significant variation between test and control conditions.

 

Line 330: Clarify the term .“the state of energy resources”.

The sentence has been integrated as follows: “… the state of energy, resources, namely the intracellular AMP/ATP ratio“ (line 677)

 

Line 384–387: "It appears that redox imbalance is a main cause of multiple tissue, cell and molecular disorders..." This sentence is too broad and should be supported by specific references to major findings from Sections 2 and 3. Otherwise, it reads like an unsupported claim.

This statement has been deleted from revised section 2.2 (formerly 2.1).

 

Line 414: "The effects of ROS/RNS, ALEs, and AGEs on scavenger receptor pathways should be elaborated upon. Consider discussing specific receptor types (e.g., RAGE, CD36) and downstream consequences."

We have added at this point a reference to section 3.6 “Interactions of oxidized macromolecules with scavenger receptors” lines 770-771). Section 3.6 has been largely rewritten and expanded with new data and several novel references (please see main text, lines 1268-1345).

 

Line 578–580: "These data show that not all ROS/RNS are harmful for muscle..." Important conceptual statement, but it would benefit from inclusion of a specific example of protective ROS (e.g., H₂O₂-induced PGC-1α signaling) to reinforce the redox balance concept.

The dual nature of ROS/RNS-mediated effects in muscle across a spectrum of concentrations is now discussed in the dedicated section 2.1. Oxidation-induced PGC-1α signaling is also discussed extensively in the revised section 2.2 (formerly 2.1), along with other examples of protective actions of ROS. The sentence in line 578 has been reworded as follows:

“Thus, ROS/RNS may be beneficial or detrimental to muscle, as it has been discussed in section 2.1 above. Distinguishing between oxidative eustress and distress may provide opportunities to counteract sarcopenia.” (lines 938-940).

 

Line 608-610, 647-652, 653-658, 695-696, 775-778, 1029-1033, 1033-1037,1564-1567, 1319-1320: add reference.

 

Lines 608-610 (now lines 965-969):

The following references have been added:

Jaganjac, M.; Tirosh, O.; Cohen, G.; Sasson, S.; Zarkovic, N. Reactive aldehydes – second messengers of free radicals in diabetes mellitus. Free Radic. Res. 2013, 47(suppl 1), 39-48. doi: 10.3109/10715762.2013.789136. PMID: 23521622.

Schaur, R.J.; Siems, W.; Bresgen, N.; Eckl, P.M. 4-Hydroxy-nonenal - A bioactive lipid peroxidation product. Biomolecules 2015, 5, 2247-337. doi: 10.3390/biom5042247. PMID: 26437435; PMCID: PMC4693237.

 

Lines 647-652:

This paragraph has been rewritten and enlarged with new bibliographic references (please see main text, lines 1036-1085):

 

Lines 653-658:

This paragraph has been rewritten, with four novel references added (please see main text, lines 1086-1100):

 

Lines 695-696 (now lines 1127-1130):

This sentence is one with the following sentence, with which it shares the reference. The two propositions have been brought together in the same period, to make this more explicit.

 

Lines 775-778 (now lines 1227-1231):

The same consideration made in the previous point also applies to this sentence and the following one, which have been joined too.

 

Lines1029-1033 and 1033-1037 (now lines 1528-1536):

There were already relevant references in this section, but they needed to be better positioned, which we have done.

 

Lines 1319-1320 (now line 1811):

The following reference has been added:

Meng, X.; Zhou, J.; Zhao, C.N.; Gan, R.Y.; Li, H.B. Health benefits and molecular mechanisms of resveratrol: A narrative review. Foods 2020, 9, 340. doi: 10.3390/foods9030340. PMID: 32183376; PMCID: PMC7143620.

 

Lines 1564-1567:

This sentence has been reworded, with two novel references added (please see lines 2013-2017):

 

Lines 696–697: "The age-associated decline in antioxidant responses was due in part to dysfunctions in redox signaling mediated by NRF2..." NRF2 is mentioned throughout the paper but inconsistently contextualized. Consider adding a dedicated paragraph summarizing its central role in redox adaptation and therapeutic targeting.

The role of NRF-2 in muscle adaptation to oxidative stress is discussed in the revised section 2.2 (formerly 2.1), consistent with the purpose of that section. A dedicated section on NRF2 follows (section 4.3 “NRF2, the master regulator of antioxidant responses”), which was already present in the first version of the manuscript.

 

Lines 713–716 (start of Section 3.5): "Glycation endproducts may be formed by the non-enzymatic, non-oxidative addition of glucose..." Please clarify the link between AGEs and redox status, as glycation is typically considered a parallel but not directly ROS-mediated process. How does glycoxidation differ in aging muscle?

We have integrated and rewritten a large part of section 3.5 to address this point (please see the revised maintext, lines 1146-1171, 1181-1182), highlighting the close interplay between the formation of AGEs and oxidative stress. We have also further elaborated on the effects of AGEs on ageing muscle and the peculiarities of glycoxidation in sarcopenia (lines 1222-1266). Figure 4 (formerly Fig. 3) has been redrawn and seven updated references have been added to reflect these improvements.

 

Lines 763, 945, 968, 1300: The font should be consistent

Font consistency has been ensured.

 

Line 1651-1654: Several references cited are over 10 years old. Please update key citations with more recent literature (within the last 5 years) to reflect the current state of knowledge.

Sixty-four (64) obsolete references have been replaced with more recent ones, to take into account developments in the field. In several cases, this has necessitated rewording the text containing the citation. Additionally, due to the reorganization of large parts of the body of the text, some references introduced to replace old ones may have been relocated. Numerous additional updated references have also been added, reflecting the additions made to the text in response to other comments.

Obsolete references eliminated (64):

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Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

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