Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for the interesting review.

I suggest to: 

1. When talking about skeletal muscle, to highlight the importance, structure and function of both:

a. The "Myotendinous Junction" ;

b. The "Costamere".

Whereas most of the integrin molecules are subcellular localized.

2. To search and avoid for redondancy in all manuscript.

3. To add a paragraph in section 6. highlighting the importance of future personalized and adaptive mechanotherapy, with, if possible, some examples and mybe a "Graphical Abstract" especially for the readers who are not familiar with the particular topic.

 

Author Response

Thank you for your thorough review. I have addressed all comments and revised the manuscript accordingly. The revised version and related materials are attached for your consideration.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Exercise-Based Mechanotherapy: From Biomechanical Principles and Mechanotransduction to Precision Regenerative Rehabilitation.

This work proposes to study the biochemical mechanism of the mechanotransduction generated during exercise as a therapeutic and regenerative approach for skeletal muscle.

The manuscript is well organized, following a logical progression from historical context and macroscopic biomechanical principles of mechanotransduction to molecular pathways and clinical application. The scientific content reflects current paradigms in mechanobiology, identifying key biochemical pathways such as integrins, Piezo channels, and TRPV4, as well as nuclear effectors such as YAP/TAZ. The synthesis of literature is clearly presented through distinct sections: bone, cartilage, muscle, and tendon. The conclusions are well supported by the evidence provided.

The figures and tables are clear and well-presented, illustrating the complex concepts described.

Some concerns

If the journal's editorial board allows it, consider adding a figure for each subsection in Chapters 3 and 4, or an integrating figure for each chapter. The information is detailed but difficult for a non-specialist audience to understand.

Section 3.2. Mechanosensitive Calcium Channels.

It is mentioned that TRPV4 mediates slower, more stable calcium oscillations compared to the rapid spikes of Piezo1. I suggest explicitly mentioning how these different temporal signatures might lead to distinct downstream gene-expression patterns in chondrocytes versus osteoblasts to enhance the precision of your thesis.

Section 4: Recent Advances

Muscle: You correctly identify the role of Piezo1 in satellite cell proliferation and the suppression of p53-dependent senescence. This is a high-impact point; ensure this is highlighted as a potential anti-aging mechanism of exercise.

Cartilage: You note that a fully integrated mechanotransduction loop is still being established. To be more proactive, propose specific future research directions (e.g., using multi-omics or live-cell imaging) that could close this loop.

Section 5.1. Advances in Mechanosensitive Biomaterials.

Provide more detail on the clinical potential of piezoelectric polymers. Specifically, discuss how these materials might eliminate the need for external power sources for therapeutic electrical stimulation in deep tissues.

Section 6: Clinical Translation

You say patients need to be grouped by their mechanical phenotypes. This is a crucial concept. It would be helpful to provide a brief hypothetical case or a more detailed description of what a mechanical phenotype would include (e.g., baseline tissue stiffness, age-related nuclear lamin expression levels) to make this issue more concrete for clinicians.

Conclusion:

Ensure the conclusion reiterates the central role of standardized mechanical prescriptions. You might consider adding a concluding sentence about the necessity of cross-disciplinary training (biology and engineering) for the next generation of physical therapists.

Analogy for Understanding: Consider mechanotransduction to be a biological translation service: the “physical language” of movement (stretching, pressing, or sliding) is translated by cellular receptors into the “chemical language” of DNA instructions, which then directs the body to build or repair its own infrastructure.

Author Response

Thank you for your thorough review. I have addressed all comments and revised the manuscript accordingly. The revised version and related materials are attached for your consideration.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is clear, intriguing, and original. The authors did a good job. I have no further recommendations.