Determinants of the maximal functional reserve during repeated supramaximal exercise by humans: The roles of Nrf2/Keap1... 2023 Galvan-Alvarez et al

[Andy]

Full title: Determinants of the maximal functional reserve during repeated supramaximal exercise by humans: The roles of Nrf2/Keap1, antioxidant proteins, muscle phenotype and oxygenation

Abstract

When high-intensity exercise is performed until exhaustion a “functional reserve” (FR) or capacity to produce power at the same level or higher than reached at exhaustion exists at task failure, which could be related to reactive oxygen and nitrogen species (RONS)-sensing and counteracting mechanisms. Nonetheless, the magnitude of this FR remains unknown. Repeated bouts of supramaximal exercise at 120% of VO2max interspaced with 20s recovery periods with full ischaemia were used to determine the maximal FR. Then, we determined which muscle phenotypic features could account for the variability in functional reserve in humans.

Exercise performance, cardiorespiratory variables, oxygen deficit, and brain and muscle oxygenation (near-infrared spectroscopy) were measured, and resting muscle biopsies were obtained from 43 young healthy adults (30 males). Males and females had similar aerobic (VO2max per kg of lower extremities lean mass (LLM): 166.7 ± 17.1 and 166.1 ± 15.6 ml kg LLM−1.min−1, P = 0.84) and anaerobic fitness (similar performance in the Wingate test and maximal accumulated oxygen deficit when normalized to LLM). The maximal FR was similar in males and females when normalized to LLM (1.84 ± 0.50 and 2.05 ± 0.59 kJ kg LLM−1, in males and females, respectively, P = 0.218).

This FR depends on an obligatory component relying on a reserve in glycolytic capacity and a putative component generated by oxidative phosphorylation. The aerobic component depends on brain oxygenation and phenotypic features of the skeletal muscles implicated in calcium handling (SERCA1 and 2 protein expression), oxygen transport and diffusion (myoglobin) and redox regulation (Keap1). The glycolytic component can be predicted by the protein expression levels of pSer40-Nrf2, the maximal accumulated oxygen deficit and the protein expression levels of SOD1. Thus, an increased capacity to modulate the expression of antioxidant proteins involved in RONS handling and calcium homeostasis may be critical for performance during high-intensity exercise in humans.

Open access, https://www.sciencedirect.com/science/article/pii/S2213231723002604

 

[Ash]

This looks interesting…

 

[SNT Gatchaman]

This is good to see specified in the methods —

Sex and gender of the participants were defined based on self-report during participant recruitment. All participants reported cis-gender, and thereafter the terms males and females were applied in the study analysis and reporting. All females were eumenorrheic, without taking oral contraceptives and were evaluated randomly in different phases of the menstrual cycle.

 

[SNT Gatchaman]

This looks like a really well done study and a great write up. From a subjective view it looks very relevant to my (our?) experience. The pathological fatigue feels like that experienced at "task failure" following maximal exertion prior to illness. In that state there does feel like a functional reserve - albeit very limited. This can presumably be (mis)interpreted as "no actual pathology" as you can push-through — which we learn not to do quite early on, despite no/contrary advice.

I'll be interested in expert comments on the muscle/vascular physiology, but I'd like to highlight this aspect, as it has never felt to me anything like a central/CNS block —

Insufficient muscle and brain oxygenation can contribute to fatigue, and particularly a lower brain oxygenation during exercise performed until exhaustion has been associated with fatigue in several studies

Since part of the functional reserve could be explained by mechanisms delaying central fatigue including the agonistic capacity to overcome fatigue, we also examined whether differences in brain oxygenation could explain our findings.

Thus, we also hypothesized that the “functional reserve” may be greater in the subjects experiencing a lesser reduction in brain oxygenation during high-intensity exercise.

No association was observed between brain oxygenation and perfusion, as indicated by the frontal lobe TOI [Tissue Oxygenation Index] and the MCAv [Middle Cerebral Artery velocity], and the MFR [Maximal Functional Reserve] in kJ⋅kg LLM−1. No significant differences were observed in frontal lobe oxygenation between the ISR [Ischaemic Recovery] and FCR [Free Circulation Recovery] sessions (64.2 ± 5.6 and 65.7 ± 4.8 a.u., n = 25, P = 0.21).

Multiple regression analysis indicated that the main variables predicting the MFR expressed as total work normalized to LLM [Lower extremities Lean Mass] were the accumulated O2 uptake per kg of LLM during the MFR test, which explained 94.1% of the variance; the O2 deficit per kg of LLM during the MFR test, which explained an additional 2.9% of the variance …

That is the total MFR - ie both the aerobic and anaerobic components. This would leave 3% over for other things, eg myosin heavy chain variance (0.3%)

frontal lobe oxygenation explained 6.1% of the variability in the aerobic component of MFR

We hypothesized that subjects with higher brain oxygenation levels would perform better during repeated supramaximal exercise to exhaustion.

Paradoxically, the results point in the opposite direction, as indicated by the negative coefficient [...] implies that subjects with a higher MFR achieve greater levels of brain deoxygenation during intense exercise. Thus, we believe that the lower frontal lobe oxygenation observed in the subjects with a greater aerobic component of the functional reserve is a consequence and not the cause since humans can tolerate much lower levels of brain oxygenation during sprint exercise in severe acute hypoxia when assessed using the same equipment and laboratory conditions than in the present experiments

 

[Andy]

The pathological fatigue feels like that experienced at "task failure" following maximal exertion prior to illness. In that state there does feel like a functional reserve - albeit very limited.

Funnily enough I was talking with my wife about how I feel, and I was describing that, even before I do anything else, I feel a lack of a large part of my energy, which in itself is a weird thing to me - 40 years ill and I still feel as if I am missing energy, I would have thought I would have got used to that feeling by now. So to me, continually feeling as if I have experienced "task failure" seems to come close to my experience.

 

[SNT Gatchaman]

We surmise that lower availability of Keap1 in the rested state may facilitate greater levels of pSer40-Nrf2 and antioxidant enzymes allowing a more efficient counteraction of RONS [Reactive Oxygen and Nitrogen Species] production during repeated cycles of ischaemia-reperfusion.

For a detailed review article of the Keap1-Nrf2 axis, with Nrf2 as a "master regulator of cellular defense mechanisms" see —

The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis (2018, Physiological Reviews)