Physical Activity and Redox Balance in the Elderly: Signal Transduction Mechanisms

Round 1

Reviewer 1 Report

Galli et al proposed an interesting review updating information on redox balance and related signal transduction modulation via physical activity in both young and elderly.

The review is well written and does not require substantial changes.

However, I do realize that the author did not take into consideration the well-known interplay between oxygen species and calcium signalling. Mitochondria Ca²⁺ uptake, Calcium channels, SERCA, Na/Ca exchanger, CaMK, RyR etc.,  bidirectionally interact with ROS in a myriad of signals (Gorlach et al Redox Biology, Volume 6, December 2015, Pages 260-271), Zima et al (Cardiovascular Research, Volume 71, Issue 2, July 2006, Pages 310–321).

In the skeletal muscle Szenesi et al considered Ca²⁺ transient, mitochondrial dysfunction and ROS crosstalk with Aging (Oxid Med Cell Longev 2019 Jan 17;2019:4617801doi: 10.1155/2019/4617801. eCollection 2019, while in the Cabassi et al the authors summarized the state of the art of mitochondrial metabolism and mechanosensation in the failing heart, focusing on ROS and RNS formation (Cabassi et al Int J Mol Sci. 2017 Jul 10;18(7):1487. doi: 10.3390/ijms18071487 )

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I would suggest adding a subparagraph into “Insight into signal transduction” for - Redox balance and Ca signalling –

Author Response

Galli et al proposed an interesting review updating information on redox balance and related signal transduction modulation via physical activity in both young and elderly.

The review is well written and does not require substantial changes.

However, I do realize that the author did not take into consideration the well-known interplay between oxygen species and calcium signalling. Mitochondria Ca²⁺ uptake, Calcium channels, SERCA, Na/Ca exchanger, CaMK, RyR etc.,  bidirectionally interact with ROS in a myriad of signals (Gorlach et al Redox Biology, Volume 6, December 2015, Pages 260-271), Zima et al (Cardiovascular Research, Volume 71, Issue 2, July 2006, Pages 310–321).

In the skeletal muscle Szenesi et al considered Ca²⁺ transient, mitochondrial dysfunction and ROS crosstalk with Aging (Oxid Med Cell Longev 2019 Jan 17;2019:4617801doi: 10.1155/2019/4617801. eCollection 2019, while in the Cabassi et al the authors summarized the state of the art of mitochondrial metabolism and mechanosensation in the failing heart, focusing on ROS and RNS formation (Cabassi et al Int J Mol Sci. 2017 Jul 10;18(7):1487. doi: 10.3390/ijms18071487 )

.

I would suggest adding a subparagraph into “Insight into signal transduction” for - Redox balance and Ca signalling –

R: We thank the reviewer. We introduced a subchapter “Redox balance and Ca signalling”  that is reported below:

“Also ROS can affect Ca²⁺signalling at the level of channels, pumps and exchangers [90]. Alterations in ROS signalling can modify Ca²⁺communication system likely contributing to disease onset. In the heart, for example, Zima and Blatter [91] showed that the ROS, produced during reperfusion of cardiac ischemic injury, can affect ischemia-related Ca(2+) overload. More recently, Cabassi and Miragoli [92] reviewed the important role of local environment (namely ROS and Ca²⁺) in mitochondrial re-organization and fusion in failing cardiomyocytes. In particular, a correct interplay between Ca²⁺and ROS is important to avoid intracellular Ca²⁺increase during diastole that leads to cardiac arrhythmia [92]. The relevance of interaction between Ca²⁺signalling and ROS has been described also in skeletal muscle aging [93]. In fact, the increase of ROS in skeletal muscle can alter the Ca²⁺signalling pathway that is necessary for the fibre contraction, leading to a decrease in muscle strength. Interestingly, physical activity can help to contrast strength loss by reducing ROS [93]”.

Reviewer 2 Report

The authors propose that western countries contain many elderly persons with well-studied pathologies associate with aging; however, reactive oxygen species (ROS) need to be brought into the conversation. While some metabolic processes synthesize ROS, there is an upper threshold as cellular damage can occur; this becomes ever more apparent during exercise as the balance of oxidant/antioxidants is crucial. Regardless, it seems that the body’s antioxidant responses are proportional to exercise to some extent. The purpose of the review is to assess relationships of aging, redox balance, and physical activity as these variables tend to influence oxidative stress and, furthermore, overall health. In general, regardless of age, antioxidant foods and physical activity are beneficial for maintaining oxidant/antioxidant balance while also maintaining and/or improving many physiological and mental cognition systems. While the article holds merit, there are several recommendations which would help clarify a few issues.

Comment 1: What purpose is served by the figure in the n=0 box?

Comment 2; Line 173: emphasis on cellular muscle injury or tissue injury would clarify the claim.

Comment 3; Lines 188-94: Clarification is needed as the qualifying statements do not match the number of claims being made.

Comment 4; Line 233: Include muscle specific- or whole body-aerobic training.

Author Response

The authors propose that western countries contain many elderly persons with well-studied pathologies associate with aging; however, reactive oxygen species (ROS) need to be brought into the conversation. While some metabolic processes synthesize ROS, there is an upper threshold as cellular damage can occur; this becomes ever more apparent during exercise as the balance of oxidant/antioxidants is crucial. Regardless, it seems that the body’s antioxidant responses are proportional to exercise to some extent. The purpose of the review is to assess relationships of aging, redox balance, and physical activity as these variables tend to influence oxidative stress and, furthermore, overall health. In general, regardless of age, antioxidant foods and physical activity are beneficial for maintaining oxidant/antioxidant balance while also maintaining and/or improving many physiological and mental cognition systems. While the article holds merit, there are several recommendations which would help clarify a few issues.

Comment 1: What purpose is served by the figure in the n=0 box?

R: We thank the reviewer and we apologize for the mistake. We now added a correct figure

Comment 2; Line 173: emphasis on cellular muscle injury or tissue injury would clarify the claim.

R: We thank the reviewer and modified the sentence as follows: “After 30 days of chocolate intake, the elite football players showed a significant decrease in their levels of muscle-damage markers such as Creatin Kinase (CK), Lactate dehydrogenase (LDH) and Myoglobin and an increased antioxidant power, suggesting that polyphenols positively modulated redox balance and reduced muscle tissue injury in elite football players”

Comment 3; Lines 188-94: Clarification is needed as the qualifying statements do not match the number of claims being made.

R: We thank the reviewer and we apologize for the mistake. We modified the paragraph as follows: “These results, however, apparently depend on sport intensity. In fact, in amateur women gymnasts, low-moderate-intensity training increases total antioxidant activity after 48 hours [24]. Instead, 48 hours’ recovery after high-intensity training is not enough to restore redox balance. A modest ROS increase is necessary for normal force generation, while higher ROS levels induce damage in a dose- and time-dependent manner [25]. Thus, a diet rich in antioxidants and sessions of low-moderate intensity training should be recommended to amateur gymnasts after high-intensity training [24]”.

Reviewer 3 Report

This review very nicely describes and summarizes the associations between age, physical activity, and oxidative stress.  The main purpose of this review is to clarify the alleviation possibility of the aging signs by modulations of oxidative stress markers.  

Even though this is article is well written, I have some comments for its improvement.

Some shortcuts in the text are explained but not used in the text.
The text is not very well organized. The chapter: Insights into signal transduction should be divided into several subchapters and maybe this chapter will better fit at the beginning of the text.

Author Response

This review very nicely describes and summarizes the associations between age, physical activity, and oxidative stress.  The main purpose of this review is to clarify the alleviation possibility of the aging signs by modulations of oxidative stress markers.  

Even though this is article is well written, I have some comments for its improvement.

Some shortcuts in the text are explained but not used in the text.
The text is not very well organized. The chapter: Insights into signal transduction should be divided into several subchapters and maybe this chapter will better fit at the beginning of the text.

R: We thank the reviewer. We divided the chapter “Insights into signal transduction” in 4 subchapters for the different tissues where the effects of ROS and physical activity have been correlated with age: 3.1 Plasma and Adipose tissue, 3.2 Nervous system, 3.3 Liver, 3.4 Skeletal and cardiac muscle. We did not move the chapter “Insights into signal transduction”at the beginning of the text because we wanted to focus on the relationship between redox balance and physical activity during aging. Thus, we think it is important to start with chapters on physical activity in the young, in the adults and in aged people.