The Muscle Function Deficit Concept and Inflammaging

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript is interesting, but there are several concerns that should be addressed in the manuscript.

1. IL-6 is a cytokine that is classified as a myokine, meaning it is produced and released by muscle cells. It is secreted in response to muscle contraction during physical activity. IL-6 is also associated with muscle hypertrophy and repair. It helps regulate muscle growth and can counteract muscle wasting conditions, such as sarcopenia, by promoting muscle regeneration on adaptation to exercise, whereas a pro-inflammatory cytokines IL-6 is involved in the body’s immune response. The authors should discuss about IL-6 in more details.
2.  In page 3, line 143, which source of IL-10 is the author referring to?
3. Are the authors trying to say that the spread of inflammatory changes from the peripheral level to the central nervous system is involved in the onset of sarcopenia?

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This study provides interest information. However, the following points should be checked before publication.

(1)    According to this paper, the viewpoint of skeletal Muscle Function Deficit (SMFD) appears to be similar to that of frailty. What is better about SMFD, compared to the Fried’s frailty score or frailty index score. 
(2)    This paper is very similar to their recent paper (Ref. number 16; MedRxiv 2025:2025.10.06.25337404. 241 https://doi.org/10.1101/2025.10.06.25337404.) The originality and novelty of this article should be more clearly indicated in comparison with their recent paper (Ref. 16). 
(3)    What is the most important impact of this study?
(4)    Comments regarding “limitations of this study” and/or “new directions” are necessary in the discussion.
(5)    In Line 76, “(Figure 1)” is indicated. However, I cannot find this figure.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Comments

Manuscript's title: The Muscle Function Deficit Concept and Inflammaging

 

Decision: accept with minor revision.

A brief summary 

This Viewpoint article aims to examine age-related muscle deterioration through an integrated neuromuscular and immune approach—Skeletal Muscle Function Deficit (SMFD)— that unifies the quantity and quality of skeletal muscle into a single, function-based definition. These findings support a shared neuro-muscular–inflammatory pathway in which inflammatory processes simultaneously target cortical circuits, motor neurons, peripheral nerves, and muscle fibers. It moved beyond the traditional, mass-centered definition of sarcopenia.

Its main contributions: SMFD provides a unifying and function-oriented model of muscle aging that transcends fragmented phenotypic definitions. Its implementation could facilitate earlier detection, more precise risk stratification, and mechanism-based interventions to preserve muscle function and independence in older adults.

Comments on general concepts:

1. This article is opinion type which the author highlighted the strengths and weaknesses of the topic presented which is “The Muscle Function Deficit Concept and Inflammaging”. The theoretical model of the SMFD, as operationalized in the InCHIANTI-study, redefines the muscle age-related process of decline under a wider umbrella. The InCHIANTI study is the first and only analysis to validate an operational SMFD score against major geriatric outcomes was performed. 

Abstract:          Appropriate

Introduction:

1. Line 39: In “The aging process induces a progressive muscle decline, traditionally defined as sarcopenia [1]”, please clarify more on muscle. What aspect of muscle is declined?
2. Line 41-42: In “Muscle mass loss leads to a decrease in quality of life, affecting overall well-being and self-sufficiency [2].”, not only “Muscle mass loss” that decreases quality of life. Muscle function also decreases quality of life, affecting overall well-being and self-sufficiency. Please complete this sentence.
3. Line 65-67: In “The delay in sarcopenia identification may also explain the proliferation of definitions such as sarcopenic obesity [11], dynapenia [12], powerpenia [7], and myosteatosis [13]”, please explain more on four of these terms.
4. Please add more information which are city and country of Chianti area.
5. Line 76: Figure 1 is absent.
6. This article may provide more helpful information by adding more detail of the InCHIANTI-study including number and characteristics of participants, methods, and weak point (if available). 

Conclusion: Appropriare

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

General Comments
This Viewpoint proposes Skeletal Muscle Function Deficit (SMFD) as an integrative framework to unify fragmented concepts of age-related muscle dysfunction and highlights inflammaging as a common biological link across neuromuscular decline. The perspective is timely and conceptually coherent, and it draws on high-quality longitudinal data from the InCHIANTI study. However, the manuscript relies heavily on a single cohort and largely on author-led evidence, limiting generalizability. The conceptual novelty of SMFD relative to existing multidimensional definitions remains insufficiently delineated, and causal claims regarding inflammaging and neuro-muscular pathways are overstated given the predominantly associative evidence. Clarification of clinical feasibility and broader engagement with independent literature would substantially strengthen the manuscript.

Major Comments
1.While the manuscript proposes Skeletal Muscle Function Deficit (SMFD) as an integrative umbrella concept encompassing sarcopenia, dynapenia, powerpenia, and myosteatosis, it does not sufficiently clarify the substantive conceptual or mechanistic advances beyond existing multidimensional definitions. At present, SMFD appears largely as a re-labelling or consolidation of existing constructs rather than a clearly novel paradigm.
2.The manuscript repeatedly characterizes inflammaging as the “main driver” or “orchestrating factor” of SMFD. However, the majority of cited evidence is observational and associative in nature. Strong causal language is therefore not fully supported by the available data, and the distinction between correlation and causation should be made more explicit.
3.The proposed neuro-muscular inflammaging axis is conceptually appealing, yet the mechanistic links between central nervous system changes, peripheral nerve dysfunction, and muscle impairment remain largely inferential. 

Minor Comments
1.Terms such as “function-centered,” “integrative framework,” and “umbrella concept” are used repeatedly throughout the manuscript and could be streamlined to improve readability.
2.Expressions such as “immunological symphony to cacophony,” while illustrative, may be overly figurative for mechanistic discussions and could be replaced with more precise scientific language.
3.Several sections（eg. Page 4, Lines ~144–147）shift from “associated with” to “drives” or “orchestrates” without clear justification. Greater consistency and precision in causal terminology are recommended.
4. Some paragraphs contain long, information-dense sentences that could be simplified or divided to enhance clarity and reader comprehension.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have no further comments.

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Reviewer 4 Report

Comments and Suggestions for Authors

Accept in present form